Assembly for use in the treatment of dementia, depression, HRV regulation, raynaud's syndrome, asperger's syndrome, migraine, dizziness, sleep disorders, burnout, ADHD, muscular and / or joint pain, or autism

Abstract

The present invention relates to an assembly having an EEG appliance, in particular a QEEG appliance and a head part, which has at least two applicators which generate a low-frequency electromagnetic field of an application frequency in a frequency range of 1 Hz to 100 Hz, preferably to 300 Hz, and having a field strength below 20 mT, for use in the treatment of dementia, depression, HRV regulation, Raynaud's syndrome, Asperger's syndrome, migraine, dizziness, sleep disorders, burnout, ADHD, muscular and / or joint pain, or autism.

Description

[0001] Indication for use in the treatment of dementia, depression, HRV regulation, Raynaud's disease, Asperger's syndrome, migraine, dizziness, sleep disorders, burnout, ADHD, muscular and / or joint pain or autism

[0002] The present invention relates to a device for treating neuronal diseases.

[0003] Magnetic field therapy is commonly understood to mean pulsating PEMF (pulsed electromagnetic field therapy) or PST (pulsed signal therapy) as well as the use of permanent magnets.

[0004] The tissue components of the central nervous system (CNS) are divided into gray matter (substantia grisea) and white matter (substantia alba). Both differ in their composition and their characteristic location in the brain (cerebrum) and spinal cord (medulla spinalis). As is well known, charge transport in tissue does not occur via moving electrons, but rather through the exchange of ions. This is very well possible in the consistency of cerebrospinal fluid, whereas fatty tissue or bone exhibit resistance values ​​8-15 times higher. Determining tissue resistance results in, in descending order:

[0005] Bone > white matter > gray matter > cerebrospinal fluid

[0006] The induced current is inversely proportional to the level of tissue resistance. Even in gray matter, this resistance is still so high that the induced currents are only 5-10 times the coil current, even though its propagation is already facilitated by the surrounding cerebrospinal fluid. The magnetic field weakens exponentially with distance from its source. Of the maximum 2 Tesla that can be measured directly at the coil, only about 0.5 Tesla can be detected in the cortex. Excitation above the motor threshold, which can require a current flow of up to 6 mA, is only possible up to a maximum depth of 5 cm below the coil. If the interstitium of the nerve tissue is depolarized by ion fluctuations below 30% of the membrane potential (approximately < 55 mV), the fast sodium channels of the surrounding neurons open. The membrane potential briefly assumes positive values, and an action potential (AP) is generated.This depolarization only occurs directly at the soma at high stimulus intensities. Although the transsynaptic depolarization of a single axon does not trigger an action potential, it promotes the transmission of incoming action potentials, which increases the general cortical excitability. The duration of the refractory period following a depolarization determines whether a second stimulus will trigger another action potential or not. This is important for paired TMS stimuli. In this case, a subthreshold conditioning stimulus is followed by a suprathreshold test stimulus. If the interval between the two stimuli is 1-5 ms, the test stimulus is inhibited, which can be measured by the amplitude of the triggered motor evoked potential. After 8-20 ms, however, amplification occurs. This is referred to as intracortical inhibition (ICI) and intracortical facilitation (ICF). Depolarization has different effects depending on the location of the individual neurons.

[0007] If the axon and dendrites are aligned, the induced currents act antagonistically. In a recurrent axon, however, a synergistic effect occurs. The macroscopic position of the neurons is also important for excitation: Due to the induction geometry, only structures parallel to the stimulation coil, such as intrasulcal pyramidal cells, can be directly excited. Extrasulcal cells, i.e., cells located vertically to the coil, are only indirectly activated via horizontal pathways. Since these pathways make up the majority of all neuronal structures parallel to the coil, it can be assumed that most neurons are excited transsynaptically. This excitation can also be transmitted to distant but anatomically connected cortical areas via association fibers. Illmoniemi et al. found that excitation spread to contralateral and parietal areas when the motor cortex was stimulated in high-resolution EEG recordings.It is known from transcranial electrical stimulation that most excitatory pathways of the motor cortex run occipitofrontally. For this reason, the cathode was always positioned frontally to the anode to generate a current flow in the same direction. While the facilitating effects are most strongly observed with current flows posterior to anterior, according to Ziemann et al., the coil direction has no influence on inhibitory effects. The molecules and ions that make up the cells largely have electric charges or electric and magnetic dipole moments. The temporal change of the magnetic field is directly related to the temporal change of the current. A direct current produces a temporally constant magnetic field, whereas alternating current or temporally pulsed currents produce alternating magnetic fields or pulsed magnetic fields.

[0008] Alternating magnetic fields or pulsed magnetic fields generated by an alternating current in a conductor loop or coil are also linked to an alternating electric field according to Maxwell's equations. Both fields cause a periodic or pulsed reversal of the electric and magnetic moments in the cells. This means that the electric and magnetic moments of the molecules are excited to oscillate in time (i.e., at the frequency) of the applied magnetic field and can influence biochemical reactions. Due to time-varying electric fields, a periodic or pulsed shift in the ion concentration occurs in the region of the cell membrane. The associated change in the potential gradient in the region of the cell interface can cause increased permeability of the cell membrane.The increased mobility of molecules and ions in the cell and in the cell membrane as well as changes in the potential gradient in the area of ​​the cell membrane can have a positive effect on metabolism and, for example, lead to an increase in the partial pressure of oxygen in the tissue, which positively influences oxygen uptake.

[0009] This improves the supply of energy to the cells, thus increasing well-being and vitality. Furthermore, it has a circulation-stimulating, muscle-relaxing, and calming effect.

[0010] Various factors, such as poor nutrition, environmental pollution, and stress, can negatively impact membrane potential. This can lead to impaired cell function, which can lead to a wide variety of symptoms, such as constant fatigue, headaches, decreased performance, and sleep disturbances. In 1980, PA Merton and HB Morton succeeded in transcranially stimulating the corticospinal motor system by applying an electrical impulse using a high-voltage stimulator (TES = transcranial electrical stimulation), thereby inducing contraction of the contralateral hand muscles. This provided the first non-invasive, electrophysiological method to examine the function of the corticospinal motor pathways through the intact skull in conscious humans.However, because this method requires high current intensities to overcome the resistance of the skull, TES is very painful and results in violent contractions of the temporalis muscle. Therefore, this method has not become routinely used in clinical practice or research.

