RU2304988C2 - Method for normalizing sleep architecture of patients suffering from depression, anxiousness disorders, obsessive compulsive disorders and heavy insomnia by applying pulsating magnetic and electric stimulation during slow wave phase of human nocturnal sleep - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves applying low-amplitude electric and/or magnetic stimulation without wakening patient. The stimulation treatment is carried out during slow wave phase of human nocturnal sleep at frequency belonging to 0.5-4 Hz bandwidth selected to be maximum close to patient delta-activity characteristic frequency. Continuous stimulation cycle duration is not less than 10 min repeated in all slow wave phase of sleep during night time. The total treatment course is not less than 10 nights long one after another. Positive dynamics being achieved, the treatment course is to be continued. No dynamic changes being observed, another stimulation is to be selected by changing electric stimulation for magnetic one or vice versa or for combined stimulation using electric and magnetic stimuli in turn during one night or during two following nights.

EFFECT: enhanced effectiveness of treatment.

Description

The invention relates to medicine, namely to somnology and psychiatry, and can be used to normalize the temporary sleep architecture of patients with depression, anxiety disorders, obsessive-compulsive disorders and severe insomnia in clinical and outpatient practice.

The proposed method is aimed at normalizing the sleep architecture of people suffering from depression, obsessive-compulsive syndrome, anxiety disorders and severe insomnia.

The architecture of human sleep is characterized by the degree of distinctness of the expression of the individual phases of sleep, the spectral composition of the EEG during different phases of sleep, the duration of night sleep in general and its individual phases, the frequency of eye movements in different phases of REM sleep (Rapid Eyes Movements Sleep - sleep with fast eye movements , paradoxical dream), the density of time distribution of K-complexes, sleep spindles, etc. The sleep architecture of people with depression has specific differences from the sleep architecture of healthy people. In particular, they have a reduced proportion of phases of slow-wave (non-REM) sleep, especially its deep (3rd and 4th) phases, during which delta waves prevail in the spectrum (A. Wayne “Depression and sleep” - a chapter from the book “Depression in Neurological Practice”, A. A. Wayne et al., MIA, Moscow, 2002; Ya. I. Levin et al., “Night Sleep in Depression”, breast cancer, 1-3, 1998). Moreover, the severity of these deviations is usually the higher, the more severe the condition of a depressed patient. Thus, in severe suicidal forms of depression accompanied by suicidal obsessions, a significant reduction in the 2nd phase and almost complete absence of the 3rd and 4th phases of slow-wave sleep can be observed against the background of the dominance of REM phases in night sleep. The characteristics of the REM phases in healthy and sick individuals also have significant differences (objectively, in the frequency of eye movements, etc.). In addition, as a rule, in patients with depression, the time interval from the moment of falling asleep to the first appearance of REM sleep (the “latent period” of REM sleep) is reduced, etc. (Rotenberg VS, “REM sleep function and brain monoamine regulation. An application of the search activity concept”, chapter in the book: “Sleep and Sleep Disorders: A Neuropsychopharmacological Approach, ed. M. Lader, et al., 2004, Landes Bioscience / Eureka.com.) This inevitably affects the quality of sleep of these patients and the degree to which the individual phases of sleep perform their neurophysiological functions (Rotenberg VS, et al. "The relationship between subjective sleep estimation and objective sleep variables in depressed patients". Int. J. Psychophysiol .: 2000 Sept., 37 (3): 291-297).

Significant deviations of sleep architecture from normal options occur almost always with pathologies such as anxiety disorders and obsessive-compulsive disorders.

It is fundamentally important that the development of depression does not just lead to disturbances in sleep architecture. The most important depressive symptoms (suicidal obsessions, decreased mood, anhedonia, a feeling of loss of meaningfulness of life, anergy, etc.), on the one hand, and severe sleep disturbances accompanying this symptom, on the other hand, are consequences of the same underlying pathological processes in the brain person. The genesis of depressive symptoms is always associated with disturbances in the functioning of the very centers of the brain that regulate the circadian rhythm of "sleep-wakefulness", as well as with disorders of other neuronal (including neurotransmitter and neuromodulatory) and neurohumoral processes that are directly related to the formation of sleep architecture (Bao AM, et al. “Colocalization of corticotropin-releasing hormone and oestrogen receptor-alpha in the paraventricular nucleus of hypothalamus in mood disorders”, Brain 2005, June, 128, 1301-13; Maiberg HS, et al. “Deep Brain Stimulation for Treatment-Resistant Depression ", Neuron, Vol. 45, 651-660, March 3, 2005). There is reason to believe that similar complex connections are involved in the formation of other psychiatric pathologies close to depression - anxiety disorders, obsessive-compulsive disorders. Severe night insomnia (disturbances of night sleep), not comorbid for depression, is also associated with disturbances in the functioning of the deep neural and neurohumoral systems of the brain that regulate the sleep-wake cycle and the entire architecture of night sleep.

