WO2006021820A1

WO2006021820A1 - System and methods to treat headache and migraine

Info

Publication number: WO2006021820A1
Application number: PCT/GB2005/050137
Authority: WO
Inventors: Tuvi Orbach; Yoko Nagai; Holger Kaube
Original assignee: University College London; Health-Smart Limited
Priority date: 2004-08-24
Filing date: 2005-08-24
Publication date: 2006-03-02
Also published as: GB0418907D0

Abstract

Apparatus is provided for monitoring a plurality of physio logical parameters corresponding to a user's psycho-physiological condition. The apparatus comprises (i) an input device comprising a plurality of sensors (1) able to detect different physiological parameters corresponding to the ASS of a person (ii) a receiver unit (9) adapted to input data from said sensors (iii) a processing system (10, 20, 23) able to convert the input data from the sensors to an output detectable by the user and means whereby increasing the ASS of the user causes corresponding changes in the output. The above apparatus may be used in a method for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased activity of the sympathetic nervous system may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack attaApparatus is provided for monitoring a plurality of physio logical parameters corresponding to a user’s psycho-physiological condition. The apparatus comprises (i) an input device comprising a plurality.

Description

SYSTEMANDMETHODSTOTREATHEADACHEANDMIGRAINE

The present invention relates to methods and apparatus for the management of headache and migraine by interactive behavioural techniques.

BACKGROUND OF THE INVENTION

Migraine is a chronic condition which affects 15-20 percent of the world population. Typically patients suffer from 1 or more attacks per month. The attacks consist of moderate to severe headache, accompanied by nausea, vomiting and oversensitivity to light and sound. Typical attack duration is 1-3 days. During the attacks patients are disabled and cannot pursue their normal social and professional activities. Migraine is an inherited condition which affects brain processing and metabolism. Therefore migraine cannot be 100% cured but only treated and managed. Treatment consists of acute pain control and in patients who suffer frequent attacks prevention (25% of patients suffer 2 or more attacks per month). Preventive treatment is usually obtained by daily intake of drugs over many months or years. When the treatment is stopped the migraine frequency will increase again. The pathophysiology of migraine is not completely understood but the current data suggest that the disposition to migraine is linked to abnormal sensory processing in the brain and an impaired energy metabolism of the brain. The exact mechanism by which migraine is reduced by preventive drugs is not fully understood but some drugs seem to normalize sensory processing whereas others improve energy supply to the brain.

Papers by Yoko Nagai et al, Epilepsy and Behaviour, 5 (2004) 216-223; Yoko

Nagai et al, Neurolmage, 22 (2004) 243-251; Yoko Nagai et al, Epilepsy Research 58 (2004) 185-193; and Yoko Nagai et al, Neurolmage 21 (2004) 1232-1241 disclose that negative amplitude shifts of cortical potential are related to seizure activity in epilepsy and that the central regulation of arousal Galvanic Skin Response (GSR) is a sensitive marker of autonomic arousal and physiological state which reflects a person's behaviour. The effect of peripheral autonomic modulation on cortical arousal was investigated with the intention of using GSR biofeedback as a therapeutic treatment for epilepsy.

Clinical and epidemiological data have suggest that migraine and epilepsy are co-morbid, that they are both paroxysmal neurological disorders and the relative risk for migraine is twice as high in patients with epilepsy. Also the prevalence of epilepsy in patients with migraine is significantly higher with a range between 1% - 7%, which is substantially greater than the normal prevalence of epilepsy of 0.5%. Although an epidemiological link exists, the mechanisms of this association are not yet understood. Several causal relationships are conceivable, for example that migraine may cause epilepsy by some changes in cortical metabolism or ischemia. On the other hand, epilepsy may trigger migraine attacks by activating the trigemino vascular system. There may be genetic factors predisposing to vascular or cortical malformations, which may increase the vulnerability both for migraine and epilepsy (Ottoman and Lipton, 1994). Many anticonvulsant drugs are effective in migraine prophylaxis. This suggests that there may be a shared neural or neurochemical mechanism in the generation of migraine and epilepsy.

Hitherto GSR biofeedback methods have only been used to bring about relaxation in a patient.

SUMMARY OF THE INVENTION

We have now discovered that the use of biofeedback to increase the activity of the sympathetic system (ASS) in a patient can be used to treat a range of conditions.

In the present method we train patients with migraine to increase ASS using biofeedback system and/or to increase their heart rate variability. The patient visualises the improvement in his condition on a screen. Therefore, even people who find it hard to visualise mentally can see these images and results on the screen. The second aspect is that the visualisation on the screen is driven specifically by the physiology of the patient's body as measured by the sensors which also monitor different autonomic parameters. Thus the patient can see a direct correlation between his/her internal actions and intentions on the one hand and the image of the relevant part of the body (as simulated in the graphical display) on the other. Biofeedback has in the past been used to treat migraine with some limited success by training patient to relax, usually by using the warmth of the patient's fingers, which provides a measure of peripheral blood circulation, as an input signal for biofeedback. We have found that it is advantageous to do the opposite - to train patients to increase their arousal and or their HRV.

In one aspect, the invention provides a method for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased activity of the sympathetic nervous system may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack, said method comprising: measuring by means of electro dermal activity (EDA), galvanic skin responses (GSR), and/or heart rate viability (HRV) at least one parameter representing the activity of the sympathetic nervous system of the patient; supplying at least one signal representing said at least one measured parameter to biofeedback apparatus; and supplying from said biofeedback apparatus to the patient a perceptible stimulus indicating the level of activity of the patient's sympathetic nervous system, the biofeedback apparatus being arranged to provide signals indicating when level has increased for assisting the patient in achieving the increased activity.

In a further aspect, the invention provides apparatus for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased activity of the sympathetic nervous system may assist in resisting the onset of a migraine or headache attack or in preventing or in overcoming a migraine or headache attack, said method comprising: a measurement unit including skin electrodes for measuring at least one parameter representing the activity of the sympathetic nervous system of the patient; and a circuit for supplying at least one signal representing said at least one measured parameter to biofeedback apparatus; and a base station including processor and stored program means responsive to said signal and arranged to supply to said patient a perceptible stimulus indicating the level of activity of the patient's sympathetic nervous system, the biofeedback apparatus being arranged to provide signals indicating when level has increased for assisting the patient in achieving the increased activity.