[0011] Just five years later, Barker introduced a new method of non-invasive cortex stimulation, repetitive transcranial magnetic stimulation (r-TMS). r-TMS is based on the principle of electromagnetic induction. By rapidly discharging a high-voltage capacitor, a current of up to 8000 amperes is delivered in a copper coil for several hundredths of a microsecond (ps). This briefly creates a local magnetic field with a high field strength (0.5–2 Tesla [T]), which passes through the skull without resistance. If the magnetic coil is applied tangentially to the skull, the magnetic field induces an electric current in the underlying cortex area. This current is predominantly aligned horizontally to the skull surface and runs in the opposite direction to the current in the coil. According to Maxwell's equation, the current evoked in the tissue is caused by the rapid temporal change of the magnetic field.When stimulating the primary motor hand area (MI-HAND), the tissue current with a posterior-anterior current direction perpendicular to the central sulcus and low stimulus intensity leads to a predominantly indirect "transsynaptic" excitation of the fast-conducting, large-caliber axons of the pyramidal tract fibers.

[0012] Computer-assisted analysis of the EEG data demonstrated that pulsating magnetic fields induce frequency-dependent changes in the subject's brainwave pattern. Figure 1 shows various effects on the EEG of different subjects. The headpiece contains four stimulus coils, and the headband two. The induced current generated in the headpiece stimulates the nerve structures in the central areas – the positive effects of the weak, low-frequency magnetic field are measurable by CERMAG® diagnostics.

[0013] The effect of stimulation can be demonstrated using a case study in Figure 2. QEEG analysis - graphic on the right: 19 Hz = best stimulus frequency. The EEG data is evaluated under the influence of a magnetic field varied over a specific frequency range. This analysis enables individually tailored, optimized therapy with a magnetic field that has objectively measurable positive effects on the respective patient. To guarantee the optimal effect of pulsed magnetic field therapy, its effect on the human brainwave profile must first be determined. This is where the so-called computer-assisted QEEG - frequency spectrum analysis method comes into play. The EEG is recorded during stimulation. During stimulation, the software calculates the frequency spectrum of the EEG signal after just 8 seconds and displays it graphically.The best frequency spectrum of the EEG (low delta, low theta, high alpha in the range 9-13 Hz and low beta) elicited by the stimulation frequency determines the repetition rate of the bursts required for therapy.

[0014] The evaluation is based on the following criteria:

[0015] 1. Amplitude of the alpha: the higher the alpha maximum, the better

[0016] 2. Right-left shift of the alpha maximum, right shift is better, thus brain activity is faster

[0017] 3. Delta: the lower the value of the maximum, the better

[0018] 4. Beta: the lower the value of the maximum, the better

[0019] This unique technology allows us to determine the optimal magnetic field frequency for each individual patient, thus enabling an optimized therapeutic effect.

[0020] Magnetic field therapy usually does not cause any noticeable effects, although some patients report a feeling of warmth or a slight tingling sensation. Dementia is an umbrella term for several diseases, which generally refers to a series of symptoms caused by brain disorders that lead to a decline in cognitive performance. The primary symptoms affected are memory, thinking ability, speech, motor skills, orientation, decision-making and judgment, and in some cases, personality. Changes in emotional control, affective state, social behavior, or motivation can also be accompanying symptoms. According to the criteria of the International Classification of Diseases (ICD-10) of the World Health Organization (WHO), symptoms must have existed for at least six months to be diagnosed with dementia. The onset of the disease is usually gradual.Although dementia is one of the most common diseases in old age, it is not part of the normal aging process.

[0021] The term comes from Latin and is composed of the syllables mens = ability to think, intellect, reason and de = decreasing.

[0022] Alzheimer's disease is the most common form of dementia, accounting for 60-80% of cases, followed by vascular dementia, which is caused by impaired blood flow to the brain—often following a stroke—at approximately 20%. However, other forms, such as Lewy body dementia, frontotemporal dementia (Pick's disease), characterized by personality changes, and mixed forms are also possible.

[0023] However, difficulties with short- and long-term memory do not necessarily indicate the presence of dementia. Symptoms of dementia can also have other underlying causes, such as depression, delirium, age-related forgetfulness, or dehydration.

[0024] Note: A vitamin B12 deficiency is closely linked to the risk of developing dementia, especially if a mild cognitive impairment is already present. This was shown by a recent study linking low vitamin B12 levels with memory impairment and an early stage of Alzheimer's disease. Depression, in particular, which, along with dementia, is the most common mental illness in old age, creates the impression of a dementia-like condition due to the apparent cognitive decline and is therefore also referred to as "pseudo-dementia." Unlike dementia, however, the memory problems subside as the depression subsides. Dr. Alois Alzheimer (1864-1915), a German neuropathologist and psychiatrist, first described the symptoms in 1906. He discovered typical microscopic changes in his patients' brains and gave the disease its name.

[0025] Alzheimer's disease is considered the most common form of dementia. It usually begins with forgetfulness and disorientation, while speech, motor skills, and cognitive abilities are also impaired. However, symptoms vary from person to person and depend on the affected brain areas. The disease usually progresses steadily, leading to the need for care.

[0026] In the EU, the current estimate is approximately 7.3 million, and worldwide, approximately 24 million. In Austria, approximately 110,000 people are affected by Alzheimer's disease. The incidence is increasing, and experts expect the number of dementia cases to double by 2050.

[0027] The gender distribution is irregular: women are more frequently affected by Alzheimer's disease than men in all age groups. With increasing age, the numbers rise exponentially, reaching 8.8% for men and 14.2% for women in those aged 85-89. In this age group, the annual incidence rate of new cases is 4.15% for women, almost twice as high as the 2.42% for men. Women exhibit more language, amnesia, semantic, and orientation deficits than men. In terms of behavioral disorders, women suffering from Alzheimer's disease are more likely to experience depression, while men are more likely to exhibit aggression.

[0028] As Alzheimer's disease progresses, there is an increasing loss of nerve cells and a deterioration of brain tissue. Connections between the cells are lost. While the exact causes are still unclear, two proteins are thought to be the triggering factors in this connection: amyloid beta protein and tau protein, both of which are also present in healthy people. As the concentration of these proteins increases and they clump together, the pathological deposits form in the brain that are the characteristic feature of Alzheimer's disease. A deeper region of the brain, the so-called Meynert nucleus (Meynert basal nucleus), is particularly affected by cell damage early on – this is where the neurotransmitter acetylcholine is produced. This messenger substance is responsible for transmitting information between nerve cells.If it is no longer produced sufficiently due to the death of cells in the Meynert nucleus, communication between the cells and thus information processing is disrupted.

[0029] There are different degrees of Alzheimer's disease. Using the Reisberg Scale, the progression of the disease can be defined in seven consecutive stages:

[0030] Stages 1 and 2 are classified as healthy. Stage 2 describes the perception of family members that the affected person is suffering from increasing forgetfulness. However, the memory impairments are not yet noticeable. The increasing forgetfulness may also have other causes. The abnormalities described in this stage are still considered "normal."

[0031] But degenerative brain diseases, such as Parkinson's disease, can also lead to a loss of the sense of smell. In these cases, loss of smell is considered an important early symptom.