It is precisely because of these connections that the improvement in the severity of phases of slow-wave sleep, in particular, lengthening of the 3rd phase, the appearance of the 4th phase (if it was previously absent or was weakly expressed), always correlates with an improvement in the condition of patients with depression and depressive disorders.

In this regard, a direct effect on the night sleep architecture of these nosological groups through low-frequency pulsed stimulation during the slow wave phases of sleep, leading to a certain normalization of the night sleep architecture in patients, at the same time leads to a weakening of the main symptoms and an improvement in the condition of patients.

Currently, there are no reliable methods for normalizing the architecture of night sleep in people who have significantly impaired it, and specialized devices aimed at solving this problem in the narrow sense have not been developed. However, a partial normalization of sleep architecture is achieved with adequate treatment of those brain diseases in which sleep architecture disturbances are observed. So, with successfully selected drug therapy for depression and other pathologies, a certain normalization of sleep structure usually also occurs. Hundreds of chemicals are already used as antidepressants (tricyclics, tetracyclines, SSRIs, SSRIs, selective MAOI and other groups) and as so-called mood stabilizers (lithium, carbamazepine, valproates, etc.). However, for a very large proportion of people suffering from depression and other pathologies accompanied by serious violations of the architecture of night sleep, it is not possible to select adequate drug therapy so that a person has the opportunity to live and work normally - with the so-called pharmacological resistant depressions, etc. In addition, pharmacological preparations have many side effects and contraindications. Persons with severe depression require almost continuous use of antidepressants and / or stabilizers. Long-term use of even the latest generation of drugs often leads to such dire consequences as disruption of the normal blood composition, disruption of the autonomic nervous system, the occurrence of cardiological pathologies, disruption of the immune system, and impaired sexual function. As a result, removing the most serious elements of depression (obsessive suicidal thoughts, appropriate actions, extremely painful feelings of mental pain, etc.), antidepressants themselves provoke a variety of disorders. In some cases (pregnancy, allergic reactions, the presence of a number of liver and kidney diseases), adequate antidepressant therapy is difficult or impossible.

The same is also true for anxiety and obsessive-compulsive disorders.

In addition to drug therapy, other methods of treatment of these pathologies are also used, which, if a positive effect is achieved, can simultaneously normalize, to one degree or another, the structure of night sleep. For example, among therapies for depression should be called such as:

- psychotherapy;

- various options for psychophysiological training and procedures (breathing and relaxation training, etc.);

- light therapy (phototherapy);

- deprivation (deprivation) of all night sleep or morning sleep;

- electroshock therapy (electroconvulsive therapy, ECT);

- pulsed magnetic stimulation (including transcranial magnetic stimulation, TMS - Transcranial Magnetic Stimulation),

- brain stimulation by stimulation of the vagal nerve (VNS - Vagus Nerve Stimulation);

- deep stimulation of selected areas of the brain through electrodes implanted directly in these areas of the brain (DBS, Deep Brain stimulation), - a method associated with electrical stimulation of specific brain structures that are supposed to be most responsible for a particular mental pathology, including depression (Maiberg HS et al. Deep Brain Stimulation for Treatment-Resistant Depression, Neuron, Vol. 45, 651-660, March 3, 2005). Some of these methods are also practiced for the treatment of obsessive-compulsive and anxiety disorders, as well as severe insomnia.

Each of these methods, in combination with pharmacotherapy or on its own, can bring an improvement in the condition of some patients, including some normalization of sleep structure, but none of them is universal. Some of them have very narrow boundaries of effectiveness. For example, the deprivation of night sleep or morning REM sleep very often gives an instant effect on the first day, which is very important for severe suicidal depression. But this effect disappears after the patient’s first night’s sleep, and he is again in serious condition. Other methods, in particular light therapy, do not lead out of acute and chronic severe depressive states, and in some cases can lead to a transition to hypomania. The ECT method, which has now become completely non-traumatic, is quite effective. However, in addition to the fact that it has certain technical limitations, it also does not work on all patients and requires occasional recurrence.