In a yet further aspect the invention provides a method for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased heart rate viability may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack, said method comprising: measuring by means of a patient transducer at least one parameter representing heart rate of the patient and determining heart rate variability (HRV) thereof; supplying at least one signal representing said HRV to biofeedback apparatus; and supplying from said biofeedback apparatus to the patient a perceptible stimulus indicating the level of HRV, said apparatus being arranged to provide signals indicating when level has increased for assisting the patient in achieving the increased HRV level.

In a still further aspect, the invention provides a method for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased HRV accompanied by increased or decreased activity of the sympathetic nervous system may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack, said method comprising: measuring by means of patient transducer means at least two parameters, one of which by is measured means of skin electrodes and represents the activity of the sympathetic nervous system of the patient, and the other of which represents heart rate of the patient; supplying at least one signal, said signal or signals containing a representation of said activity of said sympathetic nervous system and containing a representation of said heart rate viability to biofeedback apparatus; and supplying from said biofeedback apparatus to the patient a first perceptible stimulus indicating the level of HRV and a second perceptible signal indicating increase or decrease in activity of the sympathetic nervous system, said apparatus being arranged to provide signals indicating when level of heart rate variability has increased and level of sympathetic nervous system arousal has increased or decreased for assisting the patient in achieving the increased HRV levels.

The invention further provides apparatus for carrying out the two above mentioned methods.

BRIEF DESCRIPTION OF DRAWINGS

An embodiment of apparatus in accordance with the invention will now be described, by way of example, with reference to the accompanying drawings, in which:

FIG. 1 is a block diagram of apparatus for use in providing stimuli to a patient suffering, or liable to suffer from headache or migraine, to assist said patient in resisting the onset of an attack or in resisting an attack;

FIGS. 2a and 2b show front and back views of a sensor forming part of the above apparatus for attachment to a patient's wrist;

FIGS. 2c and 2d show front and back views of a hand and wrist with the sensor of FIGS. 2a and 2b attached; FIG. 3 is a block diagram of an infrared biotelemetry transmitter;

FIG. 4 is a diagram of receiver and data processor portions of the apparatus of FIG. 1;

FIG. 5 is a diagram of an infrared telemetry receiver;

FIG. 6 is a schematic view of a preferred embodiment of the present invention; FIG. 7 is an enlarged view of a portion of FIG. 6;

Fig. 8 is a graph showing results in a biofeedback pilot study on migraine patients; and

Fig 9 is a graph representing heart rate variability in the frequency domain, showing upper and lower limits between which measurement is made in one embodiment. DESCRIPTION OF PRESENTLY PREFERRED EMBODIMENTS

As used herein the following abbreviations have the following meanings: ASS: Activity of the sympathetic system Activity of one of autonomic nervous system which is regulated by adrenergic and noradrenergic neurochemicals. GSR: Galvanic Skin Response

Small changes in the electrical current on the skin or changes in the skin conductivity which reflect changes in ASS, mental, and emotional activity EDA: Electro Dermal activity SCL: Skin conductance level

One aspect of GSR which refers to tonic level of skin conductance SCR: Skin conductance response

One aspect of GSR which refers to phasic change of skin conductance. Usually stimulus related.

EEG: Electroencephalography

Electrical activity of the brain which can be recorded from human scalp. VEP: Visual Evoked Potential

A kind of EEG which is evoked by visual stimulation HRV: Heart Rate Variability

Hear rate variability (HRV) refers to the beat to beat alteration in heart rate PROCESSOR OR COMPUTER: There are several methods which are well known to calculate HRV from heart rate. It is possible to use any of these methods for the purpose of calculating the HRV in this invention. For the purpose of this invention any electronic device which can read electronic input, process the information and either present it to one or more users by way of display or audio, or transmit it to another device which can present it to the user is included. Therefore there may be used hand held organisers or mobile phones, electronic game consoles, interactive TV or purpose-made apparatus with some processing power. In the present method we train patients with migraine to increase ASS using a biofeedback system. The patient visualises the improvement in his condition on a screen or by audio feedback. Therefore, even people who find it hard to visualise mentally can see these images and results on the screen. We therefore provide methods in which we train patients with migraine and other headaches by modulating activity of sympathetic system (ASS) using biofeedback. The biofeedback comprises at least one sensor that can monitor ASS changes such as Galvanic Skin Response (GSR), EDA, Heart Rate,

Heart Rate Variability (HRV) and blood pressure. In preferred embodiments, the biofeedback training is targeted to train the user to increase its ASS, although there may also be other groups of patients for whom a reduced ASS parameter is beneficial.

A further preferred feature of the present method is that the visualisation on the screen is driven specifically by the physiology of the patient's body as measured by the sensors which also monitor different autonomic parameters. Thus the patient can see a direct correlation between his/her internal actions and intentions on the one hand and the image of the relevant part of the body (as simulated in the graphical display) on the other.

An embodiment of the invention provides a method of training patients with migraine and other headaches by monitoring their GSR/EDA and training them to increase their ASS.

A further embodiment of the invention provides a method of training patients with migraine and other headaches to increase their heart rate variability by monitoring their heart rate variability, optionally with use of a sensor for monitoring respiration, and training the patients to change their respiration rate to an optimal individual respiration that will increase their heart rate variability.

The methods of the above embodiments may additionally be combined. Furthermore the apparatus and methods described herein can be used as a diagnostic tool. The variety of ASS parameter during biofeedback performance shows prognosis of the condition. The above methods may be used for treating patients with migraine and other types of headache to prevent a migraine attack and/or to reduce migraine severity by training them to increase their arousal and or their HRV when they are symptom- free. As a preventative training, patients may be instructed to relax if they feel any sign of aura that they are going to have a migraine attack.

In one embodiment of the invention there is provided a method of treating an undesired condition of a person comprising (i) connecting the person to a biofeedback apparatus, the said apparatus including means to sense at least one physiological parameter of the person which corresponds to the activity of the sympathetic system (ASS) of the person and to provide an output detectable by that person which corresponds to a physiological system to be changed, the output changing based on changes sensed in the at least one physiological parameter;

(ii) detecting the output by the person; and

(iii) controlling change in the output by the person by increasing the activity of the sympathetic system which affects at least one physiological parameter being sensed to cause the output to change so that the physiological system represented in the output is changed to or maintained in a desired state.