[0032] Medical researchers have also already established a connection between dementia and loss of smell in various studies. Memory plays a crucial role in the ability to recognize smells.

[0033] A new study has now shown that a rapid decline in the sense of smell, in particular, can indicate Alzheimer's disease, a specific form of dementia. For the study, published in the journal "Alzheimer & Dementia," scientists at the University of Chicago examined the anonymized patient data of 515 elderly people participating in Rush University's Memory and Aging Project (MAP).

[0034] Based on the data, the scientists were able to see that those who had lost their sense of smell just a few years after the start of the study were twice as likely to develop dementia or Alzheimer's disease. The researchers found that, in these individuals, a deterioration in their sense of smell was associated with a smaller volume of gray matter in the brain areas responsible for memory and smell. These, in turn, are risk factors for declining cognitive performance and dementia.

[0035] Stages 3 and 4 are the most common stages in which Alzheimer’s dementia is diagnosed:

[0036] In stage 3, mild cognitive declines become apparent. Complex tasks can no longer be solved, orientation becomes more difficult, and word-finding difficulties and forgetfulness begin to become noticeable. This is referred to as mild dementia.

[0037] In stage 4, moderate cognitive impairment becomes apparent; the affected person finds arithmetic increasingly difficult, manages household chores, and mobility is limited. The affected person requires assistance with more difficult tasks of daily living. The deficits are often denied, and demanding situations are avoided. Mild to moderate dementia is present.

[0038] Stage 5 is considered moderate dementia. Temporal and spatial disorientation (date, day of the week, season, etc.) is common. While no assistance is needed with toileting or eating, there may be difficulty selecting appropriate clothing or following the correct dressing sequence. Many activities of daily living can no longer be performed without assistance. Common knowledge such as addresses and telephone numbers is forgotten. The dementia can no longer be denied.

[0039] In stage 6, severe cognitive impairment becomes apparent, and professional care is usually required. The affected person requires assistance with everyday activities – for example, they may become incontinent or need help finding their way around familiar places. Changes in personality, behavior, and emotions (anxiety, restlessness, hitting) become increasingly pronounced. Seasons and temporal changes are no longer perceived, and the sleep-wake rhythm is often disturbed. Short-term memory no longer functions; one's own biography and the name of one's spouse are usually forgotten; memories remain only patchy. Plans can hardly be put into action. Persecutory thoughts, delusions, anxiety and obsessive-compulsive symptoms, restlessness, and previously unknown aggressive behavior may occur. This is referred to as moderate to severe dementia.

[0040] Stage 7 is already considered severe dementia, characterized by severe cognitive impairment and complete dependence on assistance. The affected person appears to be unable to control their body – smiling, speaking, walking, sitting, or holding their head upright are barely possible. In this final stage, the affected person can no longer chew or swallow, and breathing problems become increasingly severe.

[0041] Furthermore, a transitional phase is assumed between normal aging and the earliest stage at which Alzheimer's disease can be diagnosed – a precursor to Alzheimer's dementia, in which everyday skills are still unaffected. This is known as mild cognitive impairment, or "MCI" for short. The term "mild cognitive impairment" was first used in the late 1980s by Reisberg and colleagues to describe individuals who exhibited impairments that did not yet correspond to a specific diagnosis. This phase of mild cognitive impairment thus defines a condition in older people who have experienced some degree of cognitive decline – but the changes are insufficient for a diagnosis of dementia. The concept of MCI is viewed as a pathological condition and not as a manifestation of normal aging.

[0042] The dementia problem in numbers

[0043] 55.4% mild dementia

[0044] 32.1% moderate dementia

[0045] 12.5% ​​severe dementia Different forms of dementia:

[0046] • Alzheimer's Dementia 62%

[0047] • Vascular dementia 17%

[0048] • Mixed dementia form 10%

[0049] • Dementia with Lewy bodies 4%

[0050] • Frontotemporal dementia 2%

[0051] • Parkinson's dementia 2%

[0052] • Remainder 3%

[0053] Figures from Germany

[0054] • 1.5 million people affected by dementia

[0055] • 66% have Alzheimer's

[0056] • 2050 3 million people affected by dementia

[0057] • 300,000 new patients annually

[0058] • Annual increase in dementia patients: 40,000 patients

[0059] • 100 new dementia patients per day by 2050

[0060] Increase in the number of people affected by dementia in Germany from 2010 to 2050:

[0061] Year Patients

[0062] • 2010 1,450,000

[0063] • 2020 1,820,000

[0064] • 2030 2,150,000

[0065] • 2040 2,580,000

[0066] • 2050 3,020,000

[0067] Despite intensive research, there is currently no cure for Alzheimer's. However, various therapeutic approaches offer the possibility of alleviating the symptoms of the disease on various levels and relieving the burden on family members and loved ones of those affected. Depending on the progression of the disease, targeted measures can influence thinking and memory skills or accompanying symptoms of the disease and support family members of those affected. While, for example, in the early stages of the disease, training cognitive skills to slow mental decline and thus potentially stabilize the condition is particularly important, in the later stages, training in everyday practical skills is relevant with the goal of delaying the need for care and maintaining independence for as long as possible.The frequently occurring accompanying symptomatic behavioral abnormalities such as agitation, aggression, and restlessness can be reduced with the help of specific therapeutic options. Professional counseling for relatives or caregivers, who are often under great stress, serves to increase understanding of the illness and improve interactions with those affected. Self-help groups promote the exchange of experiences and information.

[0068] Given the limited effectiveness of pharmaceutical treatments, non-pharmacological interventions have gained importance in recent years. Interventions that demonstrably aim to produce significant cognitive changes are not yet available to those affected.

[0069] It is the object of the present invention to provide a device for the treatment of dementia.

[0070] This object is achieved by a device having the features of the independent patent claims. Advantageous further developments are the subject of dependent patent claims.

[0071] An arrangement according to the invention with an EEG device, in particular a QEEG device and a head part which has at least one applicator which generates a low-frequency electromagnetic field of an application frequency in a frequency range of 1 Hz to 300 Hz and with a field strength of less than 20 mT, for use in the treatment of dementia, depression, HRV, Raynaud's disease, migraine, dizziness, muscular and / or joint pain or autism.

[0072] It has surprisingly been shown that the aforementioned device can be used in the treatment of dementia, depression, HRV regulation, Raynaud's disease, migraine, dizziness, muscular and / or joint pain or autism.

[0073] In a further development of the arrangement, the field strength is preferably less than 10 mT across all coils, in particular less than 1 mT, preferably less than 0.2 mT, and particularly preferably less than 0.1 mT. Magnetic coils (applicators) are variously shaped metal parts through which current flows, generating a magnetic field. This magnetic field changes the orientation of its poles depending on the current frequency. This generates electrical energy around the coil—a so-called induced current. Nerve cells, bones, joints, and tissue are affected.

[0074] Advantages of magnetic coils as an energy source:

[0075] • Less dangerous, no burns on the skin vs electrodes

[0076] • Reduction of risks, e.g. side effects (paradoxical reaction)

[0077] • Longer treatment time (daily therapy duration, total therapy duration)

[0078] • Easy handling by the patient himself

[0079] • Skin surface presents no resistance; therefore, transcutaneous application is possible

[0080] • Targeted application and stimulation of specific brain areas

[0081] • Non-irritation of the pain-relevant skin sensors (no skin current flow)

[0082] In a further development, the applicator has at least a first coil and a second coil, which are arranged next to one another and can be fastened to a headband in such a way that they are located on the head of a patient on the forehead in the area of ​​the frontal lobe, in particular in the area of ​​the prefrontal cortex, in particular on both sides of the longitudinal fissura.

[0083] The coils were developed based on the human head's geometric limitations for optimal comfort and to achieve the desired penetration depth of the magnetic field in the head. This resulted in a special signal shape with a specific rectangular signal duration for optimal operation of these coils.

[0084] This arrangement of coils has been shown to be particularly suitable for the treatment of dementia. In this way, the frontal brain area in the region of the frontal lobe is stimulated, which responds particularly well to treatment in dementia. The first coil and the second coil are attached to a headband in the form of a drawstring and can thus be flexibly positioned and optimally aligned. The coils of the applicator are preferably arranged so that one direction of the magnetic flux is normal to the patient's head. The windings of the coils are preferably arranged in a plane that is aligned tangentially to the patient's head. The described pairs of coils are each aligned symmetrically on the patient's head so that both hemispheres of the brain are equally exposed to the electromagnetic field.

[0085] In one embodiment, the applicator has at least a third coil and a fourth coil, which are arranged next to one another and can be aligned and arranged in such a way that they are located at the back of the head of a patient in the region of the occipital lobe or in the region of the cerebellum, in particular on both sides of the longitudinal fissura.

[0086] An arrangement of the coils in the occipital lobe area has proven particularly beneficial for the treatment of dementia, especially Alzheimer's disease. In stimulation for dementia, these two coils are located directly over the occipital region, as this is where the brain's alpha signal is generated. The better the occipital region functions, the higher the alpha value.

[0087] A coil placement in the cerebellum region has proven particularly beneficial for HRV regulation. This also stimulates the spinal cord, which in turn explains the positive changes in the ECG and HRV measurements.

[0088] Alpha activity coherence is interpreted as an indicator of cerebral connectivity, the integrity and function of axonal and synaptic connections. In Alzheimer's patients, the increase in EEG power in the slow frequency bands reflects the cholinergic deficit characteristic of the disease. In a patient whose cognitive performance is not yet significantly impaired, pronounced EEG changes are a strong indication of the presence of dementia. In a study of patients with mild cognitive impairment, it was found that patients with increased theta and decreased alpha power were at increased risk for progressive impairment. Even in depressed patients with mild cognitive impairment, EEG power in the delta and theta bands is significantly increased, possibly as an early sign of incipient dementia.

[0089] Patients with slowed baseline EEG activity experience a more rapid deterioration of cognitive and functional brain functions over time. Kuskowski et al. (1993) found a correlation between low alpha power and a decline in cognitive performance over the next four years in Alzheimer's patients.

[0090] In a further development of the arrangement, the applicator has at least a fifth coil and a sixth coil, which are arranged diametrically opposite one another and can be aligned and arranged such that they are located laterally on the head of a patient in the region of the temporal lobe.

[0091] The fifth coil and the sixth coil are placed on the side of a patient's head and arranged to serve both the temporal and parietal brain regions.

[0092] To clarify: the geometry of the coil is not so important. What's more important is that the stimulator's square-wave signal drives the coil in such a way that an excitation signal is generated in the brain, generating an extremely steep current rise. This is achieved when the coil and signal are optimally matched. It's not about the coil's geometry or the signal's time constant. The coil should never reach saturation of the hysteresis curve due to induction. Calculations have shown that the electric vortex field, as well as the associated conduction eddy current density and its specific temporal behavior, are responsible for therapeutic success.

[0093] In one embodiment, a stimulation device for generating the stimuli and controlling the coils can be arranged directly on the headband or integrated into the headpiece. The stimulation device can be controlled wirelessly via Bluetooth or Zigbee, for example.

[0094] In Peter SCHUTZ's dissertation, "Electromagnetic Radiation Interaction with Neurotransmitter Release," which was approved in 1983 at the University of Strathclyde (Glasgow), significant changes, including changes in growth behavior, were observed in cell cultures exposed to high-frequency (27 MHz) magnetic fields. Although SCHUTZ's arrangement with large Helmholtz coils and high-frequency currents cannot be directly compared with that of NEUWIRTH (small solenoid with an iron core, low-frequency currents with strong transients), SCHUTZ's suggestion that electrical eddy fields and currents are responsible for the physiological effects in relatively weak magnetic fields should also apply here.In a personal communication, which is not included in the dissertation and which Schütz was unable to follow due to his untimely death, he reported a threshold for the product of frequency and induction amplitude, below which no physiological effects would be observable—a clear indication of the effects of electric vortex fields. To maximize the inductive voltage drop (and thus the vortex fields), the parameter RT / L must be optimized.

[0095] Figure 3 shows the optimized current-voltage coil geometry relationship between the coil and the stimulation signal. The purple curve represents the current—rapid switching of the stimulation direction—and a good pulsating field.

[0096] Figure 4 shows a current-voltage coil geometry combination that is unfavorable (bad) for therapy:

[0097] No switching of the generated current is detectable. The rapidly pulsating effect of the magnetic field is lost. The coil first charges before the switching process can occur. This makes it impossible to achieve a rapid switching of the magnetic field.

[0098] In a preferred embodiment of the arrangement, the third, fourth, fifth and sixth coils are arranged in a head shell, wherein the head shell has a rear part and two side parts extending perpendicularly to the rear part and parallel to one another on two opposite sides of the rear part, wherein the third and fourth coils are arranged in the rear part and the fifth and sixth coils are each arranged in a side part.

[0099] Such a head shell creates a compact and easy-to-use device that can also be used by the patient themselves and reliably ensures alignment of the coils.

[0100] stimulus

[0101] The stimulation signal consists of a burst pattern of 3-ms rectangular pulses. This rectangular signal results from the coil's geometry. With this 3-ms rectangular signal, the coil can generate a current waveform similar to a triangular signal. This triangular signal of the generated current allows the coil to be switched very quickly and without charging effects. The resulting eddy currents with a short rise time around the cell structure and the placement of the coils on the head are optimal.

[0102] In one embodiment of the device, the application frequency when used to treat dementia is 14 Hz, 20 Hz, 40 Hz, 80 Hz, or 100 Hz to 150 Hz. Alternatively, an n-fold harmonic of 14 Hz can be used, with between 1 and 10 bursts depending on the repetition rate of the burst in the signal. When used to treat HRV, 8 Hz is used, when used to treat Raynaud's disease, 14 Hz is used, and when used to treat pain, 2 Hz is used.

[0103] It has been shown that different diseases respond to different numbers of bursts and frequencies to achieve optimal results. For dementia, between 1 and 10 bursts are used – depending on the burst repetition rate in the signal; for pain, 2 pulses; and for HRV, 8 pulses. These bursts are then delivered at the different frequencies described.

[0104] Dementia: 14, 20, 40, 80, 100 Hz to 150 Hz or n times the harmonic of 14 Hz

[0105] HRV: 8Hz

[0106] Raynaud's disease: 14Hz

[0107] Asperger syndrome: 14Hz Pain: 2Hz

[0108] 1. Case studies have shown that different signal forms with different burst patterns, as well as frequencies (how often this pattern is presented per second), must be used for different neural diseases. The same coils are always used.

[0109] 2. For HRV regulation, 7 or 8 rectangles in the burst pattern, offered 14 times per second, have proven to be optimal, which are applied to the third, fourth, fifth and sixth coil

[0110] 3. For patients with pain (muscle pain, tendons or water in the knee), a burst pattern with 10 rectangles and 2 Hz is necessary.

[0111] 4. For Asperger syndrome treatment, 8-10 rectangles in a burst with 14 Hz were used.

[0112] 5. For dementia, stimulation with 1-10 rectangles at a frequency between 20-150 Hz has been shown to be effective, applied to the first and second coils in the frontal region. Coils 3-6 in the occipital and temporal regions are stimulated at 14 Hz. 20 to 150 Hz are used for coils 1 and 2.

[0113] Currently, the optimal frequency is determined through measurements and analysis of the EEG signal, as described above. The goal of further research will be to determine biomarkers that make these measurements obsolete. Numerous parameters must be taken into account: skin thickness, water content, bone density, fat content, cell age, etc.

[0114] The present invention is explained in more detail below with reference to the accompanying figures. They show:

[0115] Figure 1 shows the effects of pulsating magnetic fields on the EEG of different subjects,

[0116] Figure 2 EEG frequency spectra during resting phase and different stimuli, Figure 3 optimized current-voltage coil geometry - signal curves,

[0117] Figure 4 non-optimized current-voltage coil geometry - signal curves,

[0118] Figure 5 Electrode positions according to the international 10-20 system,

[0119] Figure 6 a power spectrum of the EEG,

[0120] Figure 7 shows an alternative representation of the EEG data in an EEG mapping,

[0121] Figure 8 Characteristics of the groups examined in the study,

[0122] Figure 9 Group differences in neuropsychological data,

[0123] Figure 10 Overview of a spatial context memory task,

[0124] Figure 11 Signal representation of the burst pattern of the applied electromagnetic pulses,

[0125] Figure 12 Item memory analysis: significant group effect for both stimulation conditions and both retrieval tasks, with lower memory performance in AD compared to HC

[0126] Figure 13 Relative power for each EEG channel of all seven frequency bands examined for the group of Alzheimer patients (AD) and the healthy control group (HC),

[0127] Figure 14 Relative EEG power between the different data acquisitions with an increase in relative alpha power from baseline to the second resting state during the consolidation phase and from baseline to the post phase,

[0128] Figure 15 Mean peak frequency during stimulation and sham stimulation. In HC, the PSD increase persisted even after stimulation, whereas in AD, the PSD decreased immediately. Figure 16 Individual alpha peak frequency (iAPF). ANOVA on the iAPF at the occipital electrodes revealed significant interaction effects. Further within-group analyses revealed no significant differences at baseline, consolidation, or post-stimulation between stimulation and sham stimulation for either AD or HC.

[0129] Figure 17 Individual alpha peak power (iAPP), ANOVA on iAPP, no significant effects, significantly higher iAPP value during stimulation (consolidation phase) compared to sham stimulation in the AD group, no significant differences at baseline and after simulation. No significant changes in the HC group.

[0130] Figure 18 Correlation analyses within the groups, positive association between iAPP and item memory for AD, but not for HC,

[0131] Figure 19 ECG measurement method for HRV measurement,

[0132] Figure 20 Headband with 2 coils for frontal stimulation, front view,

[0133] Figure 21 Headband with 2 coils - top view with foam, artificial leather and drawstring and

[0134] Figure 22 shows a pillow which can be used to position the coils on the side and back of the subject's head.

[0135] The present disclosure involves the development of a technically optimized diagnostic (Cermag) and therapeutic device (Certis) based on the approach / method of transcranial electromagnetic stimulation. Cermag is based on a quantitative EEG (Q-EEG), in which the recording is limited to a few application-specific electrode locations. EEG stands for electroencephalography. With Q-EEG, the Fourier transform of the received signals is evaluated, i.e., a spectral analysis is performed. The evaluation of the Q-EEG data under the influence of a magnetic field varied over a specific frequency range, the positive or negative effects of which are evident in the Q-EEG pattern, enables individually targeted and optimized therapy with the magnetic field acting on the brain and / or spine via an applicator, which has measurably positive effects on the respective patient.Low-field transcranial magnetic stimulation leads to a frequency- and direction-dependent change in the Q-EEG signature.

[0136] The Certis therapy device consists of a head and base section. The head section stimulates areas of the head, as well as parts of the brain and / or the spine or parts of the spine, with a low-frequency electrical and / or electromagnetic field in the frequency range determined by the Q-EEG via applicators (iron core coils). The portable Certis therapy device, programmed with patient-specific, individualized parameters (frequency, field strength, etc.), then delivers the individualized stimulation parameters for the magnetic field. This therapy device is also distinguished by the fact that it not only delivers the magnetic field stimulation signals, but also includes a high-resolution playback unit for special therapy music. The special feature of this device is that both stimulation methods can be offered simultaneously. The therapy device also has a control unit. The patient uses the control unit to operate the device.Due to its product features, the device enables people suffering from tinnitus to participate in public, professional and private life again.

[0137] The Certis device also features both a mobile protocol data storage device and a dedicated data storage device for the customized parameters. The headpiece – stimulator – consists of a "foam cube" into which the head is placed for therapy. The stimulation coils for the magnetic field are integrated into the headpiece. The frontal headband has two integrated coils.

[0138] A completely new stimulation system for the head was developed, offering greater timing options for the therapeutic field, along with a new coil concept and signal shapes. This development was carried out between 2010 and 2013 in collaboration with the Center for Medical Physics and Biomedical Technology at the Medical University of Vienna, under Prof. Rafolt, and Seibersdorf Labor GmbH, Electromagnetic Compatibility. Further development demonstrated that this type of therapy is effective not only for tinnitus, but also for dementia, HRV regulation, and other neuronal indications. Brain activity is recorded according to the international 10-20 system using an electrode cap (Electro Cap Co., USA). Electrodes are used to record and measure the weak electrical voltage fluctuations of the brain in the range of 1-200 millionths of a volt (pV).To improve the contact resistance between the scalp and the electrode, they are filled with a highly conductive paste.

[0139] This standard system, the so-called 10-20 system, was developed by Jasper (1958) and is shown in Figure 5.

[0140] The 10-20 system is a standardized and internationally recognized system for electrode placement in electroencephalography (EEG). It is used to enable comparable recording and interpretation of brain activity. The importance of a standardized method for electrode placement was discussed at the first International EEG Congress in London (1947). Subsequently, the 10-20 system was defined in 1958 and became the de facto standard for clinical EEG measurements. The 10-10 system has existed as a further development since 1985. The 10-5 system for electrode placement was introduced in 2001. Both systems enable even more precise EEG measurements through a larger number of electrodes.

[0141] Electrode placement

[0142] The 10-20 system is based on relative electrode placement based on specific anatomical landmarks of the head. The positioning of the 21 electrodes is defined by specific percentages of the electrode spacing, with the numbers "10" and "20" in the name representing these percentages. The positioning of the 10-10 and 10-5 systems is based on the respective adjusted percentages.

[0143] Sensitive amplifiers are used to make weak signals visible. Built-in high- and low-pass filters suppress interference outside the EEG frequency ranges of interest. The amplified and filtered analog signals are converted into digital signal sequences. The sampling rate determines how often the analog signal is quantified per second. The digital signal sequences are continuously stored on a recording system.

[0144] EEG data are recorded in an electrically and soundproofed room. The study is conducted with participants relaxed in a chair. Brain activity is recorded for a period of at least 10 minutes with eyes open and closed. After eliminating all epochs containing artifacts (muscle potentials, eyelid and eye movements, skin potentials, interference from the electrocardiogram, and pulse fluctuations, as well as electrode artifacts that can occur when the contact between the scalp and the electrodes is unstable or the electrodes are poorly attached to the head) (visual inspection), frequency analysis (Fast Fourier Transformation) is performed over 19 real electrode positions using 2-s data epochs in real time.

[0145] The EEG data is ultimately presented in the form of brain maps, power spectra, and numerical data. Statistical analysis of the EEG data is performed using the StatView program.

[0146] Sensitive amplifiers are used to make the weak signals visible. Built-in high- and low-pass filters suppress interference outside the EEG frequency ranges of interest. The amplified and filtered analog signals are converted into digital signal sequences. The sampling rate determines how often the analog signal is quantified per second. The digital signal sequences are continuously stored on a recording system.

[0147] EEG data are recorded in an electrically and soundproofed room. The study is conducted with participants relaxed in a chair. Brain activity is recorded over a period of at least 10 minutes under both eyes-open and eyes-closed conditions.

[0148] Quantitative computer-assisted EEG (QEEG) is characterized by the fact that, after eliminating all artifactual epochs, a frequency analysis (Fast Fourier Transformation) is performed across 19 real electrode positions using 2-s data epochs in real time. Artifacts can include muscle potentials, eyelid and eye movements, skin potentials, interference from the electrocardiogram, pulse fluctuations, or electrode artifacts that can occur when the contact between the scalp and the electrodes is unstable or the electrodes are poorly attached to the head.

[0149] This quantitative computer-assisted EEG diagnosis (QEEG) reveals the extent to which the neuronal activity bioelectrically represented in the EEG is altered. The practical significance of QEEG data lies in the fact that it allows for the evaluation of therapies and, at the same time, forms the basis for the application of magnetic field therapy or neurofeedback. Furthermore, it allows for application-oriented EEG diagnostics in neuronal diseases to be limited to recordings from a few electrode sites.

[0150] Using special software, the stored raw data can be subsequently converted into any reference montage using appropriate subtraction or displayed with an average reference. Starting with the stored raw data, these transformations can be subsequently performed freely and as often as required, using the same EEG section.

[0151] The decomposition of the EEG into the classic frequency bands (<4 Hz (delta), 4-7 Hz (theta), 8-13 Hz (alpha), 14-21 Hz (beta), into 1 Hz bands and the representation in the form of brain maps enables the visual presentation of information hidden in background activity. An expanded classification of the alpha frequency range can be found in the table below.

[0152] Figure 6 shows a so-called power spectrum of the EEG, assigned to the electrode positions described above according to the 10-20 system. A representation of the frequency spectrum for each individual recording location is shown.

[0153] Figure 7 shows an alternative representation of the EEG data in a so-called EEG mapping (cartography). This map visualizes the topographical distribution of cortical activity projected onto the surface of the head.

[0154] Mapping analysis does not provide more information than the underlying EEG. However, it does present some of the data in a more informative manner. Spectral parameter mapping refers to data calculated from the frequency analysis of the EEG. The selection of frequency ranges is variable, meaning that both 1-Hz bands and frequency ranges (delta, theta, alpha, and beta) can be displayed.

[0155] In the topographical representation shown, the individual frequency ranges are: delta / theta, alpha, and beta. Regarding the color coding, the following should be noted: the colors blue / black correlate with a low energy level, and the colors red / white correlate with a high energy level.

[0156] Alpha activity coherence is interpreted as an indicator of cerebral connectivity, the integrity and function of axonal and synaptic connections. In Alzheimer's patients, the increase in EEG power in the slow frequency bands generally reflects the cholinergic deficit characteristic of the disease. In a patient whose cognitive performance is not yet significantly impaired, pronounced EEG changes are a strong indication of the presence of dementia.

[0157] A study of patients with mild cognitive impairment found that patients with elevated theta and decreased alpha power were at increased risk for progressive impairment. Even in depressed patients with mild cognitive impairment, EEG power in the delta and theta bands was significantly elevated, possibly as an early sign of incipient dementia.

[0158] Patients with slowed baseline EEG activity experience a more rapid progression of cognitive and functional impairment over the course of the disease. Kuskowski et al. (1993) found a correlation between low alpha power and a decline in cognitive performance over the next four years in Alzheimer's patients. Dementia patients predominantly exhibit a significant slowing and reduction of alpha brain waves and an increase in theta waves. Remaining brain areas otherwise exhibit a largely normal brain wave profile. Local presence of beta waves is not observed in dementia patients.

[0159] In depressed patients, a frontal (forehead area) asymmetry of theta waves can be observed in the EEG. In addition, a strong asymmetry of alpha waves (relaxation waves) can be observed in the EEG in depressed patients. This means that in depressed patients, a disproportionately high prevalence of alpha waves is present only in the left hemisphere or only in the right hemisphere.

[0160] Repetitive transcranial magnetic stimulation (rTMS) is considered a safe, non-invasive, and painless technique that is now widely used for the investigation of various brain functions and the therapeutic stimulation of cortical neurons (Kobayashi, Pascal-Leone, 2003; Rossini, Rosso, 2007). For over 15 years, it has been considered a valuable tool for the study of Alzheimer's disease; in recent years, it has also been increasingly used for treatment. Repetitive transcranial magnetic stimulation (rTMS) is a technique that uses magnetic pulses in rapid sequence at frequencies up to 100 Hz, preferably up to 300 Hz. Depending on the stimulation frequency, rTMS has been shown to influence neuronal activity – it can be applied continuously at low frequencies (1 Hz) or high frequencies (>5 Hz).High-frequency rTMS is increasingly being used successfully to treat various psychiatric and neurological problems (Mantovani and Lisbany, 2004). It is believed that rTMS is involved in increasing synaptic plasticity (Siebner and Rothwell, 2003). TMS is already being used successfully worldwide in the treatment of refractory (therapy-resistant) depression. Recently, reviews of scientific studies have increasingly demonstrated the usefulness of using TMS in Alzheimer's disease (Freitas et al., 2011; Guerra et al., 2011; Nardone et al., 2011).

[0161] Previous studies investigating the effects of rTMS on cognitive functions have found compelling evidence for improvements in some cognitive functions, including executive functions, learning, and memory (Guse et al., 2010). Three additional studies examined the effects of rTMS on naming and language performance in mild to moderate cases of dementia. In two placebo-controlled crossover studies, the dorsolateral prefrontal cortex was stimulated with rTMS during the performance of a naming task, with the result that action naming improved significantly after high-frequency rTMS was applied to either the left or right DLPFC (Cotelli et al., 2006). Cotelli et al., 2008, found an improvement in picture naming as a result of high-frequency rTMS stimulation of the DLPFC.

[0162] In a later study, Cotelli et al. (2011) investigated whether high-frequency stimulation leads to changes in speech production and comprehension in patients with moderate Alzheimer's disease and found that 2 weeks of rTMS stimulation led to a significant improvement in auditory sentence comprehension compared to placebo, with the changes still measurable after 8 weeks.

[0163] Ahmed et al. (2012) compared the effects of high- and low-frequency stimulation on the DLPFC and found that high-frequency rTMS led to improved scores on all rating scales (MMSE, ADL, GDS), which remained measurable even after 3 months. The authors concluded that high-frequency rTMS may be a useful adjunct to the treatment of patients with mild to moderate Alzheimer's disease.

[0164] In a large-scale study, Sole-Padulles et al. demonstrated the positive effects of high-frequency rTMS stimulation of the right and left PFC on associative memory performance (matching names to faces) in elderly individuals with memory and other cognitive difficulties.

[0165] It has been shown that rTMS can contribute to the restoration of brain functions and has the potential to activate the compensatory networks underlying memory encoding and other cognitive functions. The ability of rTMS to act on the brain in such a way that impaired functions can be restored or compensated makes this form of stimulation a promising application in the field of cognitive rehabilitation. Introduction

[0166] As life expectancy continues to rise, the number of people suffering from dementia and its associated social and economic consequences will continue to grow. Alzheimer's disease (AD) is the most common form of dementia (Alzheimer Europe, 2019). Until now, the effectiveness of approved medications for Alzheimer's disease (AD) against memory loss, the cardinal symptom of the disease, has been disappointing. Recently, lecanemab, an anti-amyloid drug, was approved by the FDA and offers cause for hope, even though the data for its predecessor, aducanumab, were not entirely convincing (Budd Haeberlein et al., 2022). Pharmacotherapy experts consider combination therapies to be particularly promising (Salloway et al., 2020). Therefore, non-pharmacological therapies for patients with Alzheimer's disease are urgently needed, regardless of the success of pharmacological treatments.A promising therapeutic approach already approved for the treatment of neuropsychiatric disorders such as depression is non-invasive brain stimulation (NIBS) (Weiler et al., 2020). Repetitive transcranial magnetic stimulation (rTMS) is a NIBS technique based on the principle of electromagnetic induction (Barker et al., 1985). rTMS modulates neuronal excitability and induces neuronal plasticity (Weiler et al., 2020). For clinical use, the stimulation protocol must be adapted to the disease being treated in terms of stimulation site, frequency, and intensity. In most studies on Alzheimer's disease patients, the dorsolateral prefrontal cortex (DLPFC) was stimulated by high-frequency rTMS (>10 Hz), which had a positive effect on various language functions and global cognition (Cotelli et al., 2011; Turriziani et al., 2012; Rabey and Dobronevsky, 2016).In some recent studies of Alzheimer's patients, posterior regions, including the precuneus, were stimulated, resulting in positive effects on memory, the impairment of which is the cardinal symptom of the disease (Zhao et al., 2017; Koch et al., 2018, 2022). Positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) studies also demonstrate a central involvement of the precuneus in memory processes, particularly in the consolidation and retrieval of episodic memory (Trimble and Cavanna, 2008). Furthermore, the main pathological features of Alzheimer's disease, the extracellular deposition of ß-amyloid plaques and the intracellular deposition of neurofibrillary tangles, first affect the posterior cortical brain regions, including the precuneus (PC), posterior cingulate cortex, and posterior parietal cortex (PPC) (Yokoi et al., 2018; Strom et al., 2022).Structural and functional abnormalities in these regions are observed even in early stages of the disease. Results from combined PET-MRI studies suggest that tau pathology in the posterior cortical regions may be more closely temporally linked to the observed hypometabolism than to the structural atrophy in this region. It is therefore assumed that the functional abnormalities precede the structural abnormalities (Strom et al., 2022). Stimulation of the posterior brain regions could therefore have a positive impact on metabolism in these regions and influence disease progression by delaying structural atrophy.

[0167] Regarding stimulation frequency, studies have shown that entrainment of natural brain oscillations using NIBS appears to be particularly effective (Thut et al., 2011b). Stimulation with "natural" frequencies appears promising for therapeutic use in Alzheimer's disease, as endogenous brain oscillations are altered in patients, and these disease-related changes correlate with cognitive decline (van der Hiele et al., 2007; Garn et al., 2014). Alzheimer's disease is characterized by a slowing of brain oscillations, causing a decrease in power spectral density (PSD) in fast frequency bands (alpha and beta) and an increase in slow frequency bands (theta and delta). This slowing of brain oscillations is already observed in the preclinical stages of the disease and can predict clinical progression (Gouw et al., 2017).Furthermore, alpha oscillations are associated with effective memory encoding (Klimesch et al., 2011), retrieval (Williams et al., 2006), and consolidation (Cross et al., 2020). Roh et al. (2011) even demonstrated a correlation between retrieval performance in a verbal and a visuospatial memory task and parieto-occipital alpha power in Alzheimer's patients at various stages of the disease. Consequently, it can be assumed that a NIBS-induced increase in alpha power leads to an improvement in memory performance. Several studies have already shown that rTMS with bursts tuned to the alpha frequency (Klimesch et al., 2003; Thut et al., 2011a) or transcranial alternating current stimulation (tACS) with a sinusoidal alternating current at the alpha frequency (Kasten et al., 2016; Ruhnau et al., 2016) modulates the corresponding band. Hamidi et al.(2009) even demonstrated that an rTMS-induced increase in alpha power at the mid-alpha frequency over parietal areas was associated with improved memory performance. However, these results refer to young, healthy participants and, to our knowledge, have not yet been replicated in Alzheimer's disease patients. Interestingly, in most stimulation studies in Alzheimer's disease in which cognitive improvement was observed, stimulation was performed either at 10 Hz, which corresponds to the mid-alpha frequency, or at 20 Hz, the first harmonic of the mid-alpha frequency (Weiler et al., 2020). However, since EEG or fMRI measurements were not performed in these studies either concurrently or after stimulation treatment, it remains unclear whether these stimulation protocols modulate the alpha frequency band in AD patients and whether this explains the cognitive improvement.By stimulating at natural frequencies, we can likely harness the brain's natural resonance, and therefore, even much lower field strengths than those used in conventional rTMS can achieve therapeutic effects (Frohlich and McCormick, 2010; Leuchter et al., 2015). Gonzalez-Rosa et al. (2015) even demonstrated effects on the alpha frequency band by stimulating with a field strength hundreds of times lower than that used in conventional TMS. Lower field strengths appear to be advantageous in terms of safety and portability (Leuchter et al., 2015), allowing patients and caregivers to perform the treatment at home. Several studies show that NIBS only has a sustained therapeutic effect when used regularly over several weeks (Perera et al., 2016; Koch et al., 2022). Therefore, treatment at home would offer significant benefits.The aim of this study was to investigate the potential therapeutic effect of low-intensity alpha-rTMS over parieto-occipital brain areas and to determine its suitability for long-term home treatment. Based on the literature described above, we expected a stimulation-induced increase in alpha power and associated improved performance in episodic memory in Alzheimer's disease patients and age-matched healthy controls.

[0168] A total of 36 participants were recruited. The study was approved by the Ethics Committee of the University of Cologne (No.) and conducted in accordance with the Declaration of Helsinki. Patients in the AD group (N=17) with confirmed Alzheimer's disease (AD) were recruited through the Memory Clinic of the University Hospital of Cologne. Inclusion criteria corresponded to the diagnostic criteria of the 2018 NIA-AA Research Framework (Jack et al., 2018): (1) amyloid status was confirmed by Ab42 in the CSF, the Ab42 / Ab40 ratio, or amyloid PET, (2) aggregated tau was determined by p-tau in the CSF or tau PET, and (3) neurodegenerative changes were demonstrated by structural changes in an MRI scan or by the presence of a typical hypometabolism pattern in an FDG-PET scan.Clinically, patients in the AD group met criteria for mild cognitive impairment up to mild dementia. Patients exhibited objective cognitive deficits (>1.5 SD below the mean of the normative sample) in memory and in at least one other cognitive domain. Age-matched healthy controls ( / V=19) were recruited through the Cologne Alzheimer's Prevention Registry, which targets healthy citizens. Based on a neuropsychological examination, participants in the HC (Healthy Control) control group were classified as cognitively normal (<1.5 SD below the mean of the normative sample) by an experienced neuropsychologist. Exclusion criteria for both groups included psychiatric disorders, (other) neurodegenerative or neuroinflammatory diseases, epilepsy, and the use of medications that affect the central nervous system.Due to technical problems, protocol deviations regarding the experimental procedure, and failure to meet inclusion criteria, a total of 8 participants were excluded from further analyses, leaving 28 participants (NAD=14, NHC=14). The groups did not differ in age, gender distribution, or years of education (Figure 8), all p>0.05. For group differences in neuropsychological data, see Figure 9.

[0169] Neuropsychological tests

[0170] Each participant underwent a comprehensive neuropsychological assessment. The assessment included the CERAD test battery (Morris et al., 1988), which included tests measuring verbal (word list learning, retrieval, and recognition) and visual memory (figure retrieval), semantic (animals) and phonemic verbal fluency (S-words; Benton et al., 1994), confrontational naming (Boston Naming Test), visual construction (figure drawing), selective (TMT-A) and divided attention (TMT-B; Reitan, 1958). In addition, the digit span from the Wechsler Memory Scale (Petermann and Lepach, 2012) was used for short-term and working memory, and the Letter Digit Substitution Test (van der Eist et al., 2006) was used to assess psychomotor speed. To ensure that no undiagnosed depressive disorder was present, participants completed the Geriatric Depression Scale (Yesavage, 1988).In addition, the Alzheimer's patients were assessed for their independence in activities of daily living using the Functional Activities Questionnaire (Pfeffer et al., 1982). The study comprised three appointments: an initial appointment for the neuropsychological assessment and two further appointments for non-invasive brain and sham stimulation. The appointments were separated by approximately 7 days (S£ = 6.48, S£ >= 3.59). Non-invasive brain stimulation with high-frequency, low-intensity rTMS or sham stimulation, which served as a control condition, was performed concurrently with EEG measurements (rTMS-EEG). The order of the two conditions was randomized. The subjects were not informed in which of the two sessions the stimulation took place, thus this was a simply matched, sham-controlled study.After the experiment, participants completed a questionnaire measuring sensory impressions during (sham) stimulation. The results showed that participants could not tell whether they were stimulated or not, making a placebo effect of the stimulation unlikely. To investigate the effect of the stimulation on memory performance, a spatial context memory task was administered during the rTMS-EEG sessions. For an overview, see Figure 10.

[0171] Memory paradigm

[0172] The memory paradigm consisted of an encoding phase, an initial recall, a consolidation phase, and a delayed recall. A test run was conducted prior to the experiment to familiarize participants with the task. The memory task was a modification of a well-established spatial context memory task (Cansino et al., 2002; Kukolja et al., 2009; Muecke et al., 2018). Two sets of stimuli were used, counterbalanced across both conditions. During encoding, participants were sequentially presented with ten stimuli at one of twenty possible positions in a four-by-five grid on a screen. Participants were instructed to remember both the stimuli (item memory) and their corresponding position (spatial context). The stimuli were photographs of natural (e.g., butterfly) or artificial / human (e.g., light bulb) objects.Each object was presented for four seconds. To ensure participants' attention, they were required to press a button as soon as a stimulus appeared. During an initial retrieval task immediately following the encoding task and during a delayed retrieval task following a ten-minute consolidation phase, participants were presented with twenty stimuli (ten previously learned and ten new stimuli) sequentially in random order at a neutral position outside the grid. Participants were instructed to indicate whether or not they recognized each stimulus as previously learned (item memory). Stimuli were classified as "previously learned" if an