JP2019523660A - Frontal head cooling method and apparatus for stimulating parasympathetic nervous system for treatment of insomnia - Google Patents

Abstract

In preclinical and clinical studies, the autonomic nervous system (parasympathetic and sympathetic nervous system) has been shown to show positive changes over the sleep-wake cycle. Most importantly, during sleep, the parasympathetic nervous system shows increased activity consistent with its role in resting regulation. In addition, patients with insomnia exhibit reduced parasympathetic activity and / or increased sympathetic activity during sleep, consistent with a neurobiological “hyperwakefulness” model. The present description describes a method and apparatus for activating the parasympathetic nervous system in response to a diving reflex, and surprisingly the persistence of the diving reflex results in improved sleep. The devices and methods described herein can activate this reflex specifically and / or selectively and can play a therapeutic role in sleep regulation of insomnia patients. [Selection] Figure 1A

Description

[Cross-reference with related applications]
This patent application claims priority to US Provisional Patent Application No. 62 / 337,279, filed May 16, 2016, which is incorporated herein by reference in its entirety. .

  This patent application is related to US patent application Ser. No. 14 / 749,590, filed Jun. 24, 2015, entitled “Apparatus and Methods for Modulation SLEEP”. Can do. This patent application can also be related to US patent application Ser. No. 14 / 938,705 (US-2016-0128864) filed Nov. 11, 2015. Each of these patent applications and patents is incorporated herein by reference in its entirety.

[Incorporation by quotation]
All publications and patent applications cited herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was clearly and individually indicated to be incorporated by reference. Is incorporated into.

  The devices and methods described herein reduce sleep onset in subjects, including subjects suffering from sleep-affected illnesses such as insomnia, improve sleep maintenance, extend sleep time, and for shallow sleep It can be used to improve sleep, including increasing deep sleep. Thus, the devices and methods described herein can be used to treat sleep disorders such as insomnia.

  Insomnia is most often described as an individual who has sufficient sleep opportunities cannot easily fall asleep, cannot stay asleep, or cannot obtain good quality sleep. In the United States, population-based estimates of chronic or transient insomnia range from 10 to 40% of the population in the United States, that is, 30 million to 120 million adults. Similar morbidity estimates have been reported in Europe and Asia. There are two age peaks throughout the study: 45-64 years old and over 85 years old. Women who are divorced or widowed from their husbands and whose education level is low are 1.3 to 2 times more likely to complain of sleep disorders than men. In the United States, direct medical costs due to insomnia, dysfunction, increased risk of mental health problems, loss of productivity, long absence of workers and the economic burden of excessive medical use are approaching $ 1000 billion . Insomnia is recognized as a national health problem that causes more than twice the number of medical errors caused by health care workers who do not develop the symptoms. However, currently available insomnia treatments are not completely satisfactory for various reasons. Hypnotic sedatives are a perfect solution to the problem of insomnia because they involve serious side reactions such as addiction / addiction, memory impairment, confusional awakening, sleepwalking, and possible coordination problems that can cause falls and hip fracture Is not a good solution. Most insomnia patients prefer a non-drug approach to their insomnia symptoms. Cognitive behavioral therapy is an expensive and labor intensive treatment that is effective but not available everywhere and health insurance is not always available. Over-the-counter approaches for insomnia treatment, including various drugs and devices, have not been well studied clinically to demonstrate significant effects and potentially dangerous side effects in patients with insomnia. Accordingly, there is a great need for a safe, effective, non-invasive, non-medicine insomnia treatment device.

  Recently, progress has been made in sleep neurobiology and insomnia neurobiology that can lead to innovative insomnia treatments. Considerable evidence suggests that sleep can help recovery functions. The sleep homeostasis EEG marker is EEG spectral power in the delta frequency range (1-4 Hz). The constant sleep urge can be accompanied by restoration of brain energy metabolism through replenishment of depleted brain glycogen stores during arousal. This function can have some regional specificity. It has been reported that EEG spectral power in the delta EEG spectral power range is dominant in the frontal region. It has also been reported that the increase in delta power after lack of sleep is dominant in the frontal region. This cerebral cortex region plays a major role in the arousal execution function that is preferentially impaired after sleep deprivation. Such evidence suggests that sleep is essential for optimal executive behavior and that this mechanism is involved in the frontal cortex.

  “Hyperwake” at various physiological levels represents the current major pathophysiological insomnia model. Insomnia patients have increased overall brain metabolism over waking and sleep compared to healthy subjects, resting metabolic rate, heart rate and sympathetic vagal tone in HRV, cortisol secretion in the evening and early sleep, NREM sleep EEG activity during sleep, associated with high levels of arousal after sleep, particularly increased cortical glucose metabolism in the frontal cortex, impaired normal core temperature drop near sleep, and often “competitive”, unstoppable, It has been shown that cognitive hyperwakeness based on pre-sleep thinking in patients with insomnia, described as sleep intensive, is seen. Current evidence suggests that insomnia patients may show selective attention directed at sleep and bed related stimuli, which can lead to a self-enhanced feedback loop of condition awakening, sleep deprivation, and reduced wakefulness Has also been suggested. Insomnia patients have been shown to increase beta EEG spectral power in relation to increased metabolism in the ventral midline prefrontal cortex during NREM sleep. Improved sleep in insomnia patients has been associated with improved prefrontal cortex function as measured by functional neuroimaging.

  Therefore, a decrease in metabolism in the prefrontal cortex seems to be important for normal sleep function, and the increased metabolism at this site may interfere with the normal sleep function of insomnia patients. Therapeutic interventions aimed at reducing metabolic increases in the prefrontal cortex can improve sleep in patients with insomnia.

  Several lines of evidence suggest that cooling the scalp can suppress the metabolism of the cortex under stimulation. Studies have shown that the cooling of the scalp in both animals and humans reduces the underlying cortical brain temperature. In swine studies, even a weak surface cooling of 15 degrees C is associated with the scalp and brain surface being cooled to 35 degrees C. In this study, a remarkable differential surface cooling effect on the surface versus deep brain tissue was seen, with the brain surface tissue being cooled lower than the deep brain tissue. In a human study, Wang et al. Were able to reduce the brain surface temperature of subjects wearing an all-head cooling helmet by an average of 1.84 degrees C within an hour. Biomedical engineering models have shown that cerebrocortical cooling can be achieved by selective head surface cooling. These several lines of evidence support the notion that the application of a cooling stimulus in the scalp is associated with a decrease in underlying cerebral cortex metabolism.

  Brain hypothermia is a therapeutic intervention previously used to treat other medical illnesses due to neuroprotective effects. Therapeutic hypothermia after global and local ischemic and other neurotoxic events such as head injury, stroke and neuropathy during cardiopulmonary surgery has shown beneficial results in controlled animal and human studies. I came. Preclinical studies have shown many neuroprotective effects of brain cooling. These effects include metabolism, pH, neurotransmission level, free fatty acid, blood brain barrier, edema, glucose metabolism, cerebral blood flow, free radical activity, lipid peroxidation, calcium accumulation, protein synthesis, protein kinase C activity, Examples include leukocyte accumulation, platelet function, NMDA neurotoxicity, growth factors, cytoskeletal proteins, calcium-dependent protein phosphorylation, heat shock proteins, immediate early genes, NOS activity and MMP expression. It is believed that the neuroprotective benefits of cerebral cryotherapy can help patients with sleep disorders including insomnia. Pathophysiological models of adverse events associated with sleep disorders are beginning to focus on potential neurotoxicity with sleep disorders. That this neurotoxicity can occur in insomnia has been suggested by research results on the known adverse effects of increased adrenal cortex function in the evening and early sleep in patients with insomnia and on neurological function. One preliminary study showed a decrease in hippocampal volume in patients with insomnia. This may be due to the result of neurotoxic factors.

  If hypermetabolism of the frontal cortex of insomnia patients is reduced both during the pre-sleep period and during sleep, the cognitive hyperawake that is reported by insomnia patients can be suppressed. It is hypothesized that cerebral functional localization of cognitive hyperwakeness occurs in the prefrontal cortex given its executive function and role in meditation cognition.

  Applying a cooling stimulus to the frontal scalp region can also promote a normative change in body temperature regulation related to falling asleep. Heat loss through selective vasodilation of the distal skin area (measured by skin temperature gradient (DPG) between the distal and proximal parts) is the core temperature (CBT) and drowsiness over a 24-hour period. It seems to be a very important process for the regulation of The increase in DPG before extinction has attracted attention as it promotes rapid sleep and suggests a relationship between the thermoregulatory system and the arousal (sleepiness) system. As described above, insomnia patients have shown normal core temperature drop dysfunction before and after sleep onset. Thus, devices that cause heat loss, especially through the periphery, can improve sleep for insomnia patients.

  Recent studies have shown that insomnia can be associated with increased brain metabolic activity, particularly in the frontal cortex. "Non-invasive local brain thermal stimulation method and apparatus for the treatment of neurological diseases (Method and Apparatus of Noninvasive, Regional Brain Thermal Treatment Fortment" filed April 20, 2007, previously incorporated by reference. of US Patent Application No. 11 / 788,694, now US Pat. No. 8,236,038, entitled “Neurologic Disorders”). Is described. Functional neuroimaging studies show that brain metabolic activity in the insomnia patient during sleep, particularly in the frontal cortex below the cold pad, imparts cold stimulation to the scalp above the frontal cortex of the brain (“pre- It has been shown to be reduced by the head hypothermia method)). Although these studies suggest that frontal hypothermia may help clinical management of insomnia patients, the most appropriate parameters for applying the device have not yet been fully elucidated.

  Preliminary data using forehead hypothermia suggests that the relative metabolism in the subcranial cerebral cortex where the device is applied is reduced. The application of the device is not necessarily limited to insomnia pathology, but also applies to various neuropsychiatric disorders, each of which can be attributed to insomnia, or which can be characterized by unique abnormal brain metabolic patterns. Can do.

  Several diseases have been found to be associated with insomnia as a concomitant condition and / or a relatively specific change in brain metabolism that can benefit from treatment with a frontal cooling device. These patients often have already received multiple other medications, some of which have a sleep effect on the therapy itself, so these combined conditions make medication more difficult. Concomitant insomnia itself has rarely been studied using either form of treatment. Depression is associated with severe sleep disturbances including sleep disturbances, sleep disturbances, early morning awakenings or non-restorative sleep. Functional neuroimaging studies have shown that the decrease in normal prefrontal cortex metabolism changes from arousal to NREM sleep. The lifetime prevalence of depression in the United States is 17.1%, or currently 52 million, suggesting that this is a major problem. The neurobiology of sleep problems in patients with chronic pain shares another significant overlap with that of patients with insomnia, suggesting another disease that can benefit from frontal cooling devices. The most common causes of pain that disturbs sleep are low back pain (social costs estimated to exceed $ 1000 million annually), headache (50% of these patients have sleep problems that cause headaches, migraine patients 71% awake from sleep due to migraine), fibromyalgia, and arthritis (autoimmune diseases such as osteoarthritis, rheumatoid arthritis and lupus). Estimates of prevalence of chronic pain in the United States are 10.1% back pain, 7.1% leg / foot pain, 4.1% arm / hand pain, 3. 5% have headaches. 11.0% and 3.6% of respondents complain of chronic local pain and widespread pain, respectively. Based on US census data, this will be converted into an additional market of over 50 million people. 70-91% of patients with post-traumatic stress syndrome (PTSD) are associated with sleep deprivation or sleep disorders. Treatment of sleep problems in PTSD has revolved around the management of pharmacotherapy with associated adverse events. A study conducted as part of the National Comorbidity Survey (NCS) reports a lifetime prevalence of PTSD in the United States of 7.8%, which is now a market of over 23 million people.

  It has been shown that sleep can be improved by cooling the subject's skin (eg, frontal), possibly utilizing a mechanism involving cooling of the underlying brain region. This clinically proven effect can generally indicate that warming (as compared to ambient temperature) adversely affects sleep rather than cooling the subject's forehead. To date, however, studies relating to the effect of applying high temperatures to the subject's skin, particularly the subject's frontal region, are somewhat uncertain.

  Apart from the main single insomnia therapy, this device can also benefit insomnia patients who are partial responders of conventional hypnotic sedative insomnia therapy or cognitive behavioral insomnia therapy. Although clinical trial data suggest that approved hypnotics show a statistically significant improvement in about 2/3 of patients, significantly fewer patients report complete symptomatic remission. This means that about two-thirds of patients prescribed sleeping pills are non-responders or partial responders of these treatments, and thus foreground cooling insomnia devices such as the devices and systems described herein. It suggests that you can benefit from the adjuvant therapy used.

US Patent Application No. 62 / 337,279 US patent application Ser. No. 14 / 749,590 US patent application Ser. No. 14 / 938,705

  Recently, progress has been made in sleep neurobiology and insomnia neurobiology that can lead to innovative insomnia treatments. However, it would be beneficial to provide a method and apparatus that can address the needs described above.

  The methods and devices described herein non-invasively perform region-selective brain cooling or warming that changes brain metabolism in a focused manner, thereby reducing (but not limited to) insomnia. It is possible to treat a neurological disease characterized by a change in brain function peculiar to the included region. These methods and devices can generally be used to improve sleep.

  In general, herein, a method, apparatus, and method for applying hypothermia therapy within a highly controlled parameter to skin on the prefrontal cortex to reduce metabolism in this brain region by cooling the prefrontal cortex The system will be described. As explained in detail below, prefrontal cortex hypothermia can improve insomnia. Thus, in many of the therapies described herein, the device or system is configured to be placed in contact with or in thermal contact with the patient's skin, particularly over the prefrontal cortex. It includes an applicator having a heat transfer area (eg, a pad, etc.). The applicator can be a mask or a garment that cools and heats the heat transfer area by any suitable means including coolant (eg, cooling water) or solid (eg, Peltier elements) or some combination thereof. Can be controlled.

  Specifically, the present specification controls the application of cooling to the subject's forehead to induce a diving reflex (or partial diving reflex) and adjusts the cooling application based on this diving reflection. Describes a method and apparatus for reducing sleep latency, increasing sleep depth, and / or extending subject sleep time.

  For example, the devices described herein are all adapted to be worn on the subject's forehead and have a heat transfer surface applied directly to the subject's skin or through a sleeve or cover. An applicator, one or more cooling units configured to cool the heat transfer surface, and the output and drive of the one or more cooling units electrically coupled to the one or more cooling units A controller configured to regulate cooling and one or more sensors configured to detect a physiological parameter from the subject, wherein the one or more sensors are coupled to the controller, Determine whether the subject is experiencing diving reflexes from physiological parameters detected by one or more sensors and based on this determination Configured to adjust one or both of the cooling timing in degrees or heat transfer area.

  In general, one or more sensors can be sensors that detect physiological parameters indicative of diving reflexes, or as described in detail herein or as is well known in the art. The dive reflection can be determined from the sensor. For example, one or more sensors may include one or two of body movement, respiratory rate, heart rate, electrical skin reaction, blood oxygen concentration, electrocardiogram (ECG) signal, and electroencephalogram (EEG) signal. It can comprise so that the above may be detected. The controller can be configured to determine whether the subject is experiencing a diving reflex based on a decrease in heart rate for a short period of time (eg, within a few minutes) indicating the diving reflex.

  In general, the controller can adjust the temperature of the forehead applicator just by adjusting the temperature to induce a dive reflex. For example, the controller can be configured to reduce the temperature of the heat transfer surface of the applicator until a dive reflection is detected. The applicator can maintain the temperature at this diving reflex threshold temperature (or slightly below or slightly above this temperature) over the treatment time when a diving reflex is detected. For example, the controller may maintain the temperature of the heat transfer surface of the applicator at a temperature at which a dive reflex response is detected or less than this temperature for a maintenance period, and then change the temperature of the heat transfer surface of the applicator to a standby temperature for a standby period. Can be configured to raise.

  Both of these devices can include a stop for holding the forehead applicator on the subject's head.

  The one or more cooling units can include one or more thermoelectric coolers, and / or fans, and / or heat sinks. In some forms, cooling unit (s) are included as part of the forehead applicator. For example, one or more cooling units can be present in the forehead applicator in communication with the heat transfer surface. Alternatively, one or more cooling units can be part of a separate housing that cools the fluid circulating in the applicator to cool the heat transfer area. For example, one or more cooling units can be configured to cool fluid passing through the forehead applicator. The cooling unit can be connected to the applicator via a tube.

  Similarly, one or more sensors and / or controllers can be incorporated into a wearable forehead applicator. For example, one or more sensors can be part of the forehead applicator.

  This specification also describes a method of treating insomnia by applying hypothermia therapy non-invasively to the frontal cortex of a subject. The method includes placing an applicator on the prefrontal cortex that includes a heat transfer area in communication with the subject's skin, and the lowest temperature that the subject can withstand without causing discomfort or waking from sleep. Cooling to a first temperature comprising: maintaining a first temperature for a first period of at least 15 minutes before the target bedtime; and a second of at least 15 minutes after the target bedtime Maintaining a second temperature over a period of time.

  In some forms, the first temperature is from about 10 ° C to about 18 ° C. In some forms, the first temperature (minimum tolerable temperature) corresponds to the lowest temperature that does not cause a stimulus (or arousal) that the applicator can apply when worn by the subject, and this temperature is empirically or experimentally Can be determined. For example, the method can include determining a first temperature for the subject.

  Placing the applicator can include securing the applicator in place. For example, the applicator can be held in place by a strap. In some forms, the applicator is adhesively secured. In general, positioning the applicator can include securing the applicator just over the frontal region of the subject. In some forms, the applicator is limited to the forehead region.

  In some forms, cooling the heat transfer region to the first temperature reduces (slowly) the temperature of the heat transfer region from the ambient temperature to the first temperature for at least 5 minutes, 10 minutes, 15 minutes, etc. Including a step of reducing).

  Maintaining the first temperature can include maintaining the heat transfer region at the first temperature for at least 30 minutes, 1 hour, or the like.

  In some forms, the first temperature is the same temperature as the second temperature (eg, 10 ° C. to 18 ° C.). However, in some forms, the method includes changing the temperature of the heat transfer region to a second temperature. In general, the second temperature can be a temperature between the first temperature and 30 ° C. For example, the second temperature can be about 20 ° C. to about 25 ° C. Maintaining the second temperature over a second time includes maintaining the second temperature over a period of time greater than 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, or the entire sleep time. be able to. In some forms, the method further includes adjusting the second temperature based on feedback of the patient's sleep cycle.

  The present specification relates to a method of treating insomnia by non-invasively applying hypothermia therapy to a subject's frontal cortex, the applicator including a heat transfer region communicating with the subject's skin on the prefrontal cortex. , Cooling the heat transfer area to a first temperature comprising the lowest temperature that the subject can withstand without causing discomfort or awakening from sleep, and at least 15 minutes prior to the target bedtime. Maintaining a first temperature, maintaining a first temperature for at least 30 minutes after the target bedtime, and a second temperature between the first temperature and 30 ° C. for at least 30 minutes. A method comprising the step of maintaining is also described.

  The present specification relates to a method for reducing sleep onset by applying hypothermia therapy non-invasively to a frontal cortex of a subject, the applicator including a heat transfer region communicating with the skin of the subject on the frontal cortex Placing, cooling the heat transfer area to a first temperature of about 10 ° C. to about 18 ° C., and maintaining the first temperature for a first period of at least 15 minutes prior to the target bedtime A method including these is also described.

  The present specification relates to a method for sustaining sleep of a subject by non-invasively applying hypothermia therapy to the frontal cortex of the subject, the applicator including a heat transfer region communicating with the skin of the subject. Placing on top, after the target bedtime, maintaining the heat transfer area at a first temperature comprising the lowest temperature that the subject can withstand without causing discomfort or arousal from sleep, and after the target bedtime And maintaining a first temperature for a first period of at least 30 minutes. For example, the first temperature can be about 10 ° C. to about 18 ° C.

  In general, methods of treating insomnia (eg, by reducing sleep latency and / or increasing sleep time) are performed by non-invasive cooling, particularly by cooling the skin on the frontal cortex be able to. In some forms, this cooling is limited to the forehead region. In general, the systems and devices described herein control the profile of the applied hypothermia so that both temperature and administration timing are controlled. The system can be configured to apply a complex dosing schedule and can be further configured to modify or select the dosing schedule based on patient feedback. The feedback may be selected by the patient (eg, by adjusting or changing control inputs) or based on one or more sensors that detect physiological parameters from the patient, such as sleep level or REM / NREM status. You can also.

  As described in detail below, the devices and systems for applying hypothermia described herein generally include an applicator having a heat transfer region (eg, fixed or worn on a subject). The heat transfer area is cooled. The heat transfer area is placed in contact with the skin on the frontal cortex of the subject. In general, the applicator and heat transfer area are configured to allow the subject to wear the device comfortably and safely during or before sleep (to increase sleepiness). The entire system can be configured to be quiet (so as not to disturb sleep) and can include one or more controllers that adjust the temperature of the heat transfer area as described above. The controller can be a microcontroller (including dedicated hardware, software, firmware, etc.). In some forms, the system can include a disposable or replaceable skin contact area that is configured to be worn by the subject every night and is therefore washable. For example, the heat transfer area can be covered with a disposable material or cover that can be replaced every night after use. In some forms, one or more sensors that receive patient information and / or system performance information may also be included, and this information may be provided to the controller and used to adjust the temperature. Overall, the system can be lightweight and easy to use.