The invention also provides a method of treating an undesired physiological condition in a person comprising utilising a biofeedback apparatus which comprises a computer system having an output detectable by a user of the apparatus programmed to provide an output which changes in appearance depending on the signal received from a sensor unit which is structured for attachment to a user, which sensor unit can sense changes in a physiological parameter which corresponds to the ASS of the person and transmits data sensed by the sensor unit to the computer system; there being means for changing said output based on changes in the data sensed substantially concurrently with the changes in the data sensed so that change in the output corresponds to change in the physiological parameter, the method comprising attaching the sensor unit to the person, exposing the person to the said output and the person controlling change in said output by increasing ASS so that the physiological condition represented by the output corresponds to an improved physiological condition or the maintaining of a desired physiological condition.

The invention further provides apparatus for monitoring a plurality of physiological parameters corresponding to a user's psycho-physiological condition the apparatus comprising (i) an input device comprising a plurality of sensors able to detect different physiological parameters corresponding to the ASS of a person (ii) a receiver unit adapted to input data from said sensors (iii) a processing system able to convert the input data from the sensors to an output detectable by the user and means whereby increasing the ASS of the user causes corresponding changes in the output.

The processing system typically will be a computer system in which there is a program adapted to store the input from the receiver and to provide an output detectable by the user.

The use of more than one sensor enables two different parameters to be measured simultaneously and thus to produce an output or outputs which corresponds to a particular change in ASS.

When there is more than one output the changes in the different outputs can relate to a specific condition which is being affected by the change in the ASS.

The psycho-physiological conditions which can be used are those which extract physiological parameters via a sensor from the user which represent the ASS, such as electrodermal measurements, Galvanic Skin Response (GSR), skin temperature, skin blood flow, heart rate, heart rate variability, blood pressure, respiration and respiration rate, skin moisture, etc. The sensors can measure skin resistance, capacitance, and can also include pulse monitors, thermometers, sudometers, EEG etc. The preferred parameter is the skin resistance which decreases with increase in the ASS. With very sensitive sensors it is possible to differentiate in the EDA (or the GSR) between three sub-components: (i) tonic activity level which reflects slow changes of the skin conductance (SCL), (ii) phasic activity which is related to the response to stimulation (SCR) and (iii) spontaneous fluctuations of the skin conductivity. Previous biofeedback systems are designed to measure and measure only the tonic activity of the GSR (SCL).

In an embodiment of the invention the sub-components are measured separately and preferably simultaneously or in parallel and the values of these sub-components are processed to obtain an output which is controlled by the user which is related to any one or any combination of these sub-components. A suitably high resolution analogue to digital conversion system can be used to obtain separation of these sub-components.

The invention also provides apparatus and a method for monitoring a plurality of physiological parameters corresponding to a user's psycho-physiological condition the apparatus comprising (i) an input device comprising a sensor able to measure the GSR of a person (ii) a receiver unit adapted to input GSR data from said sensor (iii) a processing system able to separate the GSR into a plurality of sub-components and to convert at least two of the sub-components to an output detectable by the user and means whereby increasing the ASS of the user causes corresponding changes in the output.

This aspect of the invention allows measurement of the three components in parallel and produces an output related to any one or any combination of these three components. To enable to capture all these GSR components, the apparatus can make use of high resolution analogue to digital conversion system.

In an embodiment of the invention the GSR is computed in three different ways. Although biofeedback using the SCL (skin conductance level) has been used and equipment for this purpose is commercially available hitherto no system computes or analyzes the GSR in three different ways for biofeedback. It is a feature of the invention that the information gathered from multiple input sources can be computed to diagnose diseases and monitor their progress and the treatment responses.

Biofeedback performance of patients (course of responses) of patients is highly individual. Thus the system of the invention can be used for a diagnosis of many different diseases taking into account individual patient characteristics that will be treated uniquely to each patient from the information collected from various physiological parameters derived from the patients during the biofeedback procedure.

In general the method and apparatus can be used to treat any disease of the nervous system, psychiatric condition or neurological condition which are linked to abnormal cortical excitability and can be treated by increasing the ASS or increasing the HRV. The method can also be used to maintain a desired condition i.e. reducing the occurrence of changes from a desired state by increasing the ASS.

The physiological parameter signal can be transmitted to a processing device such as a computer via a wire or by a wireless means such as an infrared or radio frequency interface.

The computer can compute internal variables corresponding to the physiological parameter signals and analyse information of the state and make corresponding changes in an output device such as one or more of a pictorial or other visual display, acoustic output, tactile or olfactory output controlled by the internal variables.

The method can be used to enable human subjects to increase their ASS in contrast to established biofeedback systems which are designed to reduce sympathetic tone or ASS i.e. to induce relaxation.

The increase in ASS can be useful in treating diseases which share features of abnormal processing in the brain for example in the following conditions and diseases: migraine, trigemino-autonomic cephalgias, tension-type headache, other chronic pain syndromes, affective disorders, anxiety disorders, obsessive compulsive disorder, depersonalization disorders, attention deficit hyperactivity disorder, Tourette syndrome, schizophrenia, eating disorders, tinnitus and vertigo. All these diseases share features of abnormal sensory and cognitive processing, which may be modulated with therapeutic benefit by increased ASS.

Heart rate variability is another important physiological variable related to migraine and other types of headaches. Heart rate variability (HRV) refers to the beat- to-beat alterations in heart rate. The normal electrocardiogram (ECG) is comprised of characteristic deflections referred to as P,Q,R,S,and T waves. The P wave is caused by the current generated just before the contraction of the atria. The complex QRS wave is the result of the currents generated in the ventricles during depolarisation just prior to ventricular contraction, the R wave being the dominant component. Under resting conditions, the ECG of healthy individuals exhibits periodic variation in R-R intervals. Heart rate variability is closely linked to respiration, blood pressure and emotion, thus good indicator of autonomic functions.