As for brain stimulation methods, these methods are becoming more effective. They are distinguished by the type (modality) of the stimulus, the parameters of the stimulus (frequency, maximum amplitude of the effective value in the contact biological tissue or on the surface of the body, circadian effects parameters, etc.). However, most of them are in the testing stage, and the technique used is expensive, and in case of implantation of a stimulator it requires surgical intervention. As a result, for example, installing an implantable vagus stimulation device (VNS) costs $ 25-30 thousand. A VNS device costs $ 12,000, plus surgery for another $ 15,000 (http://www.healthyplace.com/Communities/Depression/treatment/vns/index.asp). In addition, the VNS method cannot be considered completely non-invasive and non-traumatic. The use of a stimulator-implant for VNS involves the operation of this device for many months and years. However, after a relatively short duration of the stimulant, some patients experience various complications. The leading manufacturer of implantable stimulants for VNS therapy (Cyberonics Inc.) indicates the following possible side effects of their use: ataxia (muscle twitching during stimulation), shortness of breath, cough, insomnia, disturbances of the vocal cords, nausea, vomiting, nerve disorders in the implantation zone (in the surgical zone, including the carotid artery and jugular vein), dizziness, dysphagia (difficulty swallowing), pain and ringing in the ears, paralysis of the facial nerves (usually left-sided), changes in heart rate, neck pain, toothache, increased asthma and bronchitis as a result of disruption of the vocal cords, etc. Other side effects also occur with other forms of implantation of stimulants (http://members.tripod.com/tricityepilepsy/id25.html).

One of the ways to influence sleep parameters is to use “sleep music” set forth in the patents of the Russian Federation 2096990 and the Russian Federation 2123802. Their difference from the proposed method is that in these patents it is assumed sound, and not electric and / or magnetic, effect on the patient for several minutes, and before bedtime, and not during sleep, and based on the patient's broadband EEG patterns, and not in a specialized frequency band.

This method does not have direct prototypes implemented as working devices. Closest to this invention are methods of magnetic and electrical stimulation of the brain, currently carried out during the whole time of the day or during the only daylight hours at different frequencies (George MS et al. "Transcranial magnetic stimulation", Neurosurg. Clin. N. Am., 2003 Apr; 14 (2): 283-301). Closest to the subject are applications (Europe Patent Appl., WO 2004075714) and (US Patent Appl., 20050033379 and US Patent Appl., 20050049651). However, none of these implementations, as well as patent applications, implements (and does not offer methods) brain stimulation at certain frequencies in the form of selective stimulation of the slow wave stages of sleep in order to deepen these stages (stimulate the appearance and / or deepening of 3 and 4 phases of sleep ) The application (WO2004075714) is an extremely general model of regulation of essentially all forms of effects on a biological object (including even plant objects) in all its states (not only during sleep). Applications (US PA20050033379 and US PA20050049651) cover practically all kinds of methods of brain stimulation for the treatment of depression and anxiety disorders, including implantation of stimulants in the brain, etc., however, without taking into account the possible selective stimulation of individual phases of sleep during night sleep and only at that time. The proposed method, in contrast to methods involving surgical operations on the brain or manipulations such as ECT, which can not be performed in a state of sleep, as one can assume, will be one of the least invasive methods of stimulation.

In order to normalize the architecture of night sleep by selectively stimulating the slow wave stages of sleep in order to deepen these stages (to stimulate the appearance and / or deepening of the 3 and 4 phases of night sleep), a method is provided that involves pulsed magnetic and / or electrical brain stimulation.

The specified method is implemented by non-invasive, low-amplitude, non-awakening of the patient from night sleep stimulation at a frequency as close as possible to the patient’s delta frequency, which reaches the maximum energy spectrum of the patient’s EEG in the range of 0.5 ÷ 4 Hz. Magnetic stimulation is produced by direct exposure to a magnetic field on brain structures in a state of sleep. Electrical stimulation is carried out in one of two ways: (1) by applying an active electrode to the patient's skull; (2) by acting on the sensory inputs on the patient’s body, from which ascending innervation continues to go into the brain during sleep.

The method is used to treat depression, anxiety disorders, obsessive-compulsive disorders and severe insomnia.

The method has no contraindications due to its complete non-invasiveness, lack of interruption of night sleep and the absence of complications associated with surgical interventions.

The method is as follows.