  Other features of the invention described herein are outlined in more detail below with reference to the drawings. Described herein are forehead cooling devices and methods adapted to stimulate the parasympathetic nervous system for the treatment of insomnia. The device can include a cooling cap applied to the patient's forehead that can be applied before and / or during the sleep period to improve sleep. Example embodiments of the forehead cooling system are designed for optimal use during sleep. The temperature setting / algorithm described herein modifies / improves sleep for insomnia patients based on research using the device and regulates the parasympathetic nervous system, including feedback from the parasympathetic nervous system. Specifically configured.

  There is a known relationship between the autonomic nervous system and sleep. The autonomic nervous system controls body functions without conscious control. Although there are a plurality of elements in the autonomic nervous system, it can be mainly divided into a sympathetic nervous system (SNS) and a parasympathetic nervous system (PNS). Simply put, the sympathetic nervous system allows physical struggle and escape responses to emergency situations and stress. The parasympathetic nervous system allows our rest and digestion. The sympathetic nervous system can be thought of as a mobilization system that reacts quickly, and the parasympathetic nervous system can be thought of as a slowly activated braking system. With regard to sleep, there is data showing that PNS activity increases with falling asleep and remains at a high level throughout NREM sleep. During REM sleep, PNS activity returns to wakefulness but remains slightly higher. Similarly, SNS activity is reduced during NREM sleep. During REM sleep, SNS activity is higher than the arousal level. This data suggests that the autonomic balance varies between wakefulness and NREM and REM sleep, indicating relative sympathetic dominance during wakefulness and REM sleep, and relative parasympathetic dominance during NREM sleep .

  Various physiological levels of “hyperwake” represent the current major pathophysiological model of insomnia. In insomnia patients, increased overall brain metabolism over arousal and sleep, resting metabolic rate, heart rate and sympathetic vagal tone in heart rate variability (HRV), cortisol in the evening and early sleep compared to healthy subjects Secretion, beta electroencephalogram (EEG) activity during NREM sleep, increased cortical glucose metabolism levels, especially in the frontal cortex, associated with high levels of arousal after sleep, disturbances in normal core temperature drop near sleep, and often “competition” It has been shown that cognitive hyper-arousal based on pre-sleep thinking in patients with insomnia, described as “intentional”, unstoppable, sleep intensive, is seen.

  Cardiac autonomic tone, measured by heart rate variability (HRV), has been identified as a physiological order in which sleep disorders and sleep disorders can potentially affect morbidity and mortality. Heart rate variability is highest in the NREM phase, with high frequency band (HF-HRV) power, interpreted as a parasympathetic tone measure, varying as a function of sleep as a function of NREM sleep depth. In contrast, the REM sleep stage and the shallow NREM sleep stage are characterized by a decrease in the power of the HF-HRV band. Heart rate variability can also vary as a function of sleep disorders, including insomnia. Some, but not all, studies have reported that HF-HRV power is lower in insomnia patients compared to sleepy controls. Insomnia patients may exhibit a high low-high frequency power (LF: HF-HRV) ratio that is interpreted as the tone index of the sympathetic vagus nerve. HRV changes associated with sleep are also associated with other physiological changes. For example, increased sympathetic nervous system tension during NREM sleep after experimental sleep suppression in healthy young people is associated with increased low glucose tolerance, low thyroid-stimulating hormone levels, and cortisol levels. Finally, HRV fluctuations during sleep have been found to be consistent with conditions such as PTSD, alcoholism and extreme stress.

  Given the relationship between autonomic nervous system activity and sleep and insomnia, the development of therapeutic interventions designed to influence these relationships can be beneficial in the design of therapeutic interventions for the treatment of insomnia .

  One way in which the autonomic nervous system can be adjusted is through a primitive autonomic nervous system reaction known as diving reflex. Diving reflexes are caused by immersing the body in cold water and are characterized by decreased heart rate (HR) due to increased cardiac vagal activity, primary efferent nerve activity in the parasympathetic nervous system, and often in the peripheral Is associated with selective vascular bed vasoconstriction due to increased sympathetic output to Diving reflexes are considered the most powerful autonomous reflex known. Among physiologists, diving bradycardia has been extensively studied and discussed.

  Diving bradycardia is found in all air-breathing vertebrates from amphibians to mammals. Diving reflexes represent a subgroup of trigeminal-vagal reflexes, along with trigeminal-cardiac and eye-cardiac responses.

  Diving reflexes are controlled by a complex neural network that integrates the respiratory and cardiovascular systems. This reflex is mainly caused by stimulation of receptors on afferent fibers located in the trigeminal nerve, particularly in the frontal region, periorbital region and nasal cavity. It seems that the cold receptors are mainly involved in the onset of diving reflexes. In this regard, HR deceleration does not occur when stimulating the cold receptors on the skin of body parts other than the face. The existence of a central circuit for diving reflexes in the brainstem is demonstrated by the fact that the bradycardia response is maintained in decerebrated specimens. The physiological background of this circuit was rarely the subject of research. Some data suggest that the first relay of this circuit is located in the abdominal surface medullary dorsal horn, because cardiac responses can be blocked by infusion of local anesthetics or kynurenic acid. Thus, bradycardia via the vagus nerve and vasoconstriction via the sympathetic nerve may be mediated by the trigeminal nervous system in the lower brainstem. However, the relationship between the trigeminal nervous system and the autonomic nervous system of the brainstem is unknown.

  Human diving reflexes involve bradycardia, often resulting in decreased cardiac output (CO) and selective vascular bed vasoconstriction, increased blood pressure (BP) and decreased blood flow to the surrounding capillary bed. . Human diving reflexes can be simulated by immersing your face in cold water, and this test method is known as "simulated diving reflex" or "cold pressurization test" and most of our knowledge of diving reflexes It is obtained by this procedure. To elicit a bradycardic response, it is sufficient to bring the frontal head, eyes and nose into direct contact with cold water. The bradycardic response to apneic face immersion varies widely between individuals, with a HR reduction of generally 15-40%, but the proportion of healthy people who develop bradycardia of less than 20 beats / minute Few. Reduction in HR is prevented by prior treatment with atropine, which demonstrates the role played by the vagus nervous system. The increase in BP is also very different among healthy people. A similar variable HR drop is also observed after whole body flooding, and HR tends to stabilize after falling immediately after flooding, but may drop to 20-30 beats / minute during long-term diving. When the “stress phase” is reached, HR is further reduced and cardiac contraction BP can be increased to 220-300 mmHg. After reappearance, HR and BP normalize fairly rapidly.

  Most evidence shows that the magnitude of diving bradycardia is greatly affected by the temperature of both water and air in the opposite direction, that is, the bradycardia response is more pronounced at lower water temperatures and higher temperatures. Facial cold receptors are most strongly excited by immersion in cold water (10-15C) and changing the temperature between 15-35 ° C has little effect on the bradycardic response. However, when the whole body is submerged in ultracold water (~ 0C), a paradoxical reaction, that is, tachycardia rather than bradycardia, so-called "cold shock reaction" may be induced. This is likely to involve a large afferent drive from the cold receptors in the skin that stimulate the sympathetic nervous system.

  The vagus nervous system is the primary efferent nerve pathway for animal heart coordination. After pretreatment with atropine, HR during diving was high and did not change. Furthermore, in the sealed state, a pronounced HR vibration (10-20%) that was manifested by high vagal tone after immersion was observed.

  Although the relationship between facial cooling and parasympathetic nervous system activity has been reported, the effect of selectively altering parasympathetic nervous system activity through frontal cooling during sleep has not been clarified.

  Among the body regions, the forehead has unique physiological and neurostructural properties that suggest it can play a major role in affecting diving reflexes. It has been shown that the distribution of warm and cold spots is highest on the face and forehead among all body parts. Temperature sensation is also shown to be highest in the frontal region among all body parts. In one study, thermal radiation was applied to selected skin regions to determine whether certain regions showed higher temperature sensitivity than other regions in determining physiological thermoregulatory responses. By calculating the sensitivity coefficient for each skin area, the change in thigh sweat rate was associated with the change in temperature of the irradiated skin and the range of the irradiated skin. It was recognized that the temperature sensitivity of the face measured by the influence of the sweat rate change from the thigh was about three times that of the chest, abdomen and thigh. The lower limb was found to be about ½ of the thigh temperature sensitivity. Other studies have reported the highest temperature sensitivity of the face among all body parts. Furthermore, we consider that the heat transfer function and heat transfer efficiency of hairless (hairless) skin is rare throughout the body based on the ability of very high blood perfusion rate and the new ability of dynamic blood flow regulation And the forehead, including hairless skin, was found to play a major role in the body response to thermoregulation.

  These lines of evidence support the notion that the application of cooling stimuli in the scalp on the frontal region may be related to sleep improvement in insomnia patients through parasympathetic reflex activity. Thus, a medical device that changes the skin temperature on the forehead may be a very accurate non-invasive method for regulating sleep of insomnia patients.

  To date, there is no description of the application of such devices and the specific temperatures at which this effect can occur.

  The novel features of the invention are set forth with particularity in the following claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 illustrates one form of a portion of a device that improves sleep by adjusting frontal temperature relative to ambient temperature (eg, cooling). FIG. 6 shows one form of applicator portion of a device that improves sleep by adjusting forehead temperature. FIG. 1D illustrates one form of an applicator of a device that can be used with the device of FIGS. 1A-1G to improve sleep by adjusting total head temperature. It is a figure which shows one form of the application method of the applicator of the sleep improvement apparatus demonstrated in this specification. A cartridge (container) that can be filled with a fluid (eg, water, etc.) that can be used with or included as part of a sleep improvement device such as the device shown in FIGS. 1A-1J. FIG. FIG. 4B is an exploded view of the cartridge (container) of FIG. 4A. It is sectional drawing of the cartridge which shows the valve | bulb in the cartridge interlock | cooperated with a sleep improvement apparatus. It is an enlarged view of the valve | bulb part of FIG. 4C. FIG. 2 shows a cartridge inserted into the apparatus (similar to that shown in FIG. 1D). FIG. 5 is an enlarged exploded view of a knob including a vent (eg, a hydrophobic vent or seal) that is sealed to prevent water leakage and allow air to escape. This knob can be locked in the closed position, for example during transport, or opened when inserted into the device. In the open position, an extension “wing” on the knob engages the device to hold the cartridge firmly in the device while applying force to open the valve at the bottom of the cartridge, and in this position the vent is open. Air can be taken into the cartridge. The cartridge can be transported almost full (eg, 90% filled to allow thermal expansion, 10% empty). It is sectional drawing of the knob which the cartridge assembled. FIG. 4D is a partial cutaway view of the assembled cartridge of FIG. 4G showing a vent region that opens into a hydrophobic cover (shown as a circular membrane) that blocks fluid through air. 1A is a schematic diagram of an apparatus for adjusting frontal temperature as shown in FIGS. FIG. 6 illustrates the use of the device described herein. It is a graph which shows the increase in whole-brain metabolism during awakening and sleep in insomnia. It is a figure which shows the brain area | region where an insomnia patient does not show the fall of a big relative metabolism from awakening to sleep. It is a figure which shows the brain area | region where the relative metabolism in the insomnia patient fell. FIG. 6 is a graph showing the change in mean core temperature over time for patients treated with and without treatment of localized forehead cooling therapy. FIG. 6 shows a reversal of PET scan and prefrontal hypermetabolism in an insomnia patient receiving treatment using frontal hypothermia. 6 is a graph showing the reduction in subjective arousal of insomnia patients treated using the prefrontal hypothermia method described herein. 2 is a graph showing the reduction in total brain metabolism (compared to controls) for patients treated with prefrontal hypothermia. It is a graph which shows the increase in the subjective sleepiness of the insomnia patient treated using the prefrontal hypothermia method. It is a graph which shows the reduction of arousal after the sleep of the patient treated using the prefrontal hypothermia method. 2 is a graph showing the increase in delta power during sleep for patients treated using prefrontal hypothermia. FIG. 3 is a control comparison diagram of a PET scan showing reduced local metabolism in a patient treated with prefrontal hypothermia. It is a figure which shows one form of the headpiece of the apparatus to which the hypothermia method is applied. It is a figure which shows the headpiece applied to the test subject's head. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies a prefrontal hypothermia method in insomnia patient has on sleep time. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in the insomnia patient has on the awakening after falling asleep. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in the insomnia patient has on the awakening of the first half of the night. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in the insomnia patient has on the awakening of the second half of the night. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in insomnia patient has on the total sleep time. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in insomnia patient has on sleep efficiency. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in the insomnia patient has on the ratio of stage 1 sleep. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in insomnia patient has on the ratio of stage 2 sleep. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in the insomnia patient has on the ratio of the stage 3/4 sleep. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in the insomnia patient has on the ratio of REM sleep. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in an insomnia patient has on the delta count number of the whole night. It is the figure which compared with the non-insomnia patient the influence which one form of the apparatus which applies the prefrontal hypothermia method in insomnia patient has on the spectrum power of the whole night. 1 is a schematic diagram of a vestibular sleep system (used as a controller). FIG. It is a table | surface (Table 1) which shows the change of the main endpoints of one study example, and ITT population (N = 106) which investigates the effectiveness of the apparatus and method which cool a test subject's face for sleep regulation. It is a table | surface (Table 2) which shows ITT population (N = 106) at the sleep latency of all the stages. It is a table | surface (Table 3) which shows the NREM sleep latency of a stage 1 and ITT population (N = 106). It is a table | surface (Table 4) which shows NREM sleep latency of a stage 2 and ITT (N = 106). It is a table | surface (Table 5) which shows a stage 3 NREM sleep latency and ITT group except the test subject (N = 97) who did not experience the sleep of the stage 3 either in the reference | standard night or apparatus night. It is a figure which shows the ITT population (N = 106) typically in the NREM sleep latency of stages 1, 2 and 3. It is a figure which shows typically the difference with the camouflage after adjustment, ITT (N = 106) of the stage 1, 2 and 3 of the sleep system demonstrated in this specification. Sleep improvement as described herein, including one or more sensors that detect / sense when a subject is experiencing a diving reflex, similar to the applicator shown in FIGS. 5 and 6 using circulating coolant It is the schematic of the example of an apparatus. 1 is a schematic diagram of an example sleep improvement device described herein including one or more sensors that detect / sense when a subject is experiencing diving reflexes. FIG. In FIG. 20B, the forehead applicator (along with a sensor and controller (processor) including temperature sensor (s) and a sensor for detecting a physiological parameter of the patient that can be used to detect diving reflexes). A plurality of thermoelectric coolers incorporated in the applicator (in thermal communication with the heat transfer surface). FIG. 20B is a diagram illustrating an embodiment of a sleep improving apparatus similar to the apparatus illustrated in FIG. It is a figure which shows the apparatus of FIG. 21A with which the test subject was mounted | worn.

  Described herein are devices (including devices and systems) that specifically control the temperature of the patient's frontal region for sleep regulation. For example, the present description describes an apparatus and method configured to provide cooling temperature to the patient's forehead. This temperature is low enough to provide a dive reflex to the patient over a period of time that can be a predetermined period to shorten sleep latency, increase sleep depth, and / or extend subject sleep time. (Eg, about 10 ° C to 15 ° C in some forms) or other cooling temperatures (eg, about 0 ° C to 30 ° C, about 0 ° C to 25 ° C, about 0 ° C to 24 ° C, about 0 ° C to 23 ° C). , About 0 ° C to 22 ° C, about 0 ° C to 21 ° C, about 0 ° C to 20 ° C, about 0 ° C to 19 ° C, about 0 ° C to 18 ° C, about 0 ° C to 17 ° C, and the like. . In some forms, the subject can be a subject suffering from insomnia.

Devices that improve sleep by increasing forehead temperature relative to ambient temperature Generally, any device described herein that improves sleep by increasing frontal temperature (relative to ambient temperature) Can also include an applicator (eg, a pad, etc.) that fits the subject's forehead and can be worn before and / or during sleep. FIG. 2A shows one form of applicator. In this example, the applicator has a skin contact surface worn against the (invisible) forehead and a pair of side straps 201, 201 '(fixing fixtures) that can be adjusted to fit the device to the subject. including. The applicator is connected to or includes a temperature regulator that controls the temperature of the skin contacting surface of the applicator. The temperature regulator can also include a timing control that adjusts the duration of the applied temperature. The applicator can be secured in place by included fasteners (eg, straps, adhesives, caps, etc.). One or more controls that set parameters controlled by the temperature regulator may also be included, and generally the user or bedmate will be able to operate parameters or actions as described herein through this control. A mode can be selected. In some forms, the system can include disposable elements and / or reusable elements. For example, the skin contacting surface of the applicator can be disposable that can be attached to the rest of the applicator (reusable element).

  For example, in some forms, a device that improves sleep by warming the forehead relative to the ambient temperature allows a uniquely sized head to fit a scalp area on the frontal cortex that circulates fluid at various temperatures A piece and a programmable warmer / pump that provides power and warming to circulate fluid through the headpiece.

  In one example of a device that improves sleep by increasing forehead temperature relative to ambient temperature, the device comprises a temperature regulator unit, a high temperature applicator / hose assembly (sometimes referred to as a forehead pad), And a headgear that keeps the high temperature applicator in contact with the frontal cortex. As described above, the devices described herein can be worn by a sleeping subject and thus can be adapted to be comfortable and safe and effective. In configurations that include fluid (including circulating fluids), the device can be configured to prevent fluid loss / leakage. Devices that improve sleep by raising the forehead temperature relative to ambient temperature can also be used without circulating fluids, for example, by directly heating the skin contact surface of the applicator (including resistance heating). it can. Devices that improve sleep by lowering (or increasing) the temperature of the forehead relative to ambient temperature directly cool the skin contact surface of the applicator, for example (electric heat coolers, convection coolers such as fans, etc.) It can also be used without circulating fluid.

  For example, the temperature controller unit utilizes a thermoelectric module (TEC) to directly heat (or cool) the applicator or heat the heat transfer fluid (TTF) pumped through the hot applicator transfer line. You can also. Other heaters such as resistance heating coils, chemical heating (eg exothermic reactions), high specific heat capacity materials or phase change materials can also be used as part of the temperature controller unit (including chemical coolers) ) Other coolers can be used.

  In one form, the device is configured to operate with a TTF (fluid) that heats the applicator. The main components of such a temperature controller unit are one or more heat exchangers, a heat sink, a TEC, a pump, a fan, an electronic control circuit, software, a user interface, and a TTF container. A unit enclosure, a connection for incoming power, and a TTF connection for the high temperature applicator. FIG. 2B shows a form of an applicator used with a TTF base unit including a tube 4 covered with a heat insulating material 5, and the tube 4 has a headgear (an example of a stopper 2033) having a skin contact surface 201. Connect the heat transfer area 2 of the applicator which also contains. In some forms, the stop can be an adhesive configured to hold the applicator to a subject's head, hat, hood, strap, or headband.

  In some configurations, these components are placed in thermal contact with the heat sink (s) on one side of the TEC and in thermal contact with the heat exchanger on the opposite side of the TEC heat sink. Can be assembled as The heat exchanger can be constructed of any known material and design for this purpose. The assembly can be insulated to reduce parasitic heat loads on the heat exchanger. The temperature controller unit can be operated in a warming (or cooling) mode to control the temperature of the TTF to a desired level. The temperature regulator uses a pump to circulate the TTF to the heat exchanger and high temperature applicator. The pump can be of any suitable type, i.e. a centrifugal pump, a piston pump, a gear pump, a diaphragm pump and the like. The TTF container is incorporated to supply additional TTF to replenish TTF lost for any reason. The container can be an integral fillable element within the temperature controller unit or can be configured as a replaceable cartridge. The vessel plumbing can be designed so that the capacity of the TTF in the vessel is not continuously present in the TTF circulation circuit of the heat exchanger and high temperature applicator. This design is called a sidestream container. 1A-1J illustrate one form of a temperature regulator device for use with the TTF described herein.

  This sidestream configuration effectively allows the temperature controller to quickly heat / cool the circulating TTF to the desired temperature by eliminating the need to heat / cool the TTF held in the vessel. To do. Containers or replaceable cartridges (examples shown in FIGS. 4A-4H, described below) can be sized to supply the desired volume for user convenience. The replaceable cartridge can be configured to include a valve system that allows a user to engage or remove the cartridge from the temperature regulator without leaking the TTF. The cartridge can be configured to include a unidirectional vent that allows air intake as TTL is expelled from the cartridge. This configuration can prevent re-entry into the cartridge when TTL is drained from the cartridge and back pressure is generated in the ring circuit. When utilizing this type of unidirectional vent in the cartridge, a separate vent for exhausting air trapped in the circuit can be piped into the circulation circuit. Another cartridge configuration utilizes two connection points into the temperature controller. One connection releases air trapped in the circulation circuit into the cartridge so that the TTF can flow out of the second connection point into the circulation circuit. The connection valve can be designed with any number of known configurations. One such implementation utilizes a check valve for each mating connection element. This can provide a means for engaging or disengaging the cartridge without removing the TTF from the removed cartridge or the mating connection point in the temperature regulator. In another form, the cartridge is sealed with a rubber-type material that can be punctured with a hollow needle. When punctured, the TTF creates a fluid connection with the circulation circuit. When the cartridge is removed, the needle is withdrawn and the rubber type material again seals the puncture hole to prevent TTF from leaking out of the cartridge. The needle is designed with a spring-loaded sliding rubber type material seal that slides onto the needle entrance when the cartridge is removed. Another form utilizes known ball type or O-ring seal type check valves. The size and shape of the cartridge is determined by the capacity required, the desired superficial industrial design, and the available space within the enclosure. As the cartridge engages within the temperature regulator, it is held in place by either latching mechanism. In another embodiment, the vent of the cartridge is bi-directional and can be constructed of a material such as Gore-Tex. Such materials prevent the passage of TTF while allowing air to pass.