Spectral analysis of HRV is derived from R-R interval data which may be represented on a tachogram in which the Y axis plots the R-R intervals and the X-axis plots the total number of beats. Spectral analysis of the tachogram e.g. using the fast Fourier Transform transforms the signal from time to frequency domain, frequency being represented on the X-axis and power spectral density (PSD) being represented on the Y-axis. The power spectrum contains at least two major components: a high frequency (0.18-0.4 Hz) component, which reflects parasympathetic activity of autonomic nervous system and a low frequency (0.04 to 0.15 Hz) component that appears to be mediated by both the vagus and cardiac sympathetic nerves. Reduced HRV has been used as a marker of reduced vagal activity and the impairment of HRV is reported in various range of neurological, somatic and mental diseases. Several prospective studies have shown that reduced HRV predicts sudden death in patients with myocardial infarction and impaired HRV may be related to sudden death in epilepsy. Reduced HRV appears to be the final common pathway linking negative affective states and conditions to ill health. In a study of migraine, patients suffering from sever migraine cases had significantly lower HRV compared with light migraine cases and controls subjects.

In one embodiment of the present method, by monitoring heart rate and analysing HRV using a method such as FFT or autocorrelation it is possible to analyse the specific range of the spectrum in which the amplitude is higher, and to train the user to move it and increase the amplitude by improving their respiration process, for example by breathing slowly and deeply until the feedback from the HRV will improve. Known methods of providing a signal or stimulus to the patient may be used. For example, the feedback signal may be sound which may change in intensity, pitch or frequency, by a visible signal e.g. a graphic animation which is preferred or by a touch- perceptible signal such as a mechanical vibration. Using this method the users can train themselves to increase HRV and reduce their susceptibility to migraine and other types of headache.

Heart Rate can be monitored (and calculated) by several methods such as ECG or photplethysmograph or piezo electric sensor e.t.c. HRV can be calculated in any method described in the medical literature. By combining interactive multimedia training with the biofeedback training, the user/patient is enabled to learn and implement the methods by himself without the need of expensive biofeedback specialist or clinician.

Another method that may be used is to choose a range around the peak of the maximum which related to the respiration rate (the sinus Breathing arrhythmia) of the user and/or specific range such as between about 0.04 Hz and about 0.18 Hz and calculate in almost real time the area under the graph between these two frequencies (plotted on the X-axis), or in similar way the integral of the PSD/frequency graph between these two positions (See Fig. 9, where the arrows represent the upper and lower positions). In the case of a graph which does not show a continuous function but is made up of many discrete measurements (many small rectangles with similar small base and their heights is the graph), that the area is the total area of the rectangles between the two positions. The user is shown his PSD/frequency graph and is instructed to try to increase this total area. An alternative method is to show him his PSD/frequency graph and to instruct him to try to increase the area between the two positions compared to the area which is above and below the two positions. Alternatively these ratios may be transformed into more easily comprehended graphical representations on a display which the user is instructed to adjust to bring about the required change in his heart rate variability.

Patients are preferably trained (a) to be aware to their physiology - when there are changes from their normal pattern, (b) what are the correlations between these changes and the trigger of migraine/headache attacks, and (c) what type of exercise (breathing, biofeedback) is the best for them to prevent the attack. There can be long term training prevention methods such as increasing arousal and increasing HRV and maybe for some patients - relaxation training. There should be a separate procedure when they feel "aura" - to stop and eliminate the specific Migraine attack.

By adding interactive health education specifically targeted to migraine and headache to the biofeedback training programme, (such as proper life style nutrition and other aspect that can influence headaches), patients can understand better the trigger to their headache and implement strategies to reduce or prevent them. These strategies combine with the biofeedback training can further reduce the severity and the probability to get headaches including migraine.

By adding the CCBT (computerised cognitive behavioural therapy), the patients can also benefit from psychological therapy (e.g. reducing depression levels, increasing confidence, and this can also enhance their health.

The above methods may be combined with interactive multimedia training.

In the apparatus of FIG. 1 which in intended for providing signals to enable a patient to monitor the, signals representative of a parameter being sensed by a sensor are sent via an infrared link or low power radio link from a sensor and transmitter 1 to a receiver 9. A sensor unit forming part of the above apparatus comprises an attachable wristband 2 (FIGS. 2a to 2d) carrying first and second skin electrode pads ELl, EL2 of electrically conductive rubber for making electrical contact with the patient's skin and a micro-electronic device for detecting the galvanic skin resistance (GSR) of the wearer. The device is mounted in a watch-like case 3 and is connected electrically to the two skin electrodes ELl and EL2. A stabilised voltage Vref (FIG. 3) is applied in series with resistors Rl and R2 and the two electrodes ELl and EL2. When the wearer's skin resistance increases, the voltage between the electrodes and the output voltage VO which feeds the input to high impedance buffer amplifier 4 both rise. Galvanic skin resistance levels can vary over a range of over 100 to 1. The simple input arrangement illustrated in detail in FIG. 3 offers two special benefits for GSR measurement. First, the output voltage never saturates, even though its response may be low at extreme resistance values; and second, over a useful resistance range of about 30 to 1, the output voltage responds approximately linearly to the logarithm of skin resistance. These features provide an orderly and stable compression of the large input parameter range, allowing satisfactory transmission within the rather restricted, typically 4 to 1, modulation range of the simple telemetry system used. Resistor R2 limits the minimum output voltage from the chain. The output voltage V2 from the buffer amplifier 4 feeds the input of the following voltage controlled oscillator 5 section which generates a square wave output of frequency proportional to V2. The output frequency of oscillator 5 can vary from about 100 to 400 Hz corresponding to input extremes of zero and infinite resistance at the electrodes but generally lies within the 150 to 350 Hz range in normal operation. The square wave output from the oscillator 5 is fed to the pulse forming stage 6 which generates a rectangular pulse of about 15 μsec duration following every negative going transition of the oscillator 5 output waveform. This output pulse turns on a transistor driver stage 7 which delivers a 15 μsec 0.6A current pulse to infrared emitting diodes 8. The transmitter is powered by a PP3 9 V dry battery of about 400 mAH capacity allowing for at least 60 hours of operation before battery replacement. It will be appreciated that the IR transmitter and receiver illustrated may be replaced by a corresponding analog or digital transmitter and receiver worked by low power radio. The receiver 9 is mounted in a small plasties box to be placed on top of a computer screen 10 (FIG. 4). Pulses of infrared radiation emitted by the transmitter 1 are detected by a reverse biased large area PIN photoelectrode 11 (FIG. 5) with integral infrared filter. Photocurrent from the detector diode is fed to the input of an infrared pre¬ amplifier integrated circuit 12. The passband of this pre-amplifier is designed to reject the effects of unwanted infrared radiation, e.g. from sunlight, lighting fixtures and other interfering sources. A rectangular pulse of about 25 μsec duration is generated at the pre-amplifier output following the reception of each pulse from the transmitter. The pre- amplifier output pulses are fed to the input of a one-chip micro-controller 13 which counts the incoming pulses over a sampling period of about 95 milliseconds and then computes the corresponding pulse frequency to 12-bit precision. This value is then incorporated into two data bytes which are serially output from the micro-controller at a data rate of 9600 bits per second. Additional bits identify the most significant byte and flag the received signal quality. A transistor line driver 14 then delivers this signal at the appropriate voltage levels through a receiver output cable 18 to a serial port RS232 of the host computer 10. Output sample rate is 10 per second. Output values sent from the receiver retain the quasi-logarithmic relation to the subject skin resistance. This can be expanded by the host computer if desired.