Immediately before the therapeutic effect (brain stimulation in a state of night sleep), an interview with the patient is conducted according to a standardized scheme. In the treatment of depression, this scheme includes an assessment of the current level of depression on the Hamilton scale, adapted to assess the patient’s current condition at a given time. Moreover, this and subsequent interviews are carried out at a strictly defined time of the day (most preferably immediately after waking up). In the treatment of other named disorders, appropriate psychiatric scales are used, with adaptation aimed at assessing the patient’s condition at a given time, taking into account possible circadian (by time of day) fluctuations in his condition during the day, which, in particular with depression, can be very significant. Then electrodes are placed on the patient’s head to record the somnogram, a stimulation source is fixed on his body, and the patient is laid to sleep. Recording and current analysis of the EEG is carried out throughout the night's sleep. When there are distinct signs of the 2nd stage of a slow-wave sleep in the first sleep cycle, the brain is pulsed with magnetic and / or electric sources of stimulation at a fixed frequency, which is as close as possible to the value of the patient’s delta frequency, at which the maximum energy spectrum of the patient’s EEG is reached in the range of 0.5 ÷ 4 Hz. The amplitude of the stimulation should ensure the complete non-invasiveness of the stimulus, including not awakening the patient from sleep. If the duration of the slow wave phase until the onset of signs of the onset of the REM phase of sleep exceeds 10 minutes, then stimulation in the first cycle of sleep continues until the beginning of the REM phase, otherwise it lasts about 10 minutes. The specified stimulation is then carried out in all subsequent slow-wave phases of sleep throughout the night, and in the second and subsequent cycles of sleep, its minimum duration (during the slow-wave phases) can be increased to 15-20 minutes in each cycle. After awakening the patient the next morning and throughout the course of therapy, the patient is again interviewed. The total duration of the first course of therapy is at least 10 nights with stimulation. Breaks of more than 1 night are not allowed. At the end of the period allotted for the first course of therapy, a detailed analysis of the dynamics of the objective characteristics of the patient’s sleep during the course and his subjective state is carried out, including an in-depth analysis of the dynamics of the circadian characteristics of his condition, based on data obtained during evening and morning interviews. Then they decide to continue the course, or to switch to another type of stimulation, that is, if magnetic stimulation was used in the first course of therapy, then electric impulse stimulation is used in the second and vice versa. It is also possible either alternating magnetic and electrical stimulation within the same course. The course of stimulation is carried out until a significant therapeutic effect is achieved (for depression, to a decrease in the level of depression according to the adapted Hamilton scale not less than two times). At the choice of the attending physician, stimulation can be combined with antidepressant therapy; further selection of a combination of physical (magnetic and / or electrical) stimuli and medications should be adjusted depending on the degree of effectiveness of the stimulation course.

Examples of the method.

Patient L. with severe depression (F33.2 - recurrent depressive disorder, a long-lasting current episode of severe degree without psychotic symptoms according to the classification of MBK-10) and severe disturbances in sleep architecture corresponding to his disease, was subjected to electrical stimulation during sleep at a frequency of 1.5 Hz during the slow wave phases of sleep. Before starting therapy, the patient was poorly presented with the 3rd phase of non-REM sleep and the 4th phase was completely absent. With the passage of therapy, the slow-wave sleep became more pronounced, the 4th phase appeared, the stages of sleep became more pronounced. It is also significant that the characteristics of REM sleep have normalized - the latent period of REM sleep has increased, etc. The patient noted an improvement in almost all Hamiltonian indicators reflecting the current state of the patient during morning interviews, an improvement in subjective assessments of sleep quality, and a decrease in daytime "depressive" drowsiness.

Patient B. with cyclotymia (F34.0 according to the MBK-10 classification) with dominance of depressive episodes, obsessions, serious sleep disturbances (evening insomnia, early sleep interruption, alternating with periods of hypersomnia), underwent brain electrostimulation at the patient's delta rhythm frequency equal to 1 Hz for 2, 3 and 4 phases of sleep. After one course of stimulation, the delta wave index increased noticeably, the total share of delta sleep increased, the number of sleep spindles in the night EEG increased, the depth of sleep increased (decreased muscle activity in a dream, etc.), dream reports became more positive and meaningful , decreased drowsiness in the daytime. The patient reported a surge of energy, improved mood in the morning, obsessive symptoms almost disappeared.

Claims (1)

A method of normalizing the sleep structure of patients with depression, anxiety disorders, obsessive-compulsive disorders and severe insomnia by low-amplitude electrical and / or magnetic stimulation, not awakening the patient, characterized in that the stimulation is carried out during the slow-wave stages of night sleep at a frequency in the range of 0.5- 4 Hz, continuous stimulation for about 10 minutes with a repeat in all slow wave stages of night sleep, the stimulation is carried out for at least 10 consecutive nights, and with positive dynamics, treatment they continue, but in the absence of dynamics, they switch to a different type of stimulation, from electric to magnetic and vice versa, or to combined stimulation, in which electric and magnetic stimuli are successively used for one night or two subsequent nights.