  In some forms, the cartridge can include a liner that retains the fluid within the cartridge, and the liner can be folded upon removal of the fluid and expanded upon addition of fluid to the cartridge. In configurations that include a foldable liner (bag or holder), the cartridge may or may not require a vent into the fluid, isolating the fluid container held by the liner from the environment and reducing the possibility of leakage. can do.

  The cartridge and engagement valve are designed to avoid or minimize the possibility of a user refilling the cartridge. This design ensures that the user utilizes only TTF specifically designed for the cooling unit.

  The TTF can comprise, but is not limited to, distilled water, antibacterial agents, ingredients that lower the freezing point, and wetting agents. Other TTF components can also be used. All TTFs can comply with IEC 60601 biocompatibility requirements and FDA requirements.

  4A-4H illustrate a cartridge 400 that can be used with or included as part of a sleep improvement device, such as the device shown in FIGS. 1A-1J. FIG. 4A is a perspective view of a cartridge that can be filled with TTF (eg, water, etc.). In general, the cartridge can be transported with a preload in a sealed (fully closed) configuration. When inserted into the device, the top of the cartridge includes a knob or handle 403 that can be opened to draw air into the cartridge while preventing TTF from leaking out of the cartridge, and the bottom of the cartridge can open into the device. Connector and / or valve 405 can be included. FIG. 4B shows a knob area (with a rotating handle 407, a hydrophobic filter or diaphragm 409 and an air port 411), a bias 413, a displacement member or pin 415, an outer housing 417 and 1 FIG. 4B is an exploded view of the cartridge of FIG. 4A including a valve (or two or more O-rings). FIG. 4C is a cross-sectional view of the cartridge showing the valve portion of the cartridge that works with the sleep improving device. FIG. 4D shows the pin 415 held in the blocking position in the channel formed through the outer housing 417 until the biasing portion (spring 413) is displaced to allow fluid to flow from the cartridge into the device. FIG. 4D is an enlarged view of the valve portion of FIG. 4C showing how the housing surrounds. FIG. 4E shows the cartridge inserted into the apparatus also shown in FIG. 1D. FIG. 4F can be closed and sealed to allow air in and out while preventing TTF leakage, or by rotating knob 407 through an air permeable fluid barrier (eg, hydrophobic membrane 409). 4 is an enlarged exploded view of a knob 407 including a plurality of vent forming elements on a vent housing 411 that can be opened to allow air to pass from outside the cartridge (but not fluid). FIG. The knob can be locked in a closed position, for example during transport, or can be opened when inserted into the device. In the open position, the extension “wings” 408, 408 ′ on the knob can engage the device to hold the cartridge securely in the device while applying force to open the valve at the bottom of the cartridge. In the position, the air vent is opened and air can be taken into the cartridge. The cartridge can be transported almost full (eg, 90% filled to allow thermal expansion, 10% empty). FIG. 4G is a cross-sectional view of the assembled knob of the cartridge. FIG. 4H is a partial cutaway view of the assembled cartridge of FIG. 4G showing a vent region that opens into a hydrophobic cover (shown as a circular membrane) that blocks fluid through air.

  The control circuit may or may not utilize software that controls the cooling or heating of the temperature regulator unit. The control circuit measures the temperature of the TTF by using one or more thermistors arranged in or near the circulation circuit, and adjusts the power to the TEC as necessary to obtain the TTF in the circulation circuit. Temperature can be maintained. The control circuit also utilizes one or more thermal control switches located on the heat sink and, in some cases, activates the heat exchanger when the temperature of one or both components is outside a desired threshold. It can also be used as a safety switch. The control circuit can supply power to the TEC, pump and fan using pulse width modulation (PWM). Software can also be used to provide control algorithms that control all aspects of the system. This software can control the power supplied to the TEC to generate any desired cooling curve of the TTF. In one form, the TTF is cooled more rapidly with the generation of power, and power can be applied to the TEC such that the rate of temperature change decreases as the difference between the actual TTF temperature and the target TTF temperature decreases. Other temperature curves can also be considered. Also, the TTF temperature can be controlled by the user's physiological measurements or time. The control circuit can also provide a user interface to the cooling unit. Possible forms may include, but are not limited to, an on / off switch, a heating / cooling mode selector switch, a TTF target temperature or actual temperature display. The control circuit can also control the illumination of the display. In some forms, the control circuit can monitor and display the TTF level in the container or cartridge to the user. The control circuit can also stop the unit when it detects that the TTF level is low or empty.

  FIG. 5 shows a schematic diagram of an apparatus similar to the apparatus described above. In this example, the apparatus includes a low volume cooling fluid passage that receives replenishment from a cartridge (eg, a container that can be used to fill the low volume cooling fluid passage when needed based on the volume of fluid in the cooling passage). This cooling path passes through a cooling plate that is cooled by one or more TECs. The TEC is cooled by a heat sink and / or one or more fans. The container (right side) can be a container that is manually or automatically refilled. For example, the container can be a cartridge as described in FIGS. 4A-4H. This fluid passage can then lead (via a pump) to an applicator 2003 (see FIG. 6) worn by the patient. The system can be controlled by electronics in a controller 2001 (eg, a PCA that can include a processor) that includes a user interface and / or display. The device can be powered by a battery or wall outlet.

  The enclosure provides a means to mount all the internal elements of the system and provides fan air inlets and outlets. Fan inlets and outlets can be oriented through a grid system in the enclosure designed to prevent user contact with potentially damaging components. In addition, the grid can be designed to allow the user to direct the air flow in the direction found to be desirable. The enclosure has a conveniently located user interface, container refill or cartridge replacement, visual means for determining the remaining TTF level, connection points for incoming power, high temperature applicator / hose assembly of the circulation circuit Allows connection points for inlets and outlets, as well as any other desired connection points.

  Check the hot applicator / hose assembly inlet / outlet connector and temperature regulator enclosure connector to allow the hot applicator / hose assembly to be connected to and disconnected from the regulator assembly without leaking TTF from any component. Use a valve. The hose portion of the assembly is sufficiently insulated to avoid condensation on the hose assembly or to minimize it to the desired ambient temperature and humidity conditions. The high temperature applicator element of the system can be designed to form a seal between at least two layers of flexible rubber-like material. This seal can be formed by any known technique such as ultrasonic welding, RF welding, adhesion or chemical welding. The flexible material layer is selected from a variety of known materials such as urethane or vinyl sheets that exhibit desired material properties such as flexibility, compliance, permeability, comfort for the user. This material is desirably biocompatible. The seal formed between the layers forms a flow path or flow path through which the TTF circulates while the applicator is in contact with the user's skin. The high temperature applicator functions as a heat exchanger when used in this way. The TTF temperature controlled by the temperature regulator is pumped through the hose portion of the assembly to a hot applicator that is in contact with the user's skin. Thermal energy is transferred to and from the user in accordance with the selected TTF temperature and the user's skin temperature. The design and overall length of the channel formed by forming a seal between the applicator layers affects the amount of energy transferred. The design of the channel and circulation path in the applicator also affects the temperature changes in the applicator. The channel is preferably designed to maintain a uniform temperature distribution throughout the applicator. The hose inlet and outlet connections to the high temperature applicator can be permanent or utilize a removable type of connection. The design of the channel within the applicator can have various sizes or cross-sectional areas to produce the desired pressure, temperature or flow within the channel. The expansion of the channel under pressure can also be controlled using small weld spots or weld points in the flow path. The applicator circumference is designed to contour the applicator to the user's desired skull portion proximate to the frontal / prefrontal cortex. In general, this region is defined as a region including left and right temple regions and a region defined between the eyebrows and the center of the head. The applicator perimeter can also include various cuts, cuts or other shape definitions that allow the applicator to better fit within the desired contact area of the user's head. One form of applicator shown in FIG. 2B illustrates the described design aspect.

  As shown in FIG. 3, the high temperature applicator can be held in contact with the subject's head using a headgear system. In one form of headgear element, a series of adjustable straps are used to selectively adjust the contact pressure of the applicator to the user. Other forms of headgear can also be made of an elastic type material without using the adjustment function. The elasticity of the material provides contact pressure to the high temperature applicator. Other configurations utilize both features, an adjustable strap and an elastic material. In some forms, the high temperature applicator can be permanently integrated with the headgear, and in other forms, the high temperature applicator can be removable from the headgear.

  As noted above, the applicator portion of the device generally includes a skin contact area configured to contact the subject's forehead. The skin contact area generally includes a heat transfer area. The temperature is actively adjusted only on the heat transfer region, which is preferably in the subject's frontal region. The applicator can be configured so that no other head area or facial area of the subject is in contact with the heat transfer area, so that temperature control is applied only to the frontal area, the orbit, cheek, neck, occipital area, It can be prevented from being applied to other areas such as the hairline. Thus, in some forms, the applicator can contact or cover not only the forehead but also other areas, but the heat transfer area only touches the forehead and contacts the eyes (periorbital and orbital Part) or the cheek area.

  In general, the applicator can be configured to increase wearer comfort. For example, the applicator can have a relatively thin thickness (eg, less than 5 cm, less than 2 cm, less than 1 cm, etc.) so that it can be comfortably worn during sleep. The applicator can be adjusted to fit around the heads of various patients.

  In general, any of the devices described herein can be configured to provide a temperature that is higher than the ambient temperature of the subject. In some forms, this causes the patient contact (skin contact) surface of the applicator to be at a temperature between 0 ° C. and 25 ° C. (eg, 0 ° C., 1 ° C., 2 ° C., 3 ° C., 4 ° C., 5 ° C., 6 C, 7C, 8C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23 ° C., 24 ° C., 25 ° C., or any intermediate temperature therebetween. This temperature can be held constant within a range (eg, about 10 ° C. to 15 ° C., etc.) or can be varied (or can be varied).

  In some forms, the applied temperature can be determined based on the relative ambient temperature. For example, the temperature to be applied is lower than the ambient temperature by a predetermined amount (ΔTemp) (for example, 0.5 ° C. lower than the ambient temperature, 1 ° C. lower than the ambient temperature, 1.5 ° C. lower than the ambient temperature, and lower than the ambient temperature). 2 ° C. lower, etc.).

The operation method and experimental results Figure 3 of the apparatus, illustrating one method of applying the applicator to the subject's head. The applicator can be easily applied to the subject's head. The applicator can generally be applied just before or just before going to bed. FIG. 3A shows an example of an applicator. The subject (which may also be referred to as a patient) applies the device to his / her forehead as shown in FIGS. 3 (2) to 3 (5), and in FIGS. 3 (6) to 3 (9). As shown, the straps (eg, fasteners) of the device can be adjusted so that the device is comfortable and safe. In this example, the applicator includes a TTF so that the tube extends from the applicator to the base unit shown in FIGS. 1A-1J, not shown in FIG. 3A. The form of the applicator can include one or more tubes that extend from the device to the base unit, and these tubes can be adjusted with an applicator on the subject's head. When worn, the subject can go to bed.

  As mentioned above, it has been suggested that the recovering aspect of sleep may be locally related to the atypical association cortex, particularly the frontal region. The tests described herein reveal this local cerebral metabolic correlation. The first test identified changes in local brain metabolism that occurred between arousal and sleep in healthy subjects. Fourteen healthy subjects (10 women and 4 men aged 21-49 years) were subjected to simultaneous EEG sleep tests and [18F] fluoro-2 deoxy D glucose ([18F] − An FDG) positron emission tomography (PET) scan was performed. From awakening to NREM sleep, whole brain glucose metabolism was significantly reduced. A relative decrease in local metabolism from awakening to NREM sleep was seen in the atypical frontal cortex, parietal cortex and temporal cortex, and in the hypothalamus and prethalamus. These test results are consistent with the restorative role of NREM sleep, primarily in the cortex, which assists essential executive functions in conscious behavior during arousal. The second test identified changes in local brain metabolism that occurred between normal and restorative NREM sleep after overnight sleep deprivation. In this study, constant sleep needs or sleep impulses were adjusted in the within-subject plan through sleep deprivation. Four healthy young adult male subjects (mean age + sd = 24.9 ± 1.2 years) had [18F] fluoro-2-deoxy D-glucose positron after normal nocturnal sleep and again after 36 hours of sleep deprivation NREM sleep was experienced using emission tomography ([18F] -FDG PET) evaluation. Absolute local cerebral glucose metabolism data and relative local cerebral glucose metabolism data were acquired and analyzed. Subject's restorative NREM sleep is relative to baseline NREM sleep: (1) increased slow wave activity (electrophysiological sleep impulse marker), (2) overall decrease in whole brain metabolism, and (3) some It was accompanied by a relative decrease in glucose metabolism in a wide frontal cortex region extending to the parietal cortex and temporal cortex. These results indicate that sleep-restoring after sleep deprivation is associated with an overall decline in total brain metabolism and a further relative decline in the frontal cortex, and related large areas of the parietal and temporal cortex It is proved to do. In other words, sleep deprivation makes the reduction in brain metabolism typically seen during NREM sleep significant. Thus, medical devices that change metabolism in a pattern similar to that found in healthy sleep or restorative sleep after sleep deprivation can benefit insomnia patients.

  To test this hypothesis, insomnia patients were examined to see how these normal brain metabolic changes would be disturbed in insomnia patients. [18F] Fluoro-2-deoxy D glucose positron emission tomography (PET) was used to diagnose local cerebral glucose metabolism during insomnia and healthy subjects during arousal and NREM sleep. Insomnia patients showed an increase in overall brain glucose metabolism during sleep and wakefulness as shown in FIG. 7A. By population x state interaction analysis, insomnia subjects showed ascending reticulum activation system (as shown in FIGS. 7B and 7C), hypothalamus, thalamus, insular cortex, tonsils and hippocampus, and anterior cingulate cortex and medial It was confirmed that the relative metabolic decline from awakening to NREM sleep in the prefrontal cortex was less than in healthy subjects. Insomnia subjects show relative metabolism in a large area of the frontal cortex, upper left hemisphere, parietal cortex and occipital cortex, thalamus, hypothalamus and brainstem reticular body during wakefulness to healthy subjects. It was. The study demonstrated that subjectively disturbed sleep in patients with insomnia was associated with increased brain metabolism. Drowsiness disturbance in insomnia patients can be associated with inactivity deficits in the awakening mechanism from awakening to sleep. Furthermore, daytime fatigue of insomnia patients can reflect a decrease in prefrontal cortex activity due to insufficient sleep. These test results suggest neural networks that interact in the neurophysiology of insomnia. These neural networks include the general arousal system (ascending reticular body and hypothalamus), the emotional control system (hippocampus, tonsils and anterior cingulate cortex), and the cognitive system (prefrontal cortex). In particular, the ascending arousal system is functionally associated with cortical areas with cortical cognitive arousal that can provide more primitive brainstem and hypothalamic arousal feedback and regulation. Medical devices that alter the metabolism of one or more parts of this neural network can benefit insomnia patients and provide restful sleep.

  In order to elucidate the brain metabolic correlation of post-sleep arousal (WASO) in patients with early insomnia, considering the role of prefrontal cortex in restorative sleep and cognitive arousal, insomnia patients with WASO are particularly A second test was conducted in insomnia patients to test the hypothesis that it would show an increase in relative metabolism. WASO sleep using [18F] fluoro-2deoxy-D-glucose positron emission tomography (PET) with 15 patients meeting DSM-IV early insomnia criteria and a 1-week sleep diary (subjective) A polygraph meter (objective) assessment and a local brain glucose metabolism assessment during NREM sleep were performed. Both subjective and objective WASO positively correlated with cerebral glucose metabolism for NREM sleep in the pontine and thalamocortical systems in frontal, frontotemporal and anterior zonal distribution. These effects can be attributed to increased wake activity during sleep and / or higher cognitive process activity associated with goal-directed behavior, contradiction monitoring, emotion recognition, anxiety and fear. These processes are thought to be regulated by prefrontal cortex activity. Medical devices that promote a decrease in the relative metabolism of the normal prefrontal cortex during sleep can benefit insomnia patients.

  As described above, cerebral cryotherapy has been used in other medical fields as a means for reducing the metabolic activity of the brain. Theoretical model suggests that applying a cooling stimulus to the scalp surface cools the underlying surface cortex and subsequently reduces metabolism in this area. These observations indicate that a medical device that provides local cooling to the scalp above the prefrontal cortex area reduces the hypermetabolism of this area in patients with insomnia, making it easier for insomnia patients to transition to sleep and then It increased the possibility of making it possible to acquire a peaceful sleep at night. It is also believed that these cortical effects can provide downstream effects of sleep / wake regulation on the brainstem and hypothalamic center.

  The device was configured to test the application of hypothermia to the skin on the prefrontal cortex as a method of treating insomnia and sleep related phenomena. Programmable to supply the device itself with a custom sized headpiece that circulates fluids of various temperatures and that fits the scalp area on the frontal cortex and power to provide cooling and fluid circulation to the headpiece A cooling chamber / pump was included. A test was performed to determine if the device reduced brain metabolism in the prefrontal cortex of insomnia patients. This test compared aggressive treatment (14 ° C. device) with a normal temperature control device (control). Results assessment included local brain metabolism during sleep as measured by [18F] -FDG PET. 148 subjects were screened, 12 completed the sleep test and 8 completed all PET imaging tests. Data showed that this device reduced cerebral metabolism, particularly in the underlying prefrontal cortex. Some of the test results shown in FIGS. 8A and 8B include a decrease in total brain metabolism, particularly a decrease in relative local metabolism in the prefrontal cortex (highlighted area in FIG. 8B), and wearing the device for 60 minutes before going to bed. There is a trend towards increased sleepiness and decreased arousal, decreased arousal fraction, increased EEG delta spectral power, and decreased core temperature before and after sleep onset (FIG. 8A).

  9A to 9F show some of the further test results of this test. In the following, the examination used to achieve these results and the design parameters of this examination will be described in more detail.

  Surprisingly, 9 out of 12 (75%) insomnia patients report the positive subjective effect of the device. All subjects encouraged further development of the device based on their experiences, and all subjects readily understood / accepted their insomnia treatment concept. From the subject, (1) the device is clearly preferred over the drug, (2) the device reduces the pre-sleep illness, (3) the device makes it easier to maintain sleep, and (4) the morning when it wakes up (5) There was a report that refreshment was obtained by sleeping.

  As shown in FIG. 9A, the subjective arousal of patients treated with frontal / prefrontal hypothermia decreased while the device was worn before going to bed. In FIG. 9A, the x-axis represents 60 minutes before the subject goes to bed after wearing the device. The y-axis represents the subjective arousal rating measured in 15 minute increments until the patient goes to bed (0 = no wakefulness, 3 = maximum wakefulness). FIG. 9B shows actual machine conditions in a patient with primary insomnia (wearing a device of 14 degrees C for 60 minutes before going to bed and continuing to sleep until 20 to 40 minutes after going to sleep). Whole brain measured by PET scan during NREM sleep between two conditions: a control condition (wearing a 30 degree C device at room temperature for a minute and continuing to sleep until the measurement time 20 to 40 minutes after falling asleep) It is a graph which shows the fall of metabolism. FIG. 9C is a graph showing the increase in subjective sleepiness of insomnia patients treated using prefrontal hypothermia. In FIG. 9C, the x-axis represents 60 minutes before the subject goes to bed after wearing the device. The y-axis represents a subjective assessment of sleepiness measured in 15 minute increments (0 = no sleepiness, 3 = maximum sleepiness). FIG. 9D shows actual machine conditions (wearing a 14 ° C device for 60 minutes before going to bed and continuing for 40 minutes during sleep) in a patient with primary insomnia, and 30 ° C. for 60 minutes before going to bed. FIG. 6 is a graph showing the decrease in wakefulness after sleep onset for the first 40 minutes of sleep during two conditions, control conditions (wearing device C and continuing for 40 minutes during sleep). FIG. 9E shows the actual conditions in a patient with primary insomnia (wearing a 14 degree C device for 60 minutes before going to bed and continuing to sleep until the end of measurement at 40 minutes) and (for 60 minutes before going to bed) Automatic EEG delta power (y) during the first 40 minutes of NREM sleep between two conditions: a control condition (wearing a room temperature 30 degree C device and continuing to sleep until the end of the measurement at 40 minutes) It is a graph which shows the increase in (axis). FIG. 9F shows actual machine conditions in patients with primary insomnia (wearing a device at 14 degrees C for 60 minutes before going to bed and continuing to sleep until the point of PET measurement 20 to 40 minutes after falling asleep); Localized during NREM sleep between two conditions: a control condition (wearing a 30 degree C device at room temperature for 60 minutes before going to bed and continuing during sleep until 20-40 minutes after sleep) The comparison result of brain metabolism is shown. The brain region highlighted in blue on two different brain cross sections shows the brain region where metabolism is greatly reduced compared to the actual machine condition and the control condition, particularly the frontal cortex below the region where the device is placed.

  Further tests were performed to determine the tolerability and effectiveness of medical devices that were subjected to frontal hypothermia over an extended period of time (eg, overnight) to treat insomnia. These tests were also conducted to define specific thermal energy transfer parameters related to cure.

  Subjective and objective sleep measures and tolerability of middle-aged insomnia patients were collected across four frontal hypothermia intervention conditions. These conditions were: (1) “no device” control, (2) “room temperature” 30 ° C., 7 gallon flow rate device, (3) 22 ° C., 7 gallon flow rate device, (4 ) Including two active “dose” and one neutral “dose” frontal cooling device temperature settings, such as a device at 14 ° C. and a flow rate of 7 gallons per hour, and a control without device. Based on the flow rate of the active dose, heat energy is removed from the forehead with a heat transfer rate of 10-25 W (electric power). 10A and 10B show the surface area of the applicator (eg, head piece) of the experimental apparatus.

  Twelve insomnia patients participated in this examination. Each intervention was applied over a two-night period separated by at least two nights of uninterrupted sleep at home. The order of presentation of conditions was randomized across subjects to control adaptation and take effect from one condition to the next. Key selection criteria included DSM-IV primary insomnia diagnosis, ages 18-65 years (the age range includes the most insomnia ages, but may cause the test to be misinterpreted) And minimize the effects of aging on local brain metabolism). Subjects stayed away from alcohol and avoided drugs that could affect sleep. Insomnia was defined according to the “General Insomnia Criteria” described in the International Classification of Sleep Disorders 2nd edition and the “Insomnia Disorder” criteria in the Insomnia Research Diagnostic Criteria. These criteria include at least one associated with (1) difficulty falling asleep, difficulty maintaining sleep, complaining of premature wakefulness or non-restorative sleep, (2) sufficient sleep opportunities, and (3) sleep dissatisfaction. Need evidence of type of daytime dysfunction. We have set a minimum continuation criteria of at least one month and require that sleep dissatisfaction be indicated almost every day, thereby providing “primary insomnia” in the fourth edition of the Classification and Diagnosis Guide for Mental Disorders. ”Was also followed. We needed an insomnia participant score> 14 on the Insomnia Severity Questionnaire to ensure the lowest level of overall severity and comparability with other published data. In addition, the inventors have found that the review and baseline sleep diary of these subjects is 30 minutes at least 50% at night, consistent with the above diagnostic criteria and the recommendations for quantitative insomnia criteria> It was also necessary to show an arousal state after sleep and a sleep efficiency of 85% <.

  Primary exclusion criteria include neuropsychiatry that can affect sleep, brain function or cognition alone, such as DSM-IV mood disorders, anxiety disorders, psychiatric disorders, and current major syndromic mental disorders, including substance use disorders Disease included. Specific exclusion diagnoses included major depressive disorder, dysthymic disorder, bipolar disorder, panic disorder, obsessive compulsive disorder, generalized anxiety disorder, any mental disorder and any current substance use disorder. Subjects with subsyndromic symptoms or disorders in these areas (eg, mild depression, panic attacks with limited symptoms) were not excluded. We did not exclude subjects with single phobia, social anxiety, bulimia or substance use disorders, specific learning disorders or personality disorders. Mental illness was assessed using DSM-IV structural clinical interview criteria (SCID). Other exclusion criteria include severe heart disease, liver disease, kidney disease, endocrine disease (eg, diabetes), blood disease (eg, porphyria or any bleeding disorder), other injuries, unstable medical conditions or impending Surgery, central nervous system disorders (eg, head trauma, seizure disorders, multiple sclerosis, tumors), active peptic ulcers, inflammatory bowel disease and arthritic conditions. Individuals with well-managed health conditions that did not affect sleep or health (eg, well-controlled thyroid disease, asthma or ulcers) were not excluded. We excluded women who were pregnant, breastfeeding, or sexually active but not using effective contraceptive methods. Subjects who met the selection criteria and did not have specific exclusion criteria were subjected to a complete medical history and physical examination performed by a physician assistant and a series of routine tests to exclude unexpected medical conditions . Specific tests included fasting glucose, complete blood counts, liver function tests, serum biochemical tests, thyroid function tests, urinalysis and urine drug screening to investigate hidden sedation use. Other exclusion criteria include irregular sleep schedules, AHI (apnea hypopnea index)> 20 and oxygen hemoglobin desaturation <90% over night from diagnostic sleep tests, to sleep or wakefulness function Use of drugs with known effects (eg, sleeping pills, benzodiacepines, antidepressants, anxiolytics, antipsychotics, antihistamines, decongestants, beta-blockers, corticosteroids) or more than 1 cup of alcohol per day Ingestion of beverages or more than 7 alcoholic beverages per week was included.

  Subjects were asked to report to the sleep lab about 2 to 3 hours prior to normal bedtime (GNT) on 4 separate occasions, each separated by at least 2 days, for 2 nights. Subjects were allowed to leave the sleep laboratory after waking up every morning and then waking up every morning and then returning to the next evening, after checking overnight. When the subjects arrived at the sleep laboratory, the following tests were prepared. The subject first takes a temperature monitoring tablet (to be described later) together with the last beverage. N. Over the next 3 hours. p. After keeping o, water is allowed if necessary for the rest of the examination. The subject wore a belt pack containing a monitoring device to receive the signal from the tablet. As will be described later, electrodes and thermistors were attached to monitor polysomnography, EKG (electrocardiogram) and skin temperature. About 60 minutes before bedtime (GNT), he was seated in a comfortable chair in the sleep laboratory bedroom. At this point, the questionnaire and rating scale (described below) was completed. From the completion of the questionnaire up to 45 minutes before GNT (GNT of the subject without equipment), the technicians ensure that all recording devices are recording the appropriate signal, after which the GNT 45 A temperature control forehead pad (described below) at a temperature of 30 degrees Celsius (normal body temperature) was applied a minute ago (except for the no device condition). After applying the temperature control forehead pad, the technicians would have an endpoint (14 degrees Celsius, or 22 degrees Celsius, or 30 degrees Celsius) that lasts for the rest of the night sleep that is desirable for that night study. Degree). An equilibrium with the desired temperature occurred after 10-15 minutes. The subjects completed the rating scale as defined below every 15 minutes until GNT after the device was applied. After completion of the final rating scale in GNT, subjects were asked to enter bed and were allowed to sleep undisturbed until the normal wake-up time (GMT) with the monitoring electrode and thermistor in place for the rest of the night. At the time of GMT, the recording device and forehead cooling device were removed and the morning questionnaire including the post-sleep assessment was completed, and the subject was allowed free until that day for return.

  In the examination, the temperature dose was randomized. The water bath temperatures for the three device interventions included 14 degrees, 22 degrees and 30 degrees. At a heat transfer rate of 10-25 W (electric power), the flow rate in the mask was 7 gallons per hour. The low temperature (about 14 ° C.) is determined as the limit that the subject feels cold from the cold stimulus but is not unpleasant cold enough to feel uncomfortable. A temperature of 30 ° C. is selected as the “normal temperature”, ie, the temperature that the subject feels neither cold nor warm, and a temperature of 22 ° C. is intermediate between these two to provide one additional temperature range. It is a selection. In order to eliminate any application sequence effects, the sequence of the three temperature conditions of the forehead hypothermic water bath and the no-device conditions were randomized across subjects. Preliminary tests have shown that these temperature ranges are well tolerated and do not involve adverse events.

  In the sleep laboratory, the polysomnography test was monitored every night applying forehead hypothermia or no device. While the subject is sleeping from GNT to GMT, EEG sleep is monitored overnight, and different temperature levels of frontal hypothermia for sleep latency, sleep maintenance and subsequent delta EEG spectral power measures during sleep The effect of was evaluated. The polysomnograph EEG montage for all of these consisted of a single EEG channel (C4 / A1-A2), a bilateral EOG referring to A1-A2, and a hyperbolic otogai EMG. Manual and automatic scoring of EEG was performed with emphasis on EEG spectral power in theta and delta frequency bands as a measure of arousal and sleep depth.

The night sleep montage of the sleep disorder review performed before any other night sleep includes a single EEG channel (C4 / A1-A2), a bilateral EOG referring to A1-A2, and a hyperbolic otogai EMG (muscle Electrocardiogram), single lead EKG (electrocardiogram) and anterior rib EMG. Nasal airflow was monitored by a nasal pressure transducer technique consisting of a standard nasal cannula for O ₂ delivery and attached to a pressure transducer instead of attached to an O ₂ source to detect nose pressure swings. Oral airflow was also recorded using a thermistor placed in front of the mouth. Respiratory effort was recorded by respiratory inductance plethysmography (RIP) using two stretch bands around the thorax and abdomen, each containing an implanted wire coil. As breathing effort changes the outer perimeter of the two chest wall “compartments”, the implanted wire stretches and generates a signal. SpO ₂ was recorded non-invasively by standard methods by pulse oximetry (Ohmmeda, Biox 3700, fastest reaction time).

  Visual sleep stage scoring was also performed. To ensure that scientists maintain consistency over time, the principal investigator performed inter-rater reliability scoring for the visual sleep stage four times a year. Monthly measurement of sleep-phase agreement in time (Epoch-by-epoch aggregation in sleep staging), milled modified k statistics (Fleiss' modified kappa static), intra-class correlation, and absolute percentage of time (absolute percentage) in epochs). The REM and arousal k-statistics have a value of 80> and the intraclass correlation is>. 85, and the percent match is> 90%. Visually scored sleep measures such as sleep latency, sleep time and sleep efficiency were obtained.

  Sleep latency (SL) is the interval between bedtime (GNT) and the first consecutive 10-minute period of stage 2-4 NREM or REM sleep during which the awakening time does not exceed 1 minute. SL is expressed in minutes. Sleep time (TSA) is the total time spent in NREM sleep or all stages of REM sleep after falling asleep. TSA is expressed in minutes. Sleep efficiency (SE) is the ratio of sleep time to total recording time multiplied by 100. SE is expressed as a percentage (SE = [TSA / TRP] X100).

  The frequency component of sleep EEG was quantified from 0.25 to 50 Hz using power spectrum analysis. Software for spectral analysis of sleep EEG was developed in-house. A modified periodogram is calculated using a non-overlapping 4-second epochs fast Fourier transform (FFT) of sleep EEG. An EEG spectrum for 1 minute is acquired as an average value of a 4-second spectrum that does not include artifacts over a certain period of time. These 1 minute spectra are time aligned with the hand score to allow calculation of the average spectrum over various time intervals (eg, the first NREM period). To further reduce the statistical analysis data, the spectrum can be banded as desired (e.g., to a delta band of 0.5-4 Hz). This software includes an automatic detection routine that eliminates high frequency (primarily muscle) artifacts (Bruuner et al., 1996). The signal processing using power spectrum analysis was completed. Power spectrum analysis was used to quantify EEG power over the entire frequency range. The power of the delta band was used as a dependent measure across the entire program. For example, delta power is thought to reflect a constant sleep impulse that increases exponentially as a function of pre-sleep awakening, decreases exponentially during the development of NREM sleep, and decreases as a function of aging and many sleep disorders. It is done. Delta power is expressed as micro V2 / Hz in the frequency range of 0.25 to 4.0 Hz during NREM sleep.

The temperature applicator (head piece) in this example is temperature-controlled by controlling the temperature of the circulating fluid (H ₂ O in this example). The temperature of the internal fluid was monitored and adjusted in a water tank connected to the headpiece by a tube. This temperature was monitored by a water bath and converted to a signal recorded on a polygraph.

  The temperature of the subject was measured by a temperature evaluation tablet (Vitalsense® system) that was swallowed to record the core temperature continuously throughout the night study in the sleep laboratory. The tablet was measured for core temperature using a small wireless transmitter, and information was transmitted to the belt pack worn by the subject. The tablets that passed through the subject's body were not digested and were then discharged with defecation. This device is recognized as safe by the US Food and Drug Administration (FDA) [510 (k) number K033534]. Each night, the system was checked for an activity signal indicating that no tablets were passing. If no signal was detected, a new tablet was started and swallowed. Using a thermistor, before and during the application of frontal hypothermia, (1) the frontal scalp below the pad, (2) the occipital scalp, and (3) the skin temperature of the back of the hand opposite to the dominant hand Recorded. The thermistor also measured ambient room temperature before and during application of the frontal hypothermia method.

  As described above, in this examination, a temperature control device specifically designed to apply the forehead hypothermia method was included in the present application in the device to which the forehead hypothermia method was applied. This custom cooling device circulated temperature-controlled water and pumped it from a water tank to a pad on the patient's forehead. This pad is custom-made from two sheet-like vinyl sheets so as to cover a target area on the frontal region that overlaps the prefrontal cortex. The remaining head was exposed except for the thin nylon spandex cap that held the tube in place with the pad secured. In this exemplary system, a thin layer of hydrogel between the skin and the pad increases thermal conductivity and holds the pad in contact with the forehead with minimal voids.

  The equipment used in this test included a circulating programmable laboratory water tank (eg, Polyscience: Polyscience Programmable Model 9112). The system was programmable. The headpiece included a custom shaped vinyl laminate (see FIG. 10A) produced to have a defined flow pattern and a boundary that matched the surface area of the head to be cooled. A hydrogel adhesive can be used to hold the pad in close contact with the forehead without applying excessive pressure. Adhesives can also increase the surface area in contact and provide a highly efficient heat conducting surface.

  In this example, the temperature applicator of the headpiece 400 was used with a holding device (not shown) to hold the temperature applicator on the subject's head. In this example, the head holder was a thin nylon spandex cap that was placed over the laminate to keep the laminate in position on the head before and during sleep. Applicator 400 includes a heat transfer region (surface 402) configured to be worn in contact with a patient's head. As noted above, an adhesive (eg, hydrogel, not shown) can be included to help form a thermal contact with the forehead. The applicator 400 shown in FIG. 4 includes a channel 405 through which the cooled (cooling) heat transfer liquid travels, and in this example includes an inlet 407 and an outlet 409 to pump the heat transfer fluid through the applicator. Can do. In this example, the applicator also includes at least one sensor 411 that includes a thermistor that monitors the temperature of the applicator, and this information can be fed back to a system that regulates the temperature of the applicator.

  In this analysis, the differences in sleep between insomnia and non-insomnia persons were tested over a range of activation and control temperatures for forehead hypothermia in a within-subject plan determined in random order. The main population difference analyzed was an in-subject interventional test comparing insomnia patients across various therapeutic interventions. Multivariate covariance analysis is a hybrid method used to compare multiple measures between populations while controlling known covariates such as age and gender. An iterative domain has been added to the model that examines the difference in measures across therapeutic interventions. Test these results to see if there is a linear effect on water circulating at the same flow rate using the same heat transfer pad covering the forehead to normal temperature, 22 ° C, 14 ° C. did. The graphical results displayed in FIGS. 11A-11L show the relationship with standard sleep by showing data for historical control subjects with matching age and gender.

  Twelve primary insomnia subjects examined (9 women / 3 men, 44.62 + 12.5 years average age + sd) were compared to 12 healthy historically matched age and gender When compared to control subjects, the results have a significant impact on hypothermia therapy, especially at low temperatures (close to the 14 ° C. parameter). The graphs shown in FIGS. 11A-11L also show a comparison to the normative measure of healthy control subjects tested in the same laboratory environment.

  These results indicate that the thermal effect (hypothermic effect) applied non-invasively to the skin of the subject adjacent to the prefrontal cortex has a temperature-dependent effect. This effect can also be time-dependent in applying treatment over a period of time before GNT and for a period of time after GNT, including the whole night or part of the night during sleep. Hereinafter, these effects and parameters will be shown.

  For example, the system typically has a temperature (eg, typically about 10 ° C. such as 14 ° C.) that is not perceived as unpleasantly cold (non-invasively) in the patient's skin above (adjacent) the prefrontal cortex. Apply hypothermia over a long period of time (> ° C). Normally, this therapy shortens the time to sleep as shown in FIG. 11A. In FIG. 11A, the sleep time of insomnia patients who received cooling (both moderate cooling at 22 ° C. and maximum cooling at 14 ° C.) was significantly shorter than untreated subjects. This effect seems to be temperature-dependent, and sleep was quicker when cooled significantly at 14 ° C. (“maximum cooling”).

  In addition to helping insomnia patients to fall asleep quickly, the system also improved and extended sleep time as shown in FIGS. 11B-11E, and this effect was also temperature dependent. For example, hypothermia also reduces awakening after falling asleep, and in FIGS. 11B, 11C, and 11D, the time that an insomnia patient woke up after falling asleep is within normal controls, especially in the first half of the night, as shown in FIG. 11C. Declined. This preparatory work is less definitive than the latter half in terms of the effect in the first half of the night, but it is sufficiently effective to perform hypothermia therapy for at least the first half of the night (for example, the expected sleep period) for about 2 to 6 hours, for example. This suggests that the effect diminishes beyond this point. Alternatively, it may be beneficial to change the applied temperature up or down later in sleep to further regulate the patient's sleep.

  Hypothermia increased total sleep time (as shown in FIG. 11E) and increased overall sleep efficiency to within the “normal” range (FIG. 11F). In addition, as shown in FIGS. 11G to 11I, hypothermia therapy shifts the EEG sleep stage to a deeper sleep stage. Also, in these experiments, hypothermia increases slow wave sleep toward health levels (FIGS. 11J-11L).

  The above effects appear to be dose-dependent, especially during the early application period (eg sleep onset and early maintenance), and the level of improvement increases from ambient temperature to 22 degrees Celsius and 14 degrees Celsius. Thus, depending on the type of sleep desired, the sleep can be characteristically altered by changing the temperature in a controlled manner over night sleep. Changing the temperature can also reduce system power requirements. The temperature algorithm can also be fine-tuned in real time using feedback that conveys information about the type of sleep achieved.

Devices and Systems This document describes various devices and systems that provide hypothermia therapy to the skin on the prefrontal cortex. In general, these devices include at least one heat transfer region (eg, a heat transfer pad) configured to cool the skin on the prefrontal cortex.

  This heat transfer region can be of any suitable configuration, more particularly described in detail below. For example, the heat transfer pad can be shaped to cover the frontal region on the frontal cortex of the brain. As mentioned above, the frontal cortex is considered important to provide a recovering aspect of sleep based on sleep deprivation tests. After sleep deprivation, the correlation between the amount of slow wave sleep and the constant sleep function increases in recovery sleep. The slow wave increase is locally maximized in the frontal cortex. The frontal cortex has also been shown to show a greater reduction in metabolic activity during night recovery sleep after sleep deprivation than normal sleep. Cognitive impairment related to sleep deprivation has been observed in areas that appear to be related to frontal cortical function. In brain imaging and the EEG sleep study described above, when cooling stimulation is applied to the frontal cortex with the same shape as that of the frontal cortex, the metabolic activity of the underlying frontal cortex is reduced, which is the slow wave sleep of insomnia patients. It has been shown to be associated with increased, reduced sleep latency, decreased awakening after sleep, and increased nighttime sleep. Finally, insomnia patients have been shown to have high whole brain and frontal cortex metabolism during sleep in relation to their tendency to wake up during nighttime sleep.

  In some forms, the heat transfer area may be part of a mask, clothing or other device that directs heat transfer to the scalp area on the frontal cortex to aid in sleep. In some forms, the heat transfer area is limited to cover all or part of the frontal cortex. Thus, in some forms, the system is configured to limit the heat transfer area to the skin area (eg, the forehead).

  In some forms, the shape of the heat transfer area (e.g., pad) minimizes overlap with the hairline of the individual wearing the pad so as to minimize hairstyle / pattern disturbances over night sleep. It is a special order shape. In this configuration, this shape maximizes the uncovered skin area available to minimize interaction with the hairstyle.

  The heat transfer area can be temperature controlled by any suitable mechanism including air cooling or water cooling and solid cooling (eg, Peltier elements), or some combination thereof. In configurations where the thermovoltage region is a fluid (eg, water or other coolant), the system can include a coolant container that can be placed separately from the rest of the device. For example, a mask or high temperature applicator (including a heat transfer area that contacts the patient's skin on the prefrontal cortex area) can be connected to the coolant container by a tube. This coolant can be pumped into the heat transfer area to cool the skin and thus hypothermia can be applied to the prefrontal cortex. In general, any suitable method can be used to cool the heat transfer region, including non-fluidic or non-thermoelectric methods. For example, the heat transfer region may be cooled by gas, or fluid / gas phase change, or other chemical endothermic reactions.