The micro-controller 13 operating programme incorporates several measures to maintain very low noise levels and good output recovery characteristics in spite of the effects of interference and subject movement. These include the rejection of pulses arriving at irregular intervals and the handling of periods of signal loss which occurs particularly when the pre-amplifier automatic gain control sub-system cannot adapt fast enough to sudden reductions in received pulse intensity following subject movement. Poor reception quality as determined by received pulse regularity and other criteria applied within the micro-controller programme is signalled by an auxiliary bit within the information sent to the host computer 10 as determined by a clock oscillator 19. The modest power requirements of the receiver are obtained from the host computer's communication port 15, eliminating the need for a separate receiver power supply. The data is received as a standard RS232 input and for data processing 20 (FIG. 1) is specially encoded. Meanwhile, possible errors are detected and corrected. Then data is decoded and separated into status and parametric data. The parametric data is fed as an input to the analysing systems, which coordinate with animation, audio and other specialised systems determined by the programme being run in the computer. The analysing system stores the data, which can be used to create various types, graphs and charts. These can be used to profile, compare or monitor the subject's accomplishment on-line or during subsequent analysis sessions.

Software for the computer can provide for a variety of visual stimuli for making the patient aware of the level and direction of change of his or her level of stimulation in the autonomic nervous system. For example, in an animation system 21 (FIG. 1), data is used to manipulate various segments of the computer screen. Changes in input data produce changes in the speed and path of animation. The procession of images encourages the user to progress to higher levels of stimulation which have been found to be desirable for resisting the onset of or reducing the intensity of headache or migraine.

The animation system may be programmed to allow for different layers of skill (beginner, novice and expert). This ensures the adaptation of the system to the particular variations of the user. Therefore achievement, i.e. evolution of images, will take place even before expertise is acquired. In an audio system 21 (FIG. 1), there can be an option to have an audio response which includes both music and voice which may change in response to the psycho-physiological input to provide an alternative pathway for stimuli to the patient..

FIGS. 6 and 7 show a particularly preferred embodiment of biofeedback apparatus, comprising a computer 30, a monitor 32, a receiver 34 and a sensor unit 36.

Sensor unit 36 comprises a pair of non- invasive skin contact electrodes 38, connected by wires and a jack plug 40 to a sensor box 42. Sensor box 42 contains appropriate electronics (not shown) to convert the resistance between the electrodes 38 into a digital format signal. Sensor box 42 also contains switches 44 and infrared transmitters 46.

Receiving unit 34 comprises receiver box 48 and a wire and connector 50. The connector 50 connecting into a data entry port (not shown) on computer 30. This may be a standard serial communications part. Receiver box 48 contains an infrared receiver

(not shown) and electronics appropriate to convert received infrared signals into computer usable form.

In use, electrodes 38 are applied to adjacent finger of a user's hand 52 and held in position by way of a band surrounding both electrode and finger 54. Band 54 is preferably of burr fastener material, but may be of any other suitable material. The electronics in sensor box 42, powered by a power source also contained in sensor box 42 (not shown) periodically assess the skin resistance of the user's hand 52 via electrodes 38. The electronics in sensor box 42 convert the readings of galvanic skin resistance into a data form suitable for transmission, and send the suitable data form to the infrared transmitters for transmission. Where heart rate variation is measured, the band may also support an LED-based IR transmitter/receiver (not shown) for monitoring the peripheral blood pulse.

The infrared receiver in receiver box 48 receives the transmissions from infrared transmitters 46 and directs them to the electronics in receiver box 48. There the data is converted into a form suitable for inputting into the computer 30 which is running under the control of an appropriate computer program. In this particular preferred embodiment, the software running on computer 30 is generating on monitor 32 an image of a fish 56 swimming over a seascape 58. As the user's autonomic nervous system becomes more aroused or active, the user's galvanic skin resistance will fall. This will be detected by electrodes 38 and conveyed to the computer via sensor unit 36 and receiver unit 34. The software will generate graphics showing the fish swimming from left to right on the screen. As the fish 56 swims further to the right relative to the seascape 58, which scrolls to the left, the software is arranged to change the display so that the fish metamorphoses first into a mermaid then further into a human then an angel then a star. If, during this process, the user's autonomic nervous system becomes less aroused, so causing his galvanic skin resistance to rise, the fish, or whatever form it is at that time, travels to the left and the seascape scrolls to the right. The relative movement of fish 56 and seascape 58 enable the user to ascertain whether his autonomic nervous system is becoming less or more aroused.

In the apparatus described above (see also US-A-6067468), the electrodermal activity signal constitutes a varying input to the computer programmed to respond to changes in that input. A typical program will operate under the control both of that parameter, but more importantly also under the control of the program user. For example, the program on loading may cause the screen to display a menu giving a variety of options selectable in customary fashion using a mouse, keyboard, keypad or the like. Appropriate options are informational material, text and/or graphics, an explanation of the treatment part of the program and a menu option to select actual treatment. In use there can be a computer apparatus under the control of a suitable program which provides an output under the control of the program so the output is dependent on the input from the sensor or sensors with optionally other inputs via a keyboard etc. Such systems are commercially available. In principle when the output is in the form of a visual display, the display viewed by the user may vary widely and consist of graphics, animation, text, speech, video, audio music, sound effects or combinations of any of these. The timing of image display will be controlled by the program. The program may be one which displays subliminal stimuli via the screen as well as consciously perceptible images. The program may be arranged to display to the user an indication of the physiological parameter measured, thus enabling the user to try and consciously moderate or modify their response in view thereof. When the output is in another form e.g. is an acoustic signal the program may also control audio output devices and, for example, cause a voice or sound synthesis module within the system to generate speech, music and/or other sound, all coordinated with the desired therapeutic treatment to be effected.

Apparatus as described above may be used for the treatment of migraine sufferers according to the following procedure: 1. A patient who suffers from migraine receives a bio-interactive monitor and training device (preferably a device sold under the trade name SmartMind) with an integrated sensitive EDA sensor (16 bits resolution) and HRV sensor. The sensor can transmit data in real time to a base station incorporating a processor (which will normally be a desktop or portable computer but may also be a mobile phone, PDA. or interactive game console), which provides output signals to the patient for real time feedback to the patient as an audio signal, a visible signal such as graphics on a display or even a vibration signal.

2. The patient attaches the sensors according to the instructions. It can be enough just to touch the multi sensor with the tip of the finger (or according to the specific versions of the device to put his finger inside the device etc).

3. The patient receives interactive instructions and feedback. There may be instructions for the first learning stage with just a simple exercise to try to change his state of body and mind to reach the target, and optionally with more details e.g. breathing instructions and/or muscular tension and relaxation instructions and later on.

4. The apparatus monitors the patient in real time and can present multimedia instructions and targets for training the patient to optimise his ASS and HRV.

5. The host processor or base station can record the session, can transmit it and present it to a clinician/coach in real time (e.g. over internet or through a dial-up or mobile phone connection or other methods), and the clinician can assist the patient in real time or with subsequently transmitted instructions.

6. The user can receive real time feedback and positive reinforcement when he is progressing in the right direction. 7. Both physiological data and subjective information from the user can be recorded, and information about the progress/changes from the last session (e.g. number and severity of migraine attacks during the last week.)

8. The length of the session can be varied. From about half an hour as an average to few minutes as a reminder monitoring progress for experience user.

9. The user is encouraged to manage a diary to monitor the number, the severity and the trigger circumstances of the headaches / migraine attacks.

10. The above procedure is used as training to prevent migraine.

11. There will be a separate procedure and instruction for users if they feel aura of migraine, and another procedure instruction during a migraine attack. For example during the aura the patient may receive instructions and training to relax or to increase the state of arousal of his autonomic nervous system as indicated above. During a migraine attack the user may be given instructions to treat the migraine conventionally by rest, avoidance of bright light, etc.

Example 1

The abnormality in sensory processing in migraine is detectable outside the acute headache attack. It can be measured by exposing the experimental subject to repetitive sensory stimuli such as sounds or flashing lights. Each stimulus will evoke a brain response in an alert subject and this can be quantified by surface recording of the cortical brain activity with an EEG apparatus. In subjects without migraine the brain activity immediately entrains (or synchronizes) with the pattern of the stimulus (large initial response) but in the course of seconds to minutes the brain recognizes the repetitive nature and the amplitudes of cortical brain activity become increasingly smaller of in the course of stimulation. This reduction over time is referred to as habituation. The opposite pattern occurs in migraine patients. It takes them longer to entrain with the stimulus (low initial response) but after lull activation of the brain has occurred the evoked responses become smaller over time. This means the patients display a lack of habituation.

With two effective migraine preventive drugs propranolol and valproate it could be shown that in parallel with the reduction of migraine frequency the evoked brain responses normalized ie the initial responses became larger and the ability to habituate was restored.

In clinical studies in migraine patients with high frequency stimulation with very strong magnetic fields over the occipital cortex the sensory processing was also changed to normal high initial responses and normal habituation and this was also accompanied by a reduction in migraine frequency.

It can therefore be concluded that methods that change sensory processing in migraine patients may generally be beneficial in reducing migraine frequency.

In epilepsy it was recently shown that arousal biofeedback can reduce epileptic seizure frequency.

We have therefore conducted a pilot stuffy and investigated the effect of biofeedback with increasing ASS on sensory processing in normal and migraine subjects.

12 Subjects (6 migraine patients and 6 normal controls) participated in the study. Visual Evoked Potentials were measured three times (two baseline measurement (Baseline 1 and Baseline2) and one measurement after biofeedback). Subjects were asked to take a seat in front of the xenon flash lamp (30cm). Stimulation by means of light flashes was provided at 8Hz over 90 seconds. Clear Visual Evoked Potential was derived followed by the each flash stimulation. 600 consecutive sweeps of VEP were grouped into 6 blocks of 100 averaged sweeps for each session, baseline 1 baseline 2 and the one after biofeedback with increasing ASS. In the biofeedback was performed using the Galvanic Skin Response (GSR) as a physiological parameter and biofeedback was given to increase Activity of Sympathetic System (ASS).

Initial amplitude (first blocks of 100 sweeps) were compared between averaged baseline VEP and VEP after biofeedback with increasing ASS in both the subjects with migraine and healthy controls.

The results showed increased initial amplitude of the VEP in migraine patients compared to the healthy control followed by biofeedback with increasing ASS, suggesting that the biofeedback modified. A graph of the results obtained appears as Figure 8. The implication of the results are that the biofeedback to increase ASS may be used for therapeutic tools for patients with migraine and other headaches to reduce number of patients' migraine attacks and the severity of the headache.

Example 2 - Procedure with therapist

The clinical efficacy of treating Migraine patients is investigated by training them to optimize their autonomic sympathetic-parasympathetic balance using

HealthSmart's interactive sensors with EDA (Electro Dermal Activity) and HRV, as prophylaxis of migraine. The study has the objectives of investigating the prophylactic effect of EDA and HRV training on patients with migraine attacks, investigating specific procedures, investigating correlations between HRV levels and fluctuations before, during, and after the biofeedback training and severity of migraine during these periods, and investigating changes in the EDA levels and fluctuations before, during, and after the biofeedback training and severity of migraine during these periods.

The evaluation is carried out as a randomized, controlled, double-blind parallel group study with the following groups:

A) Using EDA training to increase arousal.

B) Using EDA training for relaxation. C) Using HRV training to increase HRV

D) Using placebo biofeedback training

E) Using both EDA and HRV training simultaneously to increase arousal and HRV

F) Using both EDA and HRV training to increase relaxation and HRV

Subjects (Inclusion/exclusion criteria) 120 patients with migraine without aura (see sample size calculation) 20 patients in each group .

Inclusion criteria: diagnosis of migraine without aura (IHS 2004); aged between 18 - 60 years; migraine attack frequency 3-8 attacks / month; with patients receiving migraine preventative treatment, the latter must have remained unchanged in the 6 months prior to inclusion in the study. Exclusion criteria are major psychiatric illness (major depression, psychosis and acute anxiety disorders), a progressive neurological disorder and learning disability.

Patients are recruited from headache clinics at hospitals.

The design follows the guidelines of the International Headache Society. It consists of a one month baseline and three months treatment period. Patients attend the investigator site/clinic four times during the study: Visit 1 : Screening and inclusion if patients are eligible.

Instruction on how to use headache diary. Visit 2: Reviewing of the diary if inclusion criteria are met.

Instruction on how to use the biofeedback system at home. Vist 3: Following up and diary review after a month of treatment. Visit 4: Following up and diary review after three months of treatment.

Patients perform GSR and / or HRV biofeedback at home for half an hour three times per week throughout the three month treatment period. In the biofeedback group, patients are trained to decrease skin resistance by receiving feedback of their GSR and / or HRV change as an animation sequence on the computer screen, and in placebo control, the patients are shown a randomized animation sequence which is not related to their GSR or HRVchange. The PC based biofeedback equipment including software and sensors, is provided by Health- Smart LTD, UK.

The primary outcome measure of this study is migraine attack frequency and severity, calculated as response rate after 3 months treatment compared to baseline. A response is defined as a reduction of migraine attacks >=50%. Secondary outcome measures are: response rate after 1 and 2 months, the number of days with migraine headaches, and attack duration after 1, 2 and 3 months of treatment.

With modern prophylactic drugs typical effects on migraine frequency are reductions by 2 attacks per month in the active treatment group and by 1 attack per month in the control group. A typical mean attack frequency is 5 attacks per month with a standard deviation of ± 2.5 days. Thus, to detect a reduction by 2 days with a power of 0.90 at a type I error rate of α = 0.05 a sample size of 18 patients is required. To retain sufficient power with an expected drop out rate of <= 20% a total of 24 patients.

Responder rates with the dichotomous outcome will be compared by Fisher's Exact test. Effects of treatment on migraine attack days and duration are assessed by ANOVA for repeated measures with the within subject variable (time) and between subject variable (treatment group), with baseline measures as dynamic covariates. Post hoc tests are performed using Student's t-tests with Bonferroni correction for multiple comparisons. If assumptions of sphericity are not met, corrections of degrees of freedom according to Greenhouse-Geisser are applied.

Dry Nickel plated electrodes or gold plated electrodes or other electrodes are placed on the palmar surface of the participant's index and middle finger of their hand. Biofeedback takes the form of the same computer-generated graphics, will be presented visually on a computer monitor in front of the patient. Reduction in the participant's skin resistance (GSR) resulted in the rightward movement through a series of animations. Should the patients' GSR reverse its resistance then the display would return to an earlier form. A month baseline period, a three-month treatment period in which patients are given biofeedback treatment. A month of follow up assessment will follow. In all phases, patients were asked to keep a careful record of their number of migraine attacks. During the treatment phase, participants attend a total of 36 sessions (3 sessions / week). Each session will last 30 minutes. After the completion of the treatment, each patients will be asked to continue to keep careful headache records for another month months and to practice the skill they learned in biofeedback session at home without the biofeedback machines, preferably on a daily basis. HRV level is also presented in the form of animation. Audio feedback is also optional for example if the patient is blind, or as an add on to the visual feature.

Heart rate variability is measured using an ear lobe photoplethysmograph (PPG) which is preferred or a piezo-electric sensor or ECG electrodes, preferably a finger photoplethysmograph. A PPG is a non-invasive transducer to measure the relative changes of blood volume or arterial pressure in a subject's finger. The waveform obtained from such transducer represents the Blood Volume Pulse (BVP) of the subject. This signal provides as a safe, non- invasive mechanism to assess the Heart Rate (HR) of the subject, by focusing on the maxima of the waveform, possible following some differentiation to emphasize those peaks. Digital signal processing is used to isolate specific features of this wave form to quantify the changes in the BVP from pulse to pulse and conduct power spectrum analysis using fast Fourier transforms. 21 A low frequency component (0.4 - 0.15 Hz) is preferably selected as the basis for biofeedback because it may provide an index of parasympathetic-sympathetic balance, but less preferably a higher frequency component (0.18-0.4 Hz) may be selected. The photoplethysmograph sensor is a small IR-based sensor and where both photoplethysmograph sensing and skin conductivity sensing is required, the photoplethysmograph and the skin contact electrodes may be combined in a single unit or housing for fitting to a single finger e.g. over the tip thereof. Preferably the signal is processed to give a signal in real time from heartbeat to heartbeat or at least for a period which is relatively short compared to patient inhalation or exhalation under the test conditions. Heart rate variability changes between inhalation and exhalation, and the patient may be instructed to adjust his breathing pattern to achieve a desired increase in heart rate variability. It is expected that in at least an group of patients, increase in activity of the autonomic nervous system as indicated by increased EDA and/or HRV will be found to lead to benefits in terms of resistance to migraine onset and/or reduced migraine severity.

Example 3 - Procedure at home

A set of biofeedback system will be provided which include sensor for the GSR and / or HRV and a biofeedback program in the CD, or mobile phone or PDA (personal digital assistant). Patients will install the biofeedback system on the personal computer at home or down load it to their mobile phone or PDA. The treatment design is the same with the one with the therapist and the patients' biofeedback performance will be recorded in the biofeedback system. Patients will be strictly asked A month baseline period, a three-month treatment period in which patients are given biofeedback treatment. A month of follow up assessment will follow. In all phases, patients were asked to keep a careful record of their number of migraine attacks. During the treatment phase, patients at home perform a total of 36 sessions (3 sessions / week). Each session will last 30 minutes. After the completion of the treatment, each patients will be asked to continue to keep careful headache records for another month months and to practice the skill they learned in biofeedback session at home without the biofeedback machines, preferably on a daily basis. Patients will be asked to follow the above procedure strictly and ideally to perform biofeedback treatment around the same time of the day (morning, afternoon or evening etc). Doctors and biofeedback therapist could be available during the treatment of three month for queries. In a preferable method, users data and feedback can be sent during or after every session (using internet or mobile communication or a telephone line, to a control centre).

Claims

1. A method for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased activity of the sympathetic nervous system may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack, said method comprising: measuring by means of skin electrodes at least one parameter representing the activity of the sympathetic nervous system of the patient; supplying at least one signal representing said at least one measured parameter to biofeedback apparatus; and supplying from said biofeedback apparatus to the patient a perceptible stimulus indicating the level of activity of the patient's sympathetic nervous system, the biofeedback apparatus being arranged to provide signals indicating when level has increased for assisting the patient in achieving the increased activity.

2. The method of claim 1, wherein the measured parameter is electro-dermal activity or skin resistance.

3. The method of claim 1, wherein the measured parameter is peripheral skin temperature.

4. The method of claim 1, wherein the measured parameter is heart rate variability, heart rate or blood pressure.

5. The method of any preceding claim, wherein the perceptible stimulus is variation responsive to the measured parameter in speed, path or evolution of images displayed on a screen.

6. Apparatus for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased activity of the sympathetic nervous system may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack, said method comprising: a measurement unit including skin electrodes for measuring at least one parameter representing the activity of the sympathetic nervous system of the patient; and a circuit for supplying at least one signal representing said at least one measured parameter to biofeedback apparatus; and a base station including processor and stored program means responsive to said signal and arranged to supply to said patient a perceptible stimulus indicating the level of activity of the patient's sympathetic nervous system, the biofeedback apparatus being arranged to provide signals indicating when level has increased for assisting the patient in achieving the increased activity.

7. The apparatus of claim 6, wherein the circuit is arranged to supply a signal indicative of electro-dermal activity or skin resistance.

8. The apparatus of claim 6, wherein the circuit is arranged to supply a signal significant of skin temperature.

9. The apparatus of claim 6, wherein circuit is arranged to provide a signal significant of heart rate, heart rate variability or blood pressure.

10. The apparatus of any of claims 6-10, wherein the base station is arranged to provide in response to the received signal a stimulus in the form of speed, path or evolution of images displayed on a screen.

11. A method of treating an undesired condition of a person comprising (i) connecting the person to a biofeedback apparatus, the said apparatus including means to sense at least one physiological parameter of the person which corresponds to the activity of the sympathetic system (ASS) of the person and to provide an output detectable by that person which corresponds to a physiological system to be changed, the output changing based on changes sensed in the at least one physiological parameter;

(ii) detecting the output by the person; and (iii) Controlling change in the output by the person by increasing the activity of the sympathetic system which affects at least one physiological parameter being sensed to cause the output to change so that the physiological system represented in the output is changed to or maintained in a desired state.

12. A method of treating an undesired physiological condition in a person comprising: utilising a biofeedback apparatus which comprises a computer system having an output detectable by a user of the apparatus programmed to provide an output which changes in appearance depending on the signal received from a sensor unit which is structured for attachment to a user, which sensor unit can sense changes in a physiological parameter which corresponds to the ASS of the person and transmits data sensed by the sensor unit to the computer system; there being means for changing said output based on changes in the data sensed substantially concurrently with the changes in the data sensed so that change in the output corresponds to change in the physiological parameter, the method comprising attaching the sensor unit to the person, exposing the person to the said output and the person controlling change in said output by increasing

ASS so that the physiological condition represented by the output corresponds to an improved physiological condition or the maintaining of a desired physiological condition.

13. Apparatus for monitoring a plurality of physiological parameters corresponding to a user's psycho-physiological condition the apparatus comprising (i) an input device comprising a plurality of sensors able to detect different physiological parameters corresponding to the ASS of a person (ii) a receiver unit adapted to input data from said sensors (iii) a processing system able to convert the input data from the sensors to an output detectable by the user and means whereby increasing the ASS of the user causes corresponding changes in the output.

14. A method for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased HRV may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack, said method comprising: measuring by means of a patient transducer at least one parameter representing heart rate of the patient and determining HRV thereof; supplying at least one signal representing said HRV to biofeedback apparatus; and supplying from said biofeedback apparatus to the patient a perceptible stimulus indicating the level of HRV , said apparatus being arranged to provide signals indicating when level has increased for assisting the patient in achieving the increased HRV level.

15. A method for supplying signals to a patient suffering from, or at risk of suffering from migraine or headache and aware that increased HRV in heart rate accompanied by increased or decreased activity of the sympathetic nervous system may assist in resisting the onset of a migraine or headache attack or in overcoming a migraine or headache attack, said method comprising: measuring by means of patient transducer means at least two parameters, one of which by is measured means of skin electrodes and represents the activity of the sympathetic nervous system of the patient, and the other of which represents heart rate of the patient; supplying at least one signal, said signal or signals containing a representation of said activity of said sympathetic nervous system and containing a representation of said

HRV to biofeedback apparatus; and supplying from said biofeedback apparatus to the patient a first perceptible stimulus indicating the level of HRV and a second perceptible signal indicating increase or decrease in activity of the sympathetic nervous system, said apparatus being arranged to provide signals indicating when level of HRV has increased and level of sympathetic nervous system arousal has increased or decreased for assisting the patient in achieving the increased HRV levels.

16. The method of claim 14 or 15, wherein the measurement is by reflected light at a location for measuring peripheral circulation.

17. The method of claim 14 or 15, wherein said measurement is in reflected light at a finger or at the ear.

18. The method of any of claims 14-17, wherein the measurement is by a photoplethysmograph for measuring peripheral blood volume pulse.

19. The method of claim 18, wherein the measurement is by a photoplethysmograph, a piezo-electric sensor or ECG electrodes.

20 The method of any of claims 14-19, including the step of analysing the power spectrum of the patient's heart rate variability using R-R (peak to peak) interval data, and selecting a component having a selected range of frequencies to provide the feedback.

21. The method of claim 21 , wherein a low frequency component (0.4 - 0.15 Hz) is selected.

22. The method of claim 21, wherein a high frequency component (0.18-0.4 Hz) is selected.

23. The method in any previous claim where specific ranges of frequencies in the spectrum will be selected and the area (or totals of the amplitudes in these intervals) will be calculated and the user will be motivated to increase this area (this total sum).

24. The method of any of claims 14-23, wherein signals indicating when level has increased are derived from real time measurements of heart rate variability from heartbeat to heartbeat or in data segments shorter than an inhalation or exhalation time.

25. Apparatus for carrying out the methods of any of claims 14-24.