  In a form including a tube, the tube can be arranged so that comfort during sleep is optimized. For example, in some configurations, the heat transfer fluid does not interfere with the patient's sleep when the patient is sleeping with the device on his / her head, or is not at risk of getting entangled in the patient's head or neck. The tube leading to the mask can be configured to be connected away from the patient. In some forms, the heat transfer area is connected to the coolant source by an inlet / outlet tube that emerges from the center of the mask or applicator frontal area. People tend to sleep sideways or on their back with their temporal and occipital heads in contact with the bed surface or pillow.

  Alternatively, in some forms, any inlet / outlet tube can extend from the top of the mask and be useful when people sleep with their face down. The tube can be formed to pivot, bend, rotate, or flex with respect to the mask. For example, the joint between the applicator and the tube can be made flexible as a rotating and / or pivoting joint (particularly compared to the harder applicator and the surrounding tube region).

  The heat transfer area can be connected and held on the patient's head in any suitable manner. Similarly, any tube extending from the applicator can be fixed or held so that it extends to the top of the head and out of the center of the head. In general, the top of the head does not contact the bed surface or pillow, so other configurations of the connector and tube can also cover the front and exit the top of the head. In another configuration, the inlet / outlet tube exiting beyond the side covering the temple is shaped or configured to traverse from around the ear to the back of the head. Thus, in one configuration, the tube and connector cross across the back of the head from the top of the temple and around the ear. In this configuration, any tube and connector can be made relatively flat so as to minimize discomfort when the head rests on the tube and connector during sleep. The tube can also be configured so that it does not limit heat transfer due to leakage or collapse. Finally, the tube can also be insulated.

  The system described herein can be configured to be worn by a subject every night and can thus include a washable, disposable or replaceable skin contact area. In some forms, the entire applicator is disposable, while in other forms, only a portion is disposable. For example, the heat transfer area can be covered with a disposable material or cover that can be changed nightly for every use. Generally, this disposable area (eg, cover) is adapted to transfer heat in whole or in part so that the heat transfer area can effectively apply hypothermia therapy to the skin on the frontal cortex. In some forms, the cover is configured as a disposable biogel cover.

  In some forms, the side tube is integrated with one or more applicator securing straps that extend around the back of the head. Both of these forms utilize a strap to hold the mask on the head and integrate the tube and connector into the strap to minimize extra tube / connector / material from the mask. be able to.

  In some forms, the system includes a chin strap that helps prevent the cap from rising from the top of the head. In this configuration, pieces of material emerge from both sides of the mask and wrap under the wearer's chin. The purpose is to prevent mask withdrawal from the top of the head that can occur during posture changes over night sleep. In some configurations, strapping on the front of the applicator can be used to facilitate adjustment and minimize interference with the back of the head resting on the pillow. Fasteners or fasteners include anything that minimizes any bulkiness of the mask or strap area that can cause discomfort, such as Velcro, adhesives, snaps, and other types of fasteners Any suitable material can be used. In one example, there are fasteners in the frontal region that do not interfere with the comfort of the mask when the head is laid on the bed surface.

  In some forms, the system generally has one or more molds that approximate the forehead shape to a similarly sized forehead, and a specific forehead molding tailored to the individual's unique head size. Can be included. For example, the material used for the mask can be specifically shaped to match the general shape of the head, and more specifically can be shaped for each individual who uses the mask to help sleep. it can. In general, the heat transfer region can have a surface configured to maximize the surface contact of the heat transfer region to the head surface (skin) to increase the efficiency of heat transfer to the underlying cortex. This configuration can be temporarily molded to surface features after any permanent means such as using a non- malleable material to create a fixed size mold, or any malleable material placed on the head. This can be done by any means possible. One example is any form of expandable material having a gas or fluid filled cavity that can be expanded or expanded to match the shape of the underlying head, foam or shape memory material, etc. Can do.

  For example, in some forms, the applicator includes one or more injection / vacuum chambers incorporated into the cap to enhance comfort and increase surface contact to maximize heat transfer. An implantation or vacuum chamber can be incorporated into the mask and expanded or contracted to form a mask material that conforms to the head shape. After placing the mask on the head, remove the fluid or gas from the chamber on the back of the mask, or inject the fluid or gas into some outer layer to bring the mask into close contact with the skin, giving a natural curvature of the forehead This can form an adhesive seal that allows the mask to remain on the head. In one form, the applicator (eg, mask) has a strapless design that uses only the forehead shape to maintain the position of the applicator using an injection / vacuum chamber and / or an adhesive material. In this configuration, the adhesive material, or some form of temporary adhesion caused by some combination of expansion / contraction or temporary malleability of some material in the mask, can be further strapped to hold the mask in place or It can serve the purpose of securing the mask without the need for a cover. This strapless configuration of the applicator can increase comfort so that no material enters between the temporal and occipital regions when some sleeping individuals are sleeping sideways.

  In some forms, an integrated eyepad that blocks light and / or further cools the orbitofrontal cortex to reduce metabolism of the orbitofrontal cortex before and during sleep can be included.

  In another configuration, in addition to covering the head region on the frontal cortex, a mask can be formed such that additional material extends downward to cover the orbit above the eye. This material can serve multiple functions. First, the material can incorporate a heat transfer material so that the orbit is cooled for the purpose of cooling the underlying orbital frontal cortex to promote metabolic degradation of the frontal cortex area that promotes sleep. Another function of this material is to block visual sensory stimuli that can interfere with sleep given the effects of known light on brain arousal. Another function of this material can be to provide a relaxing, stress and anxiety reducing effect caused by the sensation that the heat transfer in the head region is cooled. This in itself can promote sleep in addition to the effects on the underlying brain metabolism. In some forms, the applicator can include insulation around the heat transfer area to prevent cooling of adjacent areas (including the eye sockets) that can be unwanted and uncomfortable.

  In some forms, the device may include an integrated earpad option that blocks noise and / or provides audio input during sleep. For example, in addition to covering the head region on the frontal cortex, the applicator can be configured such that additional material extends downward to cover the ear. This material can serve multiple functions. First, this material transfers heat so that the ear cavity, ear canal, and ear canal are cooled with the goal of cooling the underlying orbital frontal cortex to help reduce metabolism in the frontal cortex area that promotes sleep. Material can be incorporated. Alternatively or in addition, the material can block auditory sensory stimuli that may interfere with sleep given the effects of known sounds on brain arousal and / or the head It can have a relaxing effect, stress and anxiety reducing effect caused by the sense that the heat transfer in the region is cooled. This can promote sleep in addition to the underlying effect on brain metabolism.

  In some forms, the applicator provides thermal stimulation to the carotid artery to cool the brain before and during sleep to improve sleep quality by reducing brain metabolism before and during sleep An integrated neck pad can be included (or configured to be used with the integrated neck pad). In the neck, multiple arteries run near the surface of the neck skin. In another configuration, in addition to covering the head region on the frontal cortex, the mask can be configured such that additional material extends downward to cover the neck. This material can serve multiple functions. First, this material uses a heat transfer material that cools the neck to cool down the arteries that supply blood to the entire brain, thereby helping to reduce overall brain metabolism that promotes sleep. Can be incorporated. Another function of this material can be to provide a relaxing, stress and anxiety reducing effect caused by the sensation that the heat transfer in the head region is cooled.

  In another configuration, in addition to covering the head region on the frontal cortex, the mask can be formed such that additional material extends downward to cover the side and back necks. This additional material ensures that the cervix is cooled with the aim of cooling the underlying brain areas such as the brainstem, cerebellum, and occipital cortex to promote a decrease in metabolism of these brain areas that can promote sleep. A heat transfer material can be incorporated. This material can also provide a relaxing, stress and anxiety reducing effect caused by the sense that the heat transfer in this head region is cooled. This in itself can promote sleep in addition to the effects on the underlying brain metabolism.

  In some forms, the system may be configured to provide cooling stimulation to the nasal cavity / oropharynx before and during sleep for the purpose of cooling / reducing brain stem / hypothalamic metabolic activity to promote sleep. it can. For example, in another configuration, by cooling the brain regions underneath the brain stem, hypothalamus, orbitofrontal cortex, etc., to promote a decrease in metabolism of these brain regions that can promote sleep, the nasal region / throat And methods that provide heat transfer to the oropharyngeal region deep in the nasal passages can be applied.

  In general, these devices and systems can be used in combination with any other device intended to be worn by a sleeping patient (and can be integrated as part of such a device). ). For example, a respiratory treatment device (eg, ventilator, oxygen inhaler, CPAP machine, etc.) may include an integrated cooling system that helps improve sleep and / or treats sleep disorders as described herein. it can.

  As discussed above, in general, the systems described herein can include one or more sensors for monitoring one or both of a patient and a system component (eg, a heat transfer region). In some forms, the system is configured to measure various parameters on the applicator, including temperature sensors (measuring skin temperature) or electrodes (eg, measuring EEG parameters). The system can be configured to provide feedback to the patient / physician and / or to provide feedback to the system (eg, a controller) to modify system activity.

  Also, in some forms, the systems and devices described herein can include additional therapies or non-therapies that can improve comfort, relaxation, and / or sleep. For example, the systems described herein can include one or more vibrational motions or mechanisms that cause vibration / rhythm / motion sensations on the skin. In one configuration of the device, it can promote sleep and / or create relaxation, anxiety or stress reduction purposes, which can enhance sleep and other effects of the device as noted elsewhere. Can create physical sensations. For example, physical turbulence in the fluid channel can be permitted or generated. In this device configuration, the direction and movement of the fluid in the channel of the heat transfer pad can promote a positive device sensation for the wearer, soothing effect, relaxation effect, sedation effect, stress reduction effect, massage-like Configured to have an effect. Similarly, rhythmic changes in fluid pump pressure can be optimized for comfort, comfort and massage sensation. In this device configuration, various configurations that alternate the pressure cycle in the pump can change the direction and movement of the fluid in the channel of the heat transfer pad, thereby creating a positive device sensation for the wearer. It can bring about a soothing, relaxing, sedative, stress-reducing, and massage-like effect.

  In some forms, the system can include an odor or scent stimulation to help improve comfort and / or effectiveness. For example, the addition of aroma can be subjectively coordinated with relaxation / sleep. With this device configuration, by changing the odor of the heat transfer pad with various scents, it can promote a positive device sensation for the wearer, soothing effect, relaxation effect, sedation effect, stress reduction effect, massage It can bring about an effect.

  As mentioned above, the system can include direct or indirect acoustic modulation when using the device. In general, the system can produce a sound that is subjectively in harmony with relaxation / sleep (even as part of the applicator or as part of a neighboring device, even if it does not include earphones / headphones, etc.). This device configuration promotes a positive device sensation for the wearer by adding sound to the heat transfer pad or to a remote device that connects to the heat transfer pad (for devices with a remote coolant source). Can provide a pleasant effect, relaxing effect, sedation effect, stress reduction effect, massage-like effect. As described above, the device can include an ear pad or plug integrated with the heat transfer pad to block unwanted environmental noise that can interfere with sleep. In another form of the device, the system can be configured to offset various intermittent noises in the sleeping individual's environment by emitting white noise or block noise.

Controllers Any of the systems described herein can include a controller that provides hypothermia therapy by adjusting the temperature of the heat transfer area. In general, this controller (which can also be called a hypothermic controller) can control both the application temperature and its timing (or time course). Typically, the controller can be configured to apply one or more temperatures to the heat transfer area over a predetermined period of time, including following one or more time courses of applying cooling. The controller can include a plurality of inputs including user selectable inputs (timing, on / off control, etc.) and feedback (eg, from the skin surface or other system feedback described below).

  The dose or time course for activation can be referred to as a sleep heat transfer timeline or algorithm. For example, in some forms, the system is configured to provide a constant time course. In one configuration, a consistent heat transfer rate can be maintained without variation over the period of use. For example, the system can be configured to administer a dose only before sleep. In one configuration, the heat transfer applicator can apply the treatment for 45 minutes to 1 hour before going to bed to facilitate the sleep process. For example, the system can be configured to cool the heat transfer area to about 14 ° C. to promote sleep falling, and this temperature can be higher (eg, up to 30 ° C.) based on patient comfort. It can be adjusted or kept at a constant temperature. Similarly, the system can be configured to drop to a final temperature (eg, 10 ° C., 14 ° C., etc.) to acclimate the subject to that temperature. In this application, if only the effect of falling asleep is desired, the device can be removed when a person enters the bed.

  In some forms, the system can be configured or adapted to be used only when the patient is in bed and to operate after the patient sleeps. In one configuration, the applicator can be worn or applied when the patient enters the bed, and hypothermia therapy can be applied over part or all of the nighttime sleep (including the entire nighttime sleep) to facilitate the sleep process. . In this configuration, 14 ° C. or other low temperatures (eg, 10 ° C.) can exert the maximum effect in promoting deep sleep in the first half of the night and weakening the effect in the second half of the night. However, the effect is low at high temperatures.

  In some forms, the system can be configured to apply hypothermia therapy both before the desired sleep time (GNT) and after first falling asleep. For example, in one configuration, the heat transfer pad may be applied 45 minutes to 1 hour before going to bed to promote the sleep process, and may remain applied throughout the night to promote the sleep process over night sleep. it can. Thus, the controller first applies a sleep time course (eg, falls to a sleep temperature such as about 14 ° C. and maintains the temperature for a predetermined period of time, such as 30 minutes to 1 hour), and then (eg, sleep Maintain a temperature at a relatively low temperature such as about 14 ° C. for the first 2-4 hours or the rest of the night or transition to a sleep maintenance time course where the temperature is gradually increased to a higher level) can do. The maintenance time course can maintain deep sleep throughout the night, with less acceleration at higher temperatures of up to 30 ° C.

  Therefore, the time course may be constant depending on the form, or the time course may be variable (including temperature change over the sleep period). For example, in one configuration, a variable heat transfer rate can be provided that defines the change over a period of use. Changes in device temperature are immediately perceived at the skin surface, but there is a delay between when the cooling stimulus is applied to the head surface and when this cooling reaches the underlying cortex. Thus, a variable time course algorithm is built between the point of application and the point at which the desired effect on the temperature sensation on the skin surface, or the desired effect on the underlying brain temperature and the resulting effect on brain metabolism appears. Different delays can be included. In one configuration, a delay of about 30 minutes may be incorporated into the system's variable time course algorithm.

  In some forms, the systems described herein are configured to be used before falling asleep (which can be referred to as a precooler or system). Thus, the device and method of operation can be specifically configured to be worn to increase sleepiness or to reduce a patient's sleep latency. The device can be adapted by including a timing control suitable for pre-sleep cooling as described herein. In some forms, the system can be configured to distinguish between long sleep periods and short sleep periods, for example, can be configured to promote “nap” (short sleep) or long sleep. . In some forms, the system can include a control (and timer) for selecting sleep time and the applied hypothermia can be varied based on the control. In the nap mode, the system initially performs a high level of cooling (eg, from 10 ° C. to 18 ° C.) and after the first period of time it is hot (eg, 24 ° C., or some temperature of about 20-28 ° C.). Or thermally transferred to “room temperature” (for example, about 30 ° C.). In some forms, the system or device is configured as a “nap” device as opposed to a 6-8 hour sleep time device.

  As mentioned above, in some forms, the system includes one or more fall time courses. For example, applying a heat transfer area at room temperature of about 30 ° C. 45 minutes to 1 hour before going to bed, and then adjusting this descending speed to the skin surface comfort level, this temperature is about 14 ° C. in a few minutes (eg, 10-25 [deg.] C.) to promote the sleep process. Similarly, any set temperature can be achieved by first applying the intermediate comfort skin temperature device and then decreasing the temperature over time to achieve the desired final endpoint temperature.

  In some forms, the time course can be changed based on a predetermined value or feedback. For example, a sleep maintenance time course can be applied that can include changing the time course of heat transfer in concert with the probability of occurrence of NREM and REM sleep stages. Brain temperature, as well as cerebral blood flow and metabolism, vary specifically over night sleep and depend on the sleep stage the individual is experiencing and the duration from sleep onset. The NREM sleep phase includes shallow stage 1 sleep, deep stage 2 sleep, and deepest slow wave sleep, with slow wave sleep predominating in the first half of the night. REM sleep occurs periodically every 60 to 90 minutes throughout the night, and a long and strong REM period occurs gradually in the latter half of the night. Brain temperature, cerebral blood flow and cerebral metabolism tend to decrease in deep NREM sleep and increase in REM sleep. The extent to which these changes occur is considered functionally important for sleep. Thus, the cooling device can facilitate deepening of REM sleep by imitating or following a time course of a normal sleep cycle. As a result, the metabolic activity of the frontal cortex decreases, and as a result, slow wave sleep increases.

  Therefore, in one configuration of the variable heat transfer time course, maximum cooling is concentrated early in the night when slow wave sleep is likely to be maximized, and the degree of cooling toward the end of the night when REM sleep and natural brain temperature increase occur. Can be suppressed. Thus, one algorithm (e.g., time course) can be tolerated without discomfort (e.g., about 10 ° C to about 14 ° C at the beginning of the night, rising to an intermediate 30 ° C by the end of night sleep) Heat transfer at the cooling temperature can be included. This increase can be linear throughout the night or have a curve component where maximum cooling is concentrated during periods of high probability of slow wave sleep as revealed by the standard slow wave sleep generation curve throughout the night. You can also.

  For example, some diseases such as depression are known to have characteristic changes in REM sleep. The above dose-finding studies have shown that changing the temperature of the heat transfer mask has a predictable effect on the occurrence of REM sleep. Thus, one algorithm can include variable heat transfer throughout the night that is intended to therapeutically target the occurrence of REM sleep. For example, in depression, where the duration and intensity of REM sleep is likely to be concentrated in the first third of the night, using a time course with a maximum allowable cooling temperature (eg, 14 ° C.) over this period will cause abnormalities. The generation of REM sleep is expected to be suppressed, whereas when room temperature is used in the latter half of the night, the generation of REM sleep in the night portion is expected to approach normal.

  Similarly, REM sleep and NREM sleep changes may also occur in various neuropsychiatric disorders. The general principle of changing the temperature of the heat transfer area of the applicator to promote or diminish deep NREM sleep or individual aspects of REM sleep that are directly associated with a particular disease is the therapeutic utility specific to the disease. It is expected that there will be.

  As briefly mentioned above, the system can include feedback to the controller to adjust the applied hypothermia therapy. Surprisingly, as mentioned above, changing the applied hypothermia has a predictable effect on sleep physiology. Thus, heat transfer can be changed by measuring changes in sleep physiology and incorporating them into a feedback loop. In this way, the amount of heat transfer applied can be adjusted in real time to achieve some desired physiological effect.

  In one configuration, a variable heat transfer rate can be provided over the entire period of use, including prescribed changes associated with feedback from changes in body physiology over the period of use. A physiological measurement can be monitored and heat transfer adjusted in real time according to the level of this physiological measurement. For example, the system may include feedback based on the presence or absence of REM sleep or NREM sleep as assessed by any REM / NREM sleep assessment method such as EEG frequency, heart rate variability, muscle tone or other mechanisms. Thus, the device or system can include one or more sensors (such as electrodes) that provide at least some indication of the sleep cycle, and the controller inputs or monitors this information to detect the detected REM / NREM. The application dose can be adjusted based on the condition of By comparing this recognized condition to the expected or desired condition, the applied hypothermia can be altered.

  In some forms, in addition or alternatively, the system may monitor and / or respond to slow wave sleep depth as measured by EEG wave analysis or other mechanisms. it can. Similarly, the system can monitor and / or respond to the degree of autonomous arousal as measured by HR fluctuations or other mechanisms. Other example features that can be monitored (separately or in combination) to adjust the applied hypothermia and / or can be fed back to the system include electrical skin reaction, skin temperature, eye movements during sleep, and sleep There is total body movement. For example, skin temperature is the skin of the head under the device, or any other head skin not under the device, or peripheral skin temperature, or core (measured internally or by some external means) It can be measured in temperature, or any combination measure that evaluates head and peripheral thermoregulation, or a measure of core temperature versus peripheral temperature. Eye movement or body movement can be monitored optically or through one or more motion sensors or position sensors (including accelerometers).

  In many of the systems and devices described herein, the subject (and / or physician or other professional) wearing the device can adjust the control. In some forms, the person wearing the device can modify the heat transfer rate over the period of use and link this change to subjective feedback. For example, a person wearing a device can control the device to adjust the temperature up or down in some slight increments according to their immediate comfort and treatment needs.

  In another configuration, an individual sets his bedtime and desired wake-up time and inputs a pre-programmed algorithm to start and stop at these times, resulting in a relative incremental adjustment over this time To be able to. These automatic time calculations can be implemented for any variable heat transfer rate schedule over any specified time.

  In general, the skin temperature under the applicator (eg, the heat transfer area of the applicator) can also be monitored. The system and / or apparatus can apply a predetermined temperature to the skin through the applicator, but the skin temperature is not necessarily cooled to this temperature and is typically higher. In some forms, the skin temperature below the heat transfer area can be monitored and / or fed back to the controller to adjust the application temperature. As mentioned above, the thermal contact between the skin and the applicator can be optimized or adjusted. For example, the material forming the applicator (especially the heat transfer area) can be optimized or otherwise selected to determine the application temperature. In one form, the lining of the heat transfer pad that contacts the skin is a hydrogel that can increase the contact surface area and enhance the heat transfer properties. In another configuration, this backing is combined with a dermatological product that can be activated against the skin when contacted through the night. In another configuration, the inner lining can be restored at a low frequency that can have an effect on the skin when applied over night or night sleep.

  The cooling chamber, all tubes and headgear can be stored until the next night use when not in use during the day. In some forms, the device is self-contained (eg, battery operated, especially for solid state devices). Thus, the device can be recharged when not in use. In one configuration, the entire facility can be housed in a storage box that can also be functional (eg, recharge, disinfect, protect, etc.) to make the appearance attractive. In a configuration including a tube, the tube can be automatically stored in a storage area (eg, a box) when not in use to maintain an attractive appearance. In some forms, the applicator is stored with preservatives and / or in an environment that allows sterilization cleaning and sterilization storage to minimize the potential for microbial growth that can harm the wearer. The

  Since the device is intended for night use, the control can be optimized for use in low light environments. Subjects using the device need to operate the device at night when the lighting is expected to be dark, so in some forms the device or system control functions that the individual needs to operate may be Lights only when approaching.

  In another configuration of the device, the control function can be configured at an illumination level that minimally interferes with sleep. In another configuration of the device, the control function can be voice activated. In another configuration of the device, the control function has physical characteristics that can be groped and differentiated from the rest of the device so that the individual can know where the control buttons are located in the dark.

  In general, it is particularly desirable to include one or more features that record (and / or analyze) the use of the device or system. For example, in patient clinical management, a health care provider may wish to know specific parameters of a patient and / or device over multiple night uses so that care can be optimized. In some forms, the system or device includes a memory (eg, a memory card or memory chip) that can automatically record certain parameters and store them for later display by a healthcare provider. . For example, the operation of the controller can be recorded.

  As device users monitor their care, they may wish to know specific parameters of the patient and / or device over multiple night uses so that care can be optimized. Thus, in one configuration of the device, the memory can automatically record certain parameters and store them for later display. By transferring this information to the provider's office or some other central database via telephone or the Internet or some wireless technology, someone can review the information and make recommended treatment adjustments accordingly. it can. Examples of information that can be stored include, but are not limited to, device temperature, skin temperature, core temperature, measure of autonomous variation, sleep depth assessed by NREM sleep, discrete frequency band, REM sleep Or EEG power in other sleep stages, activity and / or wakefulness throughout the night, a subjective measure of sleep depth / comfort / satisfaction, and sleep time.

  In some forms, this information can be collected automatically, and in other forms can be entered by the subject or a third party.

Indices and Methods of Operation As noted above, the systems and devices described herein can generally be used to treat sleep disorders. In particular, these systems and methods can be used to treat insomnia. Thus, the systems and devices described herein can be used to promote sleep. For example, the systems and devices described herein can be used to reduce sleep latency (eg, time to fall asleep) and / or increase sleep time.

  In operation, a method of adjusting sleep (eg, increasing sleep time) is a region of the frontal cortex and (in some forms) of the frontal cortex of the subject's frontal or scalp (which may also be referred to as a patient). Positioning and / or securing the heat transfer region within the region covering the substrate. The system or device can then apply hypothermia therapy (eg, cooling) to the skin to reduce metabolic activity in the underlying frontal cortex and related areas, thereby promoting or regulating sleep.

  As noted above, in some forms, the system and device can be applied prior to sleep to aid in falling asleep. For example, the system may apply the heat transfer area to the skin on the prefrontal area for a period of time (eg, 15 minutes, 30 minutes, 45 minutes, 60 minutes, etc.) prior to the desired bedtime (GNT, the desired time to sleep). Applying in contact can be included. Local hypothermia can be used alone or in conjunction with other relaxation and / or pre-sleep treatments to increase sleepiness and reduce sleep latency.

  In some forms, usage includes (but is not limited to) methods of increasing slow wave sleep over the night, methods of increasing sleep maintenance, methods of reducing wakefulness, and / or methods of increasing sleep time. Can do. In general, each of these methods can include placing an applicator in contact (including a heat transfer area) in contact to transfer heat energy from the skin on the subject's prefrontal cortex. The system can then execute a treatment plan that includes cooling the subject to a temperature, such as a minimum temperature that can be tolerated without discomfort (including arousal) such as pain or tissue damage. Typically, this temperature can be about 10 ° C to about 25 ° C (eg, 11 ° C, 12 ° C, 13 ° C, 14 ° C, 15 ° C, 16 ° C, etc.). The temperature can be decreased slowly (eg, with a slope such as a linear slope) or more quickly. The treatment plan maintains this first target temperature for a first period (in some examples, it may be a predetermined period such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, etc.) Or can be determined based on patient feedback and / or control settings. Thereafter, the temperature can be raised and / or lowered in one or a series of dose settings. In some forms, this dose follows a predetermined treatment parameter that raises the temperature from a low value initially to a slightly higher temperature late at night to help maintain sleep.

  Although any of the methods described herein can be used to treat insomnia, these methods can generally be used to improve healthy sleep even in non-insomnia subjects. Among other things, these methods, devices and systems can be used to improve sleep of individuals who are experiencing insomnia.

  Further, the systems and devices described herein include, but are not limited to, depression, mood disorders, anxiety disorders, drug abuse, post-traumatic stress disorder, mental disorders, manic depression, personality disorders, and It can also be used as part of a method for treating and improving sleep in individuals suffering from neuropsychiatric disorders, such as any neuropsychiatric patient feeling insomnia.

  Sleep time shortening and sleep disorders have been found to be associated as comorbidities in multiple diseases, and thus the devices and systems described herein can be used in this way by partially helping to regulate and improve sleep. Can be used to help alleviate various diseases. For example, the devices and systems described herein may be used to improve sleep in patients with symptoms including pain including chronic pain, headache including migraine, heart disease, endocrine disease, lung disease and tinnitus. Can do.

  The system and apparatus can also be used with awake subjects to enhance relaxation and improve awake function. This treatment plan can be similar to or different from the treatment plan used to improve sleep and / or prolong sleep. For example, the devices and systems described herein reduce the experience and distress of tinnitus and chronic pain, increase mental and cognitive concentration, provide subjective relaxation, provide subjective relief, Awakening, including providing comfort, reducing subjective stress, improving mood for depressed patients, reducing fear, anxiety, suppressing anxiety, and / or suppressing obsession and behavior Can be used to improve arousal function by reducing metabolic activity of the frontal cortex.

  In such non-sleep forms, it may be useful to allow subject control of the system including subject duration control and level of cooling applied. In some forms, predetermined settings for different applications may be included as part of the system.

  Other applications of the systems and devices described herein include body temperature regulation and fever mitigation. These devices and systems can be used to relieve systemic fever and, in particular, can be used to control fever in individuals whose core temperature has risen due to various causes, including but not limited to infections. it can. In some forms, the systems and devices described herein are used in conjunction with (or incorporate) a system for phototherapy of circadian rhythm disorder (“CRD”). Can be configured.

  Also, the devices and systems described herein can be used to change circadian rhythms, and thus in circadian rhythm disorders such as shift work disorders, phase advance and phase delay circadian rhythm disorders. It can also be applied to use.

  Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will depart from the scope of the appended claims or spirit in light of the teachings of the invention. It will be readily apparent that several variations and modifications can be made to the invention.

Clinical cases-parasympathetic modulation Devices designed to specifically cool the frontal region described herein, the specific temperatures at which these devices can be used, and temperature ranges to improve patient sleep And the beneficial effects of these devices (systems, devices, etc.) on the temperature profile have been shown to be effective in treating insomnia patients as part of a large clinical trial.

  As described above, forehead cooling can provide an indirect pathway towards activation of the parasympathetic nervous system that can promote sleep. A medical device that provides local cooling to the scalp on the forehead improves sleep of insomnia patients and allows easy transition to sleep and subsequent acquisition of restful sleep throughout the night.

  Tests were performed to determine if the device improved sleep in insomnia patients.

Clinical Examinations We completed a 116-subject randomized, multi-center, sham-controlled trial conducted at seven clinical sites in the United States. The test showed an excellent safety profile with only 5 adverse events (AEs) in the treatment group. None of the AEs are serious and only AEs for the three headaches are described in the sleep system described herein (for convenience, it can be referred to as “Cereve sleep system” or simply “sleep system”). “Probably” or “possibly” related.

  As a priori definition, a co-primary efficacy analysis was performed on the ITT population of 106 subjects. The purpose of the primary efficacy analysis was to determine the absolute difference between the treatment groups in the two common primary endpoint measures co-primary endpoint measurements persistent sleep latency (time to sleep start for the first 10 minutes). And it was to evaluate by sleep efficiency. In order to expand the interpretation of the primary analyses, these primary analyzes were supplemented by a secondary analysis on additional populations and associated endpoint measures. To consider the clinical trial successful, one of the common primary endpoints had to be achieved. A significance level of α = 0.025 was used for each individual test to control the diversity of performing two tests simultaneously.

  The primary test that supports this application is a multicenter predictive, blinded, randomized, parallel study that compares treatment with a sleep system at a temperature of 14-16 ° C. and a camouflaged device in 116 insomnia subjects. prospective, blinded, randomized parallel study). A temperature of 14-16 ° C. is consistent with a temperature range known to stimulate parasympathetic responses. This test demonstrated that a temperature of 14-16 ° C. is safer and more effective than a camouflaged device.

  This study was designed as a multicenter, predictive, blinded, randomized, parallel study that compares sleep system treatment with camouflaged devices in patients with primary insomnia. After completion of a two-night reference PSG (polysomnographically recorded) sleep, either a sleep system with a temperature of 14-16 ° C. or a disguised device consisting of an inoperable sleep system device (“Vestibular Sleep System”) The subjects were randomly sampled to receive additional two night PSG sleep tests in parallel. As explained further below, the subject has not been informed that the device is inoperable, and this data demonstrates that the subject is effectively unaware of the treatment. All 116 subjects were enrolled in 7 trial sites (58 active treatments and 58 camouflages).

  There were two main endpoints and hypotheses in this test.

  During the polysomnography examination (PSG), sleep latency based on sleep electroencephalogram (EEG) was acquired. In the scientific hypothesis, the decrease in the PSG sleep latency from the reference evaluation to the 14-16 ° C. condition is greater than the decrease from the reference evaluation using the camouflaged vestibular stimulator control.

  Sleep efficiency (total sleep time / time in bed) based on sleep EEG was acquired during PSG. In the scientific hypothesis, the increase in PSG sleep efficiency from the reference evaluation using the 14-16 ° C. condition is greater than the increase from the reference evaluation using the camouflaged vestibular stimulator control.

  Overnight PSG sleep EEG is the ultimate criterion for confirming the effectiveness of hypnotic sedatives. In general, insomnia patients are either unable to fall asleep and / or unable to stay asleep throughout the night. In this area, the sleep latency PSG measure to assess whether the patient's ability to fall asleep in relation to therapeutic intervention has been recognized as an industry standard for assessing this aspect of insomnia. Yes. In this field, the PSG measure of sleep efficiency, defined as total sleep duration over the entire night / time in bed, is recognized as an industry standard for assessing the difficulty of staying asleep throughout the night in patients with insomnia. ing.

Description of camouflage device The camouflage device was called a “vestibular sleep system” and included three components schematically shown in FIG.

  An electrode pad 103 was placed behind the patient's ear to transmit current from the vestibular control box to the patient's vestibular nerve. These are typical pads that are also used for other diagnostic tests in the medical industry. In this test, the device was camouflaged and no current was delivered.

  The vestibular control box (vestibular stimulator) 105 controlled the perceived intensity of the vestibular stimulation through settings 1 to 5 and switched the treatment on / off. The vestibular control box (vestibular stimulator) 105 is a specially designed box configured with a selector switch 106 that can switch the unit on / off and change the perceived intensity of treatment. This control was used to adjust the perceived intensity of vestibular stimuli.

  The recording device 107 was used with an electrode pad and vestibular control box to achieve the same level of noise generation and medical reliability as experienced with a sleep system. For the camouflaged device, the recording device was identical to the clinical unit used in the sleep system, including the operation of a fan that produced the same noise in both devices. The fluid connector of the recording device is fitted with a fluid return tube so that the fluid circulating in the device is the same as that of the sleep system, but this fluid return tube is not connected to the forehead pad, so It was not affected at all by the fluid circulating through. The vestibule control box was connected to the recording device via a serial data line. Note that no data was sent to the recorder and this setting was used to increase the blindness of the examination.

Test Method This test was a multicenter predictive blinded randomized parallel design test. Telephone review was used to exclude people who did not meet the selection / exclusion criteria first. Visit 1 was scheduled for eligible potential subjects based on telephone review assessments who agreed to continue the review process. Informed consent was obtained at the time of clinic visit 1 before any testing related procedures were performed. Subjects who signed consent were considered to participate in the study. Subjects were provided with a one-week sleep diary to be completed at home when determining initial qualifications at Visit 1. This sleep diary had to be completed and returned to the site in 7 consecutive days to determine the qualification to continue based on sleep efficiency. The subject has selected PSG sleep criteria, including the absence of sleep disorders and the presence of insomnia as judged by sleep latency value> 15 and sleep efficiency value <85, if the selection criteria / exclusion criteria for sleep diary measures are met A two-night baseline PSG test was scheduled to determine if it met / excluded PSG sleep criteria. PSG scoring was performed in stages to ensure that the subject could continue the test timeline that only 3-7 nights were left between the night of the reference PSG and the device night PSG. Because the symptoms of insomnia can change over time, a time limit between evaluations was made so that the patient's clinical status could be compared between the baseline PSG night and the device PSG night. All records were scored in a standardized manner across all sites using the Henry Ford Hospital central scoring service. On-site PSG data was stored on a CD disc and sent to a central scoring site for final scoring. Since this entire process takes longer than the time allowed between the reference PSG and the instrument PSG, each individual site will be randomly sampled by the test subject to meet the PSG selection / exclusion criteria. We asked to provide a quick screen score for the reference PSG to estimate whether or not. The central scoring site later scored these records to verify that the subject met the PSG criteria selection / exclusion PSG criteria. Subjects were randomized to receive one of two conditions: a camouflaged vestibular sleep system device (control) or a sleep system device at a temperature of 14-16 ° C when deemed eligible by a simple score. Each subject, after being randomized, spent two consecutive nights in the random sampled condition. Subjects were expected to spend a total of 8 hours in bed and use the device for all time in bed. The night of the camouflaged device and the night of the active device were both separated by 3-7 nights from the baseline test with non-interventional sleep at home.

  In the camouflage device, camouflaged electrodes are arranged symmetrically on the skin at the height of the mastoid process. Five minutes after applying the electrode patch to the subject, the device was set to 3 camouflage settings (from 1 to 5 options). After 25 minutes, the patient was informed that the treatment intensity could be maximally adjusted from setting 1 (lower intensity treatment) to 5 (higher intensity treatment) according to comfort. Once the setting was selected, no further adjustments were allowed for the rest of the night. Note that the device provided no electrical stimulation at any setting. All settings were “spoofed” settings.

  Under active device conditions, a forehead pad and headpiece were placed at 30 ° C. (Setting A) on the subject's head. Five minutes after applying the headgear and forehead pad to the subject, the condition was set to 15 ° C. (level B “3” setting B). There was a 25 minute time delay between setting the device in active mode and achieving the desired 15 ° C. After 25 minutes, the patient was informed that the temperature could be maximally adjusted to a maximum of 5 (warm setting) or a minimum of 1 (cooler setting) according to comfort. Once the setting was selected, no further adjustments were allowed for the rest of the night.

Selection criteria The selection criteria for this examination were as follows.
1. Age ≧ 22.
2. Sign the medical agreement.
3. Diagnosis of insomnia that meets DSM IV primary insomnia diagnostic criteria, ISCD general insomnia criteria and RDC insomnia disease criteria. These criteria include:
4). Complaints of falling asleep, difficulty in continuing sleep, premature awakening, or non-restorative sleep.
5. Ample sleep opportunity.
6). Evidence of dysfunction during the day.
7). Minimum duration criteria of at least> 1 month.
8). There are almost daily sleep complaints.
9. Subjects must refrain from drinking and agree to avoid drugs that may affect sleep during the test.
10. Insomnia severity index> 14.
11. Sleep-wake diary demonstrates sleep efficiency <85% in at least 50% at night for 7 consecutive days.

Exclusion criteria The exclusion criteria are as follows.
1. Neuropsychiatric disorders that can affect sleep, brain function or cognition alone, such as DSM-IV mood disorders, anxiety disorders, psychiatric disorders, and current major syndrome syndromes including substance use disorders.
2. Specific exclusion diagnoses include major depressive disorder, dysthymic disorder, bipolar disorder, panic disorder, obsessive compulsive disorder, generalized anxiety disorder, any mental disorder and any current substance use disorder, severe heart disease, liver disease Kidney disease, endocrine disease (eg, diabetes), blood disease (eg, porphyria or any bleeding disorder), other injuries, unstable medical conditions or impending surgery, central nervous system disorders (eg, head trauma) , Paroxysmal disease, multiple sclerosis, tumor), active peptic ulcer, inflammatory bowel disease and (if arthritis affects sleep) anxiety pathologies including arthritis.
3. Raynaud's disease.
4). An irregular sleep schedule that includes shift workers.
5. Sustained sleep latency <15 minutes at night of sleep disorder review or at night of reference PSG sleep.
6). Sleep efficiency> 85% at night for sleep disorder review or at night for standard PSG sleep.
7). AHI (Apnea-Hypnea Index)> 10 and / or Periodic Limb Movement Arousal Index (PLMAI)> 15 from the night of sleep disorder review.
8). Body mass index> 34.
9. Use of drugs known to affect sleep or wakefulness (eg, sleeping pills, benzodiazepines, antidepressants, anxiolytics, antipsychotics, antihistamines, decongestants, beta blockers, corticosteroids). Β-blockers that do not cross the blood brain barrier are observed.
10. Ingestion of more than 1 alcoholic beverage per day or more than 7 alcoholic beverages per week before participating in the test.
11. Caffeinated beverage before test participation> 4 / day, or an amount equivalent to more than 4 cups of coffee.
12 Inability to read or understand English.
13. Randomized sampling experience for another research study using the sleep system.

Standard multi-site polysomnography (PSG) and data scoring The Henry Ford Hospital Central Scoring Service (HFH-CCS) provided the site with comprehensive PSG testing guidance. The Henry Ford Hospital Central Scoring Service also performed centralized scoring of PSG data. All sites followed a standard sleep protocol that included patient preparation procedures, standard recording montage procedures, correct instrument calibration procedures and biocalibration procedures that had to be preceded by the beginning of PSG collection. A standardized set of instructions on how to monitor the PSG, including the time to properly reattach the recording electrode and the recording method during the patient's night toilet break, was provided.

A standard PSG montage as defined in the Sleep and Related Events Scoring Manual (2007) by the American Society for Sleep Medicine (AASM) was used as follows.
・ Left electrocardiogram (E1 / M2)
・ Right electrooculogram (E2 / M1)
・ Submandibular electromyogram (chin 1 / chin 2)
・ Submandibular electromyogram (chin 2 / chin 3)
・ Electroencephalogram (C3 / M2)
・ Electroencephalogram (O1 / M2)
・ Electroencephalogram (F4 / M1)
・ Electroencephalogram (C4 / M1)
・ And electrocardiogram (ECG)
-In addition, the following was added for the night (SN1) of the sleep disorder examination.
・ Nose / oral heat sensor (TFLOW)
・ Left anterior tibial electromyogram (L LEG)

Sleep Laboratory and Clinical Procedures Subjects will report to the Sleep Laboratory approximately 2 to 3 hours prior to their scheduled bedtime (GNT) on 2 separate occasions, each separated by at least 3-7 days Asked to do. Bedtime was determined as an average of 4 hours before the midpoint of the sleep diary time in the bed at home over the course of one week when the sleep-wake diary was completed. The wake-up time was determined as 4 hours after the midpoint of the sleep diary time in the bed at home. The following PSG schedule was followed.

Examination (SN1 and SN2)
Sleep conditions and recordings were made in a separate and comfortable dark soundproof room with temperature regulation (68-72 ° F.).
Each sleep facility was equipped with a standard thermometer and the room temperature of each subject was recorded every night in the bedroom.
・ Subjects were asked to take a breath test to check for alcohol consumption.
・ Subjects were asked to have a urine test to check for drug use.
• Asked subjects about concomitant medications and completed the laboratory version of Pittsburgh's home sleep diary.
• Subjects were fitted with electrodes to monitor sleep parameters.
As with the following device night, subjects sit quietly in a comfortable chair in the bedroom of the laboratory 55 minutes prior to bedtime (GNT) and may have the potential to use a cell phone or computer or watch TV Urged not to engage in stimulating activities. During this time, subjects were restricted from contacting inspection personnel.
PSG SN1 subjects were examined for sleep apnea and periodic limb movement disorders (visit 2).
A sleep specialist clinic scored “swiftly” for each site for sleep latency, sleep efficiency, AHI and PLMAI, and scheduled SN2 if the test met the selection criteria.
• For PSG SN2 subjects, the reference EEG sleep measure was collected by sleeping well without using the device (clinic visit 3). For each individual site, a record was “scored quickly” for sleep latency and sleep efficiency, and this record was sent to the central scoring site for verification.
・ Sleep specialist clinic staff scored SN2 for sleep latency and sleep efficiency. For verification, PSG records were sent to the Henry Ford Hospital central scoring site. The Henry Ford hospital scoring was taken as the final scoring and used to determine the choice for the modified ITT population. If a simple scoring measure from the field mistakenly determined that subjects should be randomly sampled for testing, a protocol deviation was entered indicating that there were discrepancies but subjects would remain in the ITT population. The on-site PI determined the final qualification.

Random sampling and blinding When all participation criteria were met, random sampling was performed before the first night using either device. Subjects were randomly sampled in one of two conditions: 1) a control of a camouflaged device or 2) a 14-16 ° C. therapeutic device. The research center hierarchized the randomization of subjects to ensure a balanced set order across all research centers.

Home Night Between Reference Night and Device Night Subjects took sleep at home for 3-7 nights after completion of the reference night and random sampling to device night. During this time, subjects were asked to complete a sleep-wake diary to document sleep patterns and drug use between sleep facility visits.

Inspection device at night 1-2 (DN1 and DN2)
Sleep conditions and recordings were performed in a separate comfortable dark soundproof room with temperature control (68-72 ° F.).
Each sleep facility was equipped with a standard thermometer and the room temperature of each subject was recorded every night in the bedroom.
・ Subjects were asked to take a breath test to check for alcohol consumption.
• Asked subjects about concomitant medications and completed the laboratory version of Pittsburgh's home sleep diary for device nights 1-2.
・ Subjects were asked to have a urine test to check for drug use.
• Subjects were fitted with electrodes to monitor sleep parameters.

The subject identifier was directly written on the headgear and frontal pad using the “Sharpy” at night.
• The device was switched on 65 minutes before bedtime in anticipation of the time required to achieve a temperature of 30 ° C. (Setting A).
Headgear where the subject sits in a comfortable chair 60 minutes before GNT at device night (DN1, DN2) and the technician has attached a forehead pad (described above) at a temperature of 30 ° C. (setting A) Was supported and / or applied.
-As soon as the forehead pad was placed on the subject, a frontal face photograph, a side face photograph, and a topal part photograph of the subject were taken. The photos were used for internal purposes only.
The technician placed the device on the subject and then set the device to 15 ° C. (Setting B, “3”).
• Subjects were asked to sit quietly in a comfortable chair in the bedroom of the laboratory and not perform potentially stimulating activities such as using a cell phone or computer or watching TV. During this time, subjects were restricted from contacting inspection personnel. After 25 minutes, the technician had the opportunity to change ± 1 ° C. only once (cooling down to “1” or warming up to “5”). After making any setting changes, the subject continued to sit for another 25 minutes.
-GNT: After 25 minutes, the subject started the sleep period. The sleep period was defined as from turning off to turning on. The subject was to wear the device on his head for a total of 60 minutes before GNT.
• Subject entered bed for a total of 8 hours.
• Subjects were asked not to remove the device for 8 hours in bed.

Fake vestibular stimulation night / device 60 minutes prior to GNT at night (DN1, DN2), subjects were seated in a comfortable chair and the technician supported and / or applied the vestibular stimulation device. The vestibular stimulation electrode was connected to the clinical unit and the clinical unit was turned on (Setting A).
When the vestibular sleep system was placed on the subject, a frontal photo, a side facial photo, and a crown photo of the subject were taken. The photos were used for internal purposes only.
• Subjects were asked to sit quietly in a comfortable chair in the bedroom of the laboratory and not perform potentially stimulating activities such as using a cell phone or computer or watching TV. During this time, subjects were restricted from contacting inspection personnel. After 25 minutes, the technician was given the opportunity to change only once to either setting 1 (lower intensity stimulation) or setting 5 (higher intensity stimulation). After making any setting changes, the subject continued to sit for another 25 minutes.
-GNT: After 25 minutes, the subject started the sleep period. The sleep period was defined as from turning off to turning on. The subject was to wear the device for a total of 60 minutes before GNT.
• Subject entered bed for a total of 8 hours.
• Subjects were asked not to remove the device for 8 hours in bed.
-After nighttime sleep, the vestibular stimulator was removed from the subject.

In the morning after the night of the device, the subject completed the morning questionnaire at the first awakening.
Removed headgear / vestibular stimulator.
• When subjects completed both device nights, subjects were allowed to come back for the next scheduled nightly inspection or until they returned for the final visit.

Definition of adverse events No stimuli were delivered under fake vestibular stimulation conditions. Thus, every AE is related to the sense that an inert electrode is present in place on the skin and is not expected to differ from the effects on the placement of the EEG electrode for monitoring sleep as described above. . However, to protect blindness, subjects were informed about potential AEs observed when the vestibular stimulator was activated.

Statistical planning Common primary efficacy endpoints Two common primary efficacy endpoints were obtained from PSG data: sleep latency and sleep efficiency.

  Sleep latency is defined as the number of minutes from extinction to the first 10 minutes of continuous sleep. The shorter the time, the better. The reference sleep latency was calculated as the average value of the sleep latency results from two nights in the sleep laboratory under the reference conditions without using the device. The result of the treatment set sleep latency was calculated as the average value of the sleep latency results from two nights in a sleep laboratory using a sleep system set at 14-16 ° C. The camouflage set sleep latency results were calculated as the average of the sleep latency results from two nights in the sleep laboratory using the camouflaged vestibular stimulation system.

  Sleep efficiency was defined as the ratio of sleep time to total observation (PSG recording) time as a percentage. The reference sleep efficiency was calculated as an average value of the sleep efficiency results from two nights in the sleep laboratory under the reference condition without using the device. The result of treatment setting sleep efficiency was calculated as an average value of the results of sleep efficiency from two nights in a sleep laboratory using a sleep system set at 14 to 16 ° C. The camouflage set sleep efficiency result was calculated as the average of the sleep efficiency results from two nights in the sleep laboratory using the camouflaged vestibular stimulation system.

  Category data was compiled using a frequency table showing the number of subjects and the proportion of subjects. McNemar's chi-square was used to evaluate changes in bivariate response variables. Continuous variables were summarized by mean, standard deviation, median, minimum and maximum. Changes were analyzed parametrically using a t-test. Confidence intervals were generated and p-values for all tests were reported. All analyzes were performed using a SAS system.

The general hypothesis test form for two primary endpoints and two formal secondary endpoints is as follows:
H0: μTRT = μCTL
H0: μTRT ≠ μCTL
ΜTRT here is the mean within-subject change associated with the treatment group, and μCTL is the mean within-subject change associated with the control group.

  In the primary analysis of sleep latency and sleep efficiency, the reference value was adjusted by performing analysis using a plurality of attribution models.

  As shown in FIG. 13 (Table 1), the difference in sleep latency change in the adjusted treatment group compared to the camouflaged group is approximately statistically significant 8 minutes (p = 0.092). The difference in relative variation from the baseline was 20% and was statistically significant (p = 0.013). We will now perform further ancillary analyzes showing the impact of sleep systems on stage 1, 2 and 3 NREM sleep latencies to demonstrate whether the theoretical effects of these sleep systems are justified.

  FIG. 14 (Table 2) shows the measurement result of “time to any sleep stage” of the ITT population (N = 106). The effect of the sleep system on the measure of “time to any sleep stage” is statistically significant. The average absolute level of “time to any sleep stage” or “sleep latency” of the sleep system group for the ITT population was 49.2 minutes at the reference time and 21.9 minutes at the time of wearing the device. The mean time to any sleep stage of the camouflaged device group was 41.7 minutes at the reference time and 31.9 minutes when the camouflaged device was mounted. The estimated difference value was −12.4 (95% CI: −20.8, −4.1), and p = 0.004. Regarding the change in the time until the sleep stage at the time of wearing the device with respect to the reference of each subject, the change rate of the time from the reference to the sleep stage in the sleep system group to the device is 50. There was a 2% decrease and the rate of change in time to any sleep stage in the camouflaged group was a 7.6% decrease. The estimated difference was -39.0 (95% CI: -66.4, -11.6), and p = 0.006.

  In the ITT population (shown in Table 3 of FIG. 15), the effect of the sleep system on the measure “Stage 1 NREM sleep latency” is statistically significant. The similarity between this analysis result and the analysis result of the measure “time to any sleep stage” suggests that they measure the same event. The reason for this prediction is that the first sleep stage in which an individual transitions from awakening is generally stage 1 sleep. Thus, the sleep system accelerates sleep onset in insomnia patients.

  In the ITT population (shown in Table 4 of FIG. 16), the effect of the sleep system on the measure “Stage 2 NREM sleep latency” is statistically significant. In general, stage 2 NREM sleep is the second sleep stage in which an individual transitions from stage 1 NREM sleep. The active group enters stage 2 NREM sleep significantly earlier than the camouflaged group under the sleep system. This analysis shows that the sleep system not only affects sleepiness or shallow stage 1 NREM sleep alone, but also continues to have a significant impact on accelerating the depth of subsequent sleep well after the patient falls asleep. Demonstrate.

  Analysis of stage 3 NREM sleep latency is complicated by the fact that patients do not always exhibit stage 3 NREM sleep at any point in the night. For this reason, the present inventors excluded these patients from the analysis and analyzed only subjects who entered stage 3 sleep at some point in the night. In all samples, three subjects with active device conditions and six subjects with camouflaged conditions did not experience stage 3 sleep at either baseline night or device night.

  As shown in FIG. 17 (Table 5), the effect of the sleep system on the measure “Stage 3 NREM sleep latency” is beneficial in one direction. In any case, there is no reverse effect that the occurrence of stage 3 NREM sleep is delayed under active conditions. In general, stage 3 NREM sleep is the third sleep stage in which an individual transitions from stage 2 NREM sleep, and thus the slightly higher stage 3 NREM sleep latency means that the patient initially enters stage 1 NREM sleep and stage 2 NREM sleep states. This suggests that we will enter stage 3 NREM sleep after becoming. However, the active group enters stage 3 NREM sleep earlier than the camouflaged group under the sleep system.

  To be cautious, in the second analysis, a value of 480 minutes was assigned to the time to stage 3 for all subjects who did not experience stage 3 sleep. This time represents the total bedtime over the entire night (8 hours) when there is no stage 3 sleep. In the ITT population, the estimated difference in fractions of stage 3 NREM sleep latency is −15.6 (−48.8, 17.5), p =. 352, the estimated difference in percent of stage 3 NREM sleep latency is −19.6 (−39.1, −0.0), p =. 050. In the mPP population, the difference estimate in minutes for stage 3 NREM sleep latency is -16.8 (-50.9, 17.2), p = .329, and the difference estimate in percent of stage 3 NREM sleep latency. Values are -21.0 (-40.9, -1.0), p =. 039. In this second set of analyses, the number of “Stage 3 NREM sleep latency” was arbitrarily assigned, including assigning 480 minutes to individuals who did not enter Stage 3 NREM sleep at night, resulting in Stage 3 NREM sleep. Latency variation is high.

  7 and 8 show graphical representations of these results. The first graph shows the average value of the reference, camouflaged group and active group, and the second graph shows the additional benefits of the active device over the camouflaged device adjusted for any reference difference.

  Thus, there is evidence that the sleep system has a beneficial impact on shortening the time to these sleep stages across all NREM sleep stages. This applies not only to shallow stage 1 NREM sleep, but also to deep stage 2 and stage 3 NREM sleep. The inventors have found that the difference observed in improving the time to any sleep stage is a beneficial effect of the sleep system on the entire nightly process of going to bed and gradually becoming deep sleep, i.e. a wide range We interpret that these test results suggest that they reflect the effect on sleep impulses.

  In the exemplary test described in this section, the sleep system is a cooling device composed of three components: a clinical unit, a forehead pad, and headgear. The sleep system is shown to improve sleep measures for insomnia treatment. These components have been described above (see FIGS. 1A-5) and will be briefly described again below. The clinical unit is shown in FIGS. 1A-1J. The clinical unit cools the fluid and transfers the fluid from the unit to the forehead pad. Some forms of clinical units use solid state heating elements to cool a heat transfer fluid consisting of purified water and alcohol. This unit has a user interface that allows the user to switch the unit on and off and adjust the temperature to 14-16 ° C. This unit includes a pump for circulating heat transfer fluid to the tube and the forehead pad. The clinical unit is powered by a DC power source and is controlled by an integrated control unit (CU) and its firmware. The CU controls the cooler, pump and fan by pulse width modulating (PWM) the DC power to each component according to the feedback input sensed by the thermistor.

  The clinical unit (CU) of the sleep system includes a function of adjusting the fluid temperature to a temperature set point within 20 minutes of setting and setting the fluid temperature to 14 to 16 ° C. Includes a built-in safety mechanism that reduces the risk of failure conditions for all types of elements.

  The sleep system headgear and forehead pad may include a wearable portion of the sleep system. The wearable portion is comprised of a forehead pad that contacts the patient's head, headgear that holds the forehead pad in place, and a 6 foot insulated tube portion that connects to the clinical unit of the sleep system. . 2A to 2B show examples of headgear and forehead pads. A forehead pad is a design component that is shaped to cover a target area on the forehead that covers the prefrontal cortex. The remaining head is left uncovered except for headgear that is specifically designed to hold the pad and secure the tube. The forehead pad can be made from a urethane film sheet such as Bayer PT9200 used in other common medical products.

  The headgear (FIG. 2A) can provide a mechanism for securing the forehead pad containing a constant flow of coolant that recirculates the tube in place on the user's forehead. The headgear can be made from a clothing grade lycra-based material.

  The above results indicate that the devices and methods described herein can reduce insomnia patients by reducing the time to sleep (sleep latency) and / or shifting the EEG sleep phase to a deeper sleep phase. It shows that it can be effectively treated. The above research and feedback from people wearing the device supports the topical application of heat transfer pads to regulate sleep as described above.

  In one configuration of the device, a heat transfer pad is shaped to cover the frontal region on the hairless (hairless) skin. As mentioned above and as indicated by the above survey results, this facial region is the most temperature sensitive of the body surface, supplying nerves and blood vessels specialized for this function, and going to sleep during sleep applications Given that the forehead provides a convenient surface for placing the pad with minimal interference, it is considered to be unparalleled in the body area to provide temperature information that triggers the vagal response .

  A mask configuration that directs heat transfer to the scalp region of the forehead is considered beneficial for sleep. The above research results support the validity of this claim.

  There may be other electrical or mechanical methods of changing forehead skin temperature independent of heat transfer through the cooling circulation included in this disclosure. For example, the frontal head can be cooled directly (eg, by a TEC integrated with the head mounted device). The method described herein is presented in this provisional patent application for the purpose of improving sleep by simply utilizing different methods of cooling these areas by the underlying brain mechanism as described. It can also be used in areas and methods.

  Use of the device on the scalp in the area covering the frontal region is expected to provide a parasympathetic signal that encourages rest or sleep. Application of the device prior to sleep has been shown to be useful for falling asleep. Application of the device during sleep has been shown to increase slow wave sleep, improve sleep maintenance, reduce alertness, and increase sleep time over night.

  FIG. 6 shows one configuration of the surface area that covers the area of the frontal cortex that produced the demonstration effect. Based on the above effects, this device is not limited, but at least it improves healthy sleep, improves sleep of insomnia patients, improves sleep of people experiencing insomnia, but not limited Sleep for people with neuropsychiatric disorders, including depression, mood disorders, anxiety disorders, drug abuse, post-traumatic stress disorder, mental disorders, manic depression and personality disorder, and any neuropsychiatric patient experiencing insomnia Improvement of sleep in patients suffering from pain including chronic pain and headache including migraine, improvement of sleep in women around menopause who are experiencing insomnia and / or insomnia, heart disease, endocrine disease and Improving sleep in patients with insomnia or insomnia after other medical illnesses such as pulmonary disease, as well as improving sleep in patients with insomnia or insomnia, including but not limited to tinnitus There is a similar effect on the improvement of sleep in Tsu conditions.

  This document also describes various heat transfer rates and heat transfer timelines or heat transfer algorithms during sleep. For example, the above examination showed that a temperature of 14-16 C improved sleep for insomnia patients. Even in the range of 10 ° C. to 15 ° C., the same effect can be exhibited in improving sleep of insomnia patients. In addition, induction of diving reflexes in a controlled manner (as described herein) can also be used to improve sleep as described above.

  The temperature of the device can be kept constant without fluctuations over the period of use. In one configuration, a heat transfer pad can be applied before going to bed to encourage the sleep process (eg, 45 minutes to 1 hour, 5 minutes to 10 minutes, 5 minutes to 20 minutes, 5 minutes to 25 minutes, 5 minutes, Minutes to 30 minutes, 5 minutes to 35 minutes, 5 minutes to 40 minutes, 5 minutes to 45 minutes, 5 minutes to 50 minutes, 5 minutes to 1 hour, etc.). 14-16 degrees Celsius can be effective in encouraging falling asleep. Given that nerve transmission takes place within a few seconds, it can be expected that applying the device just before entering the bed will have a similar effect.

  If only the effect on falling asleep is desired, the device can be removed when the person enters the bed.

  In one configuration, a heat transfer pad can be applied throughout the night sleep after the person enters the bed to facilitate the sleep process throughout the night sleep. In this configuration, research studies have shown that 14-16 degrees Celsius can be effective in promoting deeper sleep.

  In one configuration, a heat transfer pad can be applied to enter the bed to promote the sleep process and remain throughout the night sleep to facilitate the sleep process throughout the night sleep. In this configuration, research studies have shown that 14-16 degrees Celsius is effective in encouraging sleep and maintaining deep sleep throughout the night.

  In another configuration, the application of variable temperature including defined changes can be made over the period of use. The time course of temperature is changed according to the probability that the NREM and REM sleep stages will occur. It has been found that parasympathetic and sympathetic nervous system activity changes characteristically throughout the night's sleep and depends on the sleep stage the individual appears to be experiencing and the duration from sleep initiation. The NREM sleep phase includes shallow stage 1 sleep, deep stage 2 sleep, and deepest slow wave sleep, with slow wave sleep predominating in the first half of the night. REM sleep occurs periodically every 60 to 90 minutes throughout the night, and a long and strong REM period occurs gradually in the latter half of the night. Parasympathetic activity tends to decrease with deep NREM sleep and increase with REM sleep. The extent to which these changes occur is considered functionally important for sleep.

  The maximum effect of the device at 14-16C can promote deepening of NREM sleep as predicted from a hypothetical mechanism of action for parasympathetic nervous system activation.

  Therefore, in one configuration of the variable heat transfer time course, the maximum application can be concentrated early in the night when slow wave sleep is likely to be maximized, and the degree of application can be suppressed toward the end of the night when REM sleep occurs.

  Changes in REM sleep and NREM sleep can also occur in various neuropsychiatric disorders. The general principle of changing the temperature of the heat transfer mask to promote or diminish deep NREM sleep or individual aspects of REM sleep that are directly associated with a particular disease has a therapeutic benefit specific to the disease. is expected.

  Changing the temperature characteristics of the mask has been shown to have a predictable effect on sleep physiology. Thus, heat transfer can be changed by measuring changes in sleep physiology and incorporating them into a feedback loop. In this way, the applied temperature can be adjusted in real time to achieve some desired physiological effect.

  Thus, in one configuration, a variable temperature can be provided over the entire period of use, including a defined change associated with feedback from changes in body physiology over the period of use.

  Slow wave measured by REM sleep or NREM sleep as assessed by one skilled in the art by any REM / NREM sleep assessment method such as EEG frequency, heart rate variability, muscle tone or other means, measured by EEG wave analysis or other mechanisms The depth of sleep, the degree of autonomous arousal measured by HR fluctuations or other means, the electrical skin reaction, the skin of the head under the device, or the skin of any other head not under the device Physiology, such as temperature, or peripheral skin temperature, or core temperature (measured internally or by some external means), or some combination measure to assess head and peripheral thermoregulation, or a measure of core temperature to peripheral temperature The measurement can be monitored and the temperature can be adjusted in real time according to the level of this physiological measurement.

  The person wearing the device can modify the temperature over the period of use and link this change to subjective feedback.

  In one configuration, a person wearing the device can control the device to adjust the temperature up or down in some slight increments according to their immediate comfort and treatment needs. In another configuration, an individual sets his bedtime and desired wake-up time and inputs a pre-programmed algorithm to start and stop at these times, resulting in a relative incremental adjustment over this time To be able to. These automatic time calculations can be implemented for any variable heat transfer rate schedule over any specified time.

  In one configuration, the lining of the heat transfer pad that contacts the skin is a hydrogel that can increase the contact surface area and enhance the heat transfer properties. Other materials with suitable temperature transfer characteristics can also be used.

  In another configuration, this backing is combined with a dermatological product that can be activated against the skin when contacted through the night.

  In another configuration, the inner lining can be restored at a low frequency that can have an effect on the skin when applied over night or night sleep.

  In patient clinical management, healthcare providers may wish to know specific parameters of the patient and / or device over multiple night uses so that care can be optimized.

  Thus, in one configuration of the device, some memory card or memory chip automatically records certain parameters and stores them for later display by the health care provider.

  As device users monitor their care, they may wish to know specific parameters of the patient and / or device over multiple night uses so that care can be optimized.

  Thus, in one configuration of the device, some memory card or memory chip automatically records certain parameters and stores them for later display.

  In another configuration of the device, someone can review the information and recommend it accordingly by transferring this information to the provider's office or some other central database via telephone or the Internet or some wireless technology. Treatment adjustments can be made.

  Examples of information that can be stored include, but are not limited to, device temperature, skin temperature, core temperature, measure of autonomous variation, sleep depth assessed by NREM sleep, discrete frequency band, REM sleep Or EEG power in other sleep stages, activity and / or wakefulness throughout the night, a subjective measure of sleep depth / comfort / satisfaction, sleep time, etc.

Dive Reflex Detection and Feedback Any of the methods and devices described herein can adjust treatment according to the patient's sleep cycle. Alternatively or in addition, any of the methods and devices described herein may be based on the state of the subject's autonomic nervous system (eg, the ratio of sympathetic and parasympathetic nerves) and / or Treatment can also be adjusted based on the subject's parasympathetic and / or sympathetic response. For example, these methods and devices can include one or more sensors for measuring an indication of a patient's autonomic nervous system response, which is interpreted by a controller / processor and used to One or both of the temperature and / or timing of the treatment that the applicator applies to the subject's head can be adjusted (eg, feedback).

  An indicator of the autonomic nervous system can be, for example, heart rate, heart rate variability, blood pressure, electrical skin reaction, or any other known to monitor autonomic functions, including but not limited to diving reflexes, especially parasympathetic function Any suitable one can be used, such as an indicator of. Monitors can be added to the therapy and feedback provided to adjust the device temperature to be more active or therapeutic.

  Diving reflexes can be detected by detecting peripheral vasoconstriction, bradycardia rate, blood re-induction to vital organs for oxygen maintenance, release of red blood cells stored in the spleen and irregular heart rhythm . Thus, any of the methods and apparatus described herein can use one or more sensors that detect and / or characterize a subject's diving reflexes. For example, diving reflections usually occur within a few minutes (eg, within 5 minutes, within 4 minutes, within 3 minutes, within 2 minutes, within 60 seconds, within 55 seconds, within 50 seconds, within 45 seconds, within 40 seconds, Within 35 seconds, within 30 seconds, within 25 seconds, within 20 seconds, within 15 seconds, within 10 seconds, etc.) may cause a heart rate change of 5-35% (eg, 10-25%). Thus, any of the devices described herein can include a sensor configured to detect heart rate, which can be present on the applicator or the application. Can communicate with the processor of the device. For example, the subject can wear a wearable sensor that communicates with the device. Sensors for detecting heart rate can include electrical (eg, ECG) sensors, optical sensors (eg, pulse oximetry sensors), vibration / motion sensors (eg, accelerometers), and the like. Alternatively or in addition, one or more sensors for detecting peripheral vasoconstriction may be used to integrate into or communicate with the device (eg, hand / Pulse oximetry from one or preferably two or more positions such as arm / finger and forehead). Changes in red blood cell levels can be detected non-invasively and used to detect the presence and / or magnitude of diving reflexes.

  FIG. 20A illustrates an exemplary apparatus for detecting diving reflexes and adjusting the treatment to be applied (eg, pad cooling) based on detection parameters indicative of diving reflexes. In FIG. 20A, device 2000 includes an applicator 2003 having a thermally controllable skin contacting surface 2009. This applicator can accommodate any of the applicators described above, including a circulating fluid applicator connected to the base (via one or more tubes) to cool / warm the fluid. Alternatively, or in addition, a thermoelectric cooler can be included that can be used to directly cool the forehead. Cooling can be applied directly to the skin or through a heat transfer pad, cover, etc. The device (e.g., can heat / cool fluid circulating in the forehead applicator 2003 as shown in FIG. 20A, or can be integrated into a wearable applicator (e.g., as a thermoelectric cooler not shown)). A heating / cooling unit 2005 that can be separated from the applicator can also be included. These devices all include one or more temperature sensors 2011 in the cooling / heating unit and / or in the applicator that regulates the temperature of the forehead applicator to provide feedback to the processor / controller 2001. be able to.

  One or more sensors 2007 can be included as part of a device that includes a portion of the forehead applicator as shown, or these sensors can be separated from the applicator (eg, 2005 ′). it can. As described above, these sensors can detect one or more of heart rate, heart rate variability, blood pressure, electroencephalogram, electrocardiogram, electrical skin reaction, and the like. The sensor can provide data to the processor / controller 2001, which can interpret the data to determine a patient's parasympathetic response or condition. The device can be configured to determine whether the patient is experiencing a diving reflex or how strong the diving reflex the patient is experiencing and adjust the timing and temperature accordingly.

  For example, any of the methods and devices described herein may adjust the temperature and / or timing of the device based on EEG, HRV and / or other sleep monitoring techniques, either alone or in combination with diving reflex indicators. Can be configured. The device determines the temperature to apply during the sleep period based on a feedback signal that includes a sleep state or sleep stage (eg, awakening, NREM (stage 1, stage 2, stage 3), REM, etc.) and feedback that reflects the dive reflex. Can be changed. In some forms, the device can adjust the temperature of the applicator to achieve and maintain a subject's diving reflex as determined by one or more sensors.

  In one example, the temperature of the applicator can be controlled based on the heart rate. For example, the processor monitors the heart rate and the initial heart rate exceeds 10% within a predetermined period (eg, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, etc.) (eg, 10 to 10 minutes). 35%) Descented changes that can show diving reflexes can be identified. In subjects who have not yet slept, the applicator can be cooled to a gradually decreasing temperature (eg, from body temperature such as 37 ° C. or room temperature) until a dive reflection is detected. When diving reflex is detected (using one or more indicators such as HR, HRV, blood pressure, vasoconstriction, erythrocyte elevation, etc.), the temperature can be stably maintained. Thus, the reaction temperature to the induction of the dive reflex may be lower or higher depending on the patient, so this procedure allows the cooling temperature to be customized for each patient / subject and for individual subjects between sessions. Can do.

  In addition or alternatively, detection of diving reflexes can be used to initiate the temperature adjustment application timing of the treatment. For example, after holding the temperature of the device below or below the temperature at which the dive reflex response was observed over a predetermined maintenance period (eg, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, etc.) The second (eg, standby) temperature can be raised over a second predetermined (eg, standby) period. Thereafter, the device or method can be used once or two times through the cooler temperature (eg, the temperature that triggers the dive reflex, which can be the same temperature as the first iteration or can be determined by monitoring the patient) and the standby temperature. It can circulate more than once.

  In some forms, the temperature can be adjusted, eg, within a cycle, to keep the subject in the dive reflex. Each of these devices can include a stop 2033 (see, eg, FIGS. 2A and 2B) for holding the forehead applicator on the subject's forehead.

  In general, the processor / controller 2001 of the device can receive, analyze and interpret data from one or more sensors. As described above, the processor can be part of the device, or in some forms can be separated (eg, pulled apart) from the device, such as a smartphone processor with which the device communicates.

  Any of the methods (including user interfaces) described herein can be implemented as software, hardware, or firmware and, when executed by a processor, include, but are not limited to, displaying, user and A processor (e.g., causing the processor to control the execution of any of the steps including communicating, analyzing, modifying parameters (including timing, frequency, intensity, etc.), determining, warning, etc. , A computer, a tablet, a smartphone, etc.) can be described as a non-transitory computer-readable storage medium that stores an instruction set that can be executed.

  FIG. 20B is a schematic diagram of another form of device that reduces sleep latency, increases sleep depth, and / or extends subject sleep time. This configuration is similar to the configuration illustrated and described above in FIG. 20A, but with many components of the apparatus of FIG. 20A adapted to be worn on the subject's forehead without being independent. Integrated with the main body 2003 ′. The applicator includes a heat transfer surface 2009 ′ and detects one or more temperature (feedback / control) sensors 2011 ′ (which may be, for example, a thermistor) and / or physiological parameters from the subject. One or more sensors 2007 for detecting diving reflexes can be included. On the other hand, the applicator can also include one or more cooling units 2015 ′ configured to cool the heat transfer surface, and these one or more cooling units are present in the applicator. And can be in direct thermal communication with the heat transfer surface. The applicator can also include a controller 2001 '(eg, one or more processors) that controls a cooling / heating unit 2015' (eg, TEC). The controller can be electrically coupled to one or more cooling units and can be configured to regulate the output and drive cooling of the one or more cooling units. A battery (eg, rechargeable battery, not shown) can also be included as part of the forehead applicator.

  As described with respect to the configuration shown in FIG. 20B, typically one or more sensors 2007, 2007 'are configured and coupled to the controller to detect physiological parameters from the subject. Any sensor described herein (eg, optical sensor, electrical sensor, mechanical sensor / vibration sensor, etc.) can also be used. Typically, the controller determines whether the subject is experiencing diving reflexes from physiological parameters detected by one or more sensors, and based on this determination, the temperature of the heat transfer region or the cooling timing of the heat transfer region It is comprised so that one or both of can be adjusted.

  The applicator can be secured to the forehead by a stop 2033 that can optionally be coupled or separated from the device.

  21A and 21B show examples of devices that improve sleep (eg, reduce sleep latency, increase sleep depth, and / or extend subject sleep time). The device 2003 'shown in FIG. 21A is integrated with a stop 2033, which in this example is a strap, for securing the device on the head and forehead, as shown in FIG. 21B. In addition, or alternatively, the stop can be an adhesive (eg, a releasable skin adhesive), a cap, a headband, or the like. The device 2003 'of FIG. 21A includes a plurality of small thin thermoelectric temperature regulators 2015' (cooling / heating units) disposed along the internal skin contact surface of the device. Any suitable strap can be used and can be adjustable to fit different head sizes. The device may also include one or more sensors 2007 for detecting physiological properties that allow detection of diving reflexes as described above. FIG. 21B shows a subject wearing the device 2003 'and lying on the bed.

  As used herein, when a feature or element is shown to be “on” another feature or element, the feature or element is directly present on the other feature or element. Alternatively, there may be intervening features and / or elements. In contrast, when a feature or element is shown to be “directly on” another feature or element, there are no intervening features or elements present. Also, if a feature or element is shown to be “connected”, “attached”, or “coupled” to another feature or element, this feature or element Will be understood to be directly connected, attached or coupled to other features or elements, or there may be intervening features or elements. In contrast, a feature or element is “directly connected”, “directly attached”, or “directly coupled” to another feature or element. There are no intervening features or elements. The features and elements described or illustrated with respect to one embodiment may be applied to other embodiments. Also, those skilled in the art can refer to a structure or feature that is “adjacent” to another feature, and may have portions that overlap above or below the adjacent feature. You will understand.

  The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms “a (indefinite article)” and “the (definite article)” are intended to include the plural forms as well, unless the context clearly indicates otherwise. . Furthermore, the term “comprises and / or comprising”, as used herein, indicates the presence of the features, steps, operations, elements and / or components described above, but includes one or more It should be understood that this does not exclude the presence or addition of other features, steps, actions, elements, components, and / or groups thereof. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “/”.

  In this specification, for simplicity of explanation, “under”, “below”, “lower”, “over”, “upper ( A spatial relative term such as “upper” may be used to describe the relationship between one element or feature shown in the figure and another element or feature. These spatial relative terms should be understood to include different directions of the device in use or in operation in addition to the directions shown in the figures. For example, when the illustrated apparatus is inverted, elements described as being “below” or “below” other elements or features become oriented “above” other elements or features. Thus, the exemplary term “down” can include both an upper orientation and a lower orientation. The device can also be oriented differently (rotated to 90 degrees or other orientations) and the spatial relative terms used herein can be interpreted accordingly. Similarly, terms such as “upwardly”, “downwardly”, “vertical” and “horizontal” are not specifically illustrated herein. It is only used for explanatory purposes.

  In this specification, the terms “first” and “second” may be used to describe various features / elements (including steps), Unless otherwise indicated in the context, these features / elements should not be limited by these terms. These terms can be used to distinguish one feature / element from another feature / element. Accordingly, a first feature / element described below may be referred to as a second feature / element without departing from the teachings of the present invention, and a second feature / element described below will also be referred to as a first feature / element. May also be referred to as features / elements.

  Throughout this specification and the following claims, unless the context indicates otherwise, the word “comprise” and variations such as “comprises” and “comprising” It means that various components can be used together in methods and articles (eg, configurations and devices including devices and equipment). For example, the term “comprising” is understood to include any element or step described, but is not meant to exclude any other element or step.

  In general, any of the devices and methods described herein are to be understood as being comprehensive, but all or part of the components and / or steps are exclusive and the various components, It can also be expressed as a step, sub-component or sub-step “consisting of”, or “consisting essentially of”.

  All numbers are intended to be used in the specification and claims, including use in the examples, unless otherwise expressly stated, even if not explicitly stated as “about” or “about” It can be read as if it had been prefixed with the word “approximately”. The expression “about” or “approximately” means that when describing the size and / or position, the value and / or position being described is within the expected value and / or position range. Can be used to indicate. For example, a numerical value is ± 0.1% of a value (or range of values) to be described, ± 1% of a value (or range of values) to be described, ± 2% of a value (or range of values) to be described, It can have a value such as ± 5% of the stated value (or range of values), ± 10% of the stated value (or range of values). Also, any numerical value set forth herein should be understood to include about or about that value, unless otherwise indicated in that context. For example, when the value “10” is disclosed, “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges included herein. As will be appreciated by those skilled in the art, when disclosing a value, the value “less than or equal to”, the value “greater than or equal to”, and It should be understood that possible ranges between values are also disclosed. For example, when the value “X” is disclosed, “X or less” and “X or more” (for example, X in this case is a numerical value) are also disclosed. Also, throughout this application, data is shown in a number of different formats, and it should be understood that this data represents the end point and start point, as well as any combination range of data points. For example, if a specific data point “10” and a specific data point “15” are disclosed, 10 and more than 15, 10 and 15 or more, less than 10 and 15, 10 and 15 or less, and 10 and 15 It should be understood that the equivalent and between 10 and 15 are considered disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13 and 14 are also disclosed.

  Although various exemplary embodiments have been described above, various modifications can be made to the various embodiments without departing from the scope of the present invention as set forth in the claims. For example, the order of execution of the various method steps described can often be changed in other embodiments, and one or more method steps can be omitted entirely in other embodiments. Some embodiments may include any feature of various apparatus and system embodiments, and some embodiments may not. Accordingly, the foregoing description has been presented primarily for purposes of illustration and should not be construed as limiting the scope of the invention which is set forth in the appended claims.

  The examples and illustrative examples contained herein are intended to illustrate, by way of example and not limitation, specific embodiments in which the subject matter may be implemented. As noted above, structural and logical substitutions and changes may be made by utilizing and deriving other embodiments without departing from the scope of the present disclosure. In this specification, where more than one embodiment of such inventive subject matter is actually disclosed, these embodiments may be voluntarily incorporated into any single invention or inventive concept within the scope of this application. Without intending to be limiting, they may be referred to individually or collectively for convenience only by the term “invention”. Thus, although specific embodiments have been illustrated and described herein, any configuration calculated to accomplish the same purpose may be used in place of the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Upon review of the above description, those skilled in the art will appreciate combinations of the above embodiments and other embodiments not specifically described herein.

Claims (36)

A device that shortens sleep latency, increases sleep depth, and / or extends a subject's sleep time,
A forehead applicator (2003, 2003 ′) having a heat transfer surface (2009) adapted to be worn on the subject's forehead;
One or more cooling units (2005, 2015 ′) configured to cool the heat transfer surface;
A controller (2001, 2001 ′) electrically coupled to the one or more cooling units and configured to regulate power and drive cooling of the one or more cooling units;
One or more sensors (2007, 2007 ′) configured to detect physiological parameters from the subject;
Wherein the one or more sensors are coupled to the controller, and the controller determines whether the subject is experiencing a diving reflex from the physiological parameters detected by the one or more sensors. Configured to adjust one or both of the temperature of the heat transfer region or the cooling timing of the heat transfer region based on the determination,
A device characterized by that. The one or more sensors may include one or more of body movement, respiratory rate, heart rate, electrical skin reaction, blood oxygen concentration, electrocardiogram (ECG) signal, and electroencephalogram (EEG) signal. Configured to detect
The apparatus of claim 1. The controller is configured to determine whether the subject is experiencing a diving reflex based on a decrease in heart rate;
The apparatus of claim 1. The controller is configured to reduce the temperature of the heat transfer surface of the applicator until a dive reflection is detected;
The apparatus of claim 1. The controller waits for the temperature of the heat transfer surface of the applicator after maintaining the temperature of the heat transfer surface of the applicator for a maintenance period at or below the temperature at which the dive reflection response is detected. Configured to increase to standby temperature over a period of time,
The apparatus of claim 1. A stop (201, 2033) for holding the forehead applicator on the subject's head;
The apparatus of claim 1. The one or more cooling units include a thermoelectric cooler (2015 ′),
The apparatus of claim 1. The one or more cooling units are configured to cool fluid passing through the forehead applicator;
The apparatus of claim 1. The one or more cooling units are present in the forehead applicator and communicate with the heat transfer surface;
The apparatus of claim 1. The controller is configured to control the temperature from 0 ° C. to 30 ° C .;
The apparatus of claim 1. The one or more sensors are part of the forehead applicator;
The apparatus of claim 1. Further comprising a cover having a heat transfer surface adapted to be disposed over the heat transfer surface of the forehead applicator;
The apparatus of claim 1. Method of reducing sleep latency, increasing sleep depth and / or extending sleep time of said subject by non-invasively applying hypothermia therapy to one or both of the subject's frontal cortex and prefrontal cortex Because
Placing an applicator including a heat transfer area in communication with the subject's skin on one or both of the subject's frontal cortex and prefrontal cortex;
In order to do one or more of shortening sleep latency, increasing sleep depth, and extending the sleep time of the subject, the heat transfer region is cooled to reduce the diving reflection. A triggering step;
A method comprising the steps of: Further maintaining the contact between the subject's skin and the heat transfer area for at least 15 minutes,
The method of claim 13. Locating the applicator includes securing the applicator in place;
The method of claim 13. Disposing the applicator comprises adhesively fixing the applicator;
The method of claim 13. Locating the applicator comprises securing the applicator only on the frontal region of the subject;
The method of claim 13. The step of cooling includes the step of cooling to 0 ° C. to 25 ° C.,
The method of claim 13. Cooling includes cooling to 10 ° C. to 15 ° C.,
The method of claim 13. Cooling includes passing a coolant through the applicator,
The method of claim 13. Cooling includes cooling via a thermoelectric cooler,
The method of claim 13. Cooling comprises lowering the temperature of the heat transfer region from ambient temperature to the first temperature over at least 5 minutes;
The method of claim 13. Cooling includes maintaining the heat transfer region at a first temperature;
The method of claim 13. Maintaining the first temperature comprises maintaining the first temperature for at least 20 minutes;
24. The method of claim 23. Further comprising determining that the subject is experiencing diving reflexes,
The method of claim 13. Further comprising adjusting one or both of the temperature of the heat transfer region or the cooling timing of the heat transfer region based on the determination of the diving reflection.
26. The method of claim 25. Cooling the heat transfer area includes gradually cooling the heat transfer area until the dive reflection is detected;
26. The method of claim 25. Changing the temperature of the heat transfer region to a second temperature;
The method of claim 13. Further comprising passing coolant through the applicator such that the heat transfer region is cooled to a second temperature between the first temperature and 30 ° C.
The method of claim 13. The second temperature is from about 20 ° C to about 25 ° C;
30. The method of claim 29. Further comprising maintaining the second temperature for a second time;
30. The method of claim 29. The second temperature is maintained by adjusting the temperature based on a sleep cycle;
32. The method of claim 31. The second temperature is maintained by adjusting the temperature based on a subject selection of user selectable inputs.
32. The method of claim 31. The method of reducing sleep latency, increasing sleep depth, and / or extending a subject's sleep time can reduce sleep latency, increase sleep depth in a subject with insomnia, and / or A method of extending the sleep time of the subject,
The method of claim 13. Method of reducing sleep latency, increasing sleep depth and / or extending sleep time of said subject by non-invasively applying hypothermia therapy to one or both of the subject's frontal cortex and prefrontal cortex Because
Placing an applicator including a heat transfer area in communication with the subject's skin on one or both of the subject's frontal cortex and prefrontal cortex;
Cooling the heat transfer area sufficient to induce a diving reflex;
Maintaining contact between the subject's skin and the heat transfer region such that the diving reflex shortens sleep latency, deepens sleep, and extends subject sleep time;
A method comprising the steps of: Method of reducing sleep latency, increasing sleep depth and / or extending sleep time of said subject by non-invasively applying hypothermia therapy to one or both of the subject's frontal cortex and prefrontal cortex Because
Placing an applicator including a heat transfer area in communication with the subject's skin on one or both of the subject's frontal cortex and prefrontal cortex;
Cooling the heat transfer area until the subject experiences diving reflexes;
Maintaining contact between the subject's skin and the heat transfer region such that the diving reflex shortens sleep latency, deepens sleep, and extends subject sleep time;
A method comprising the steps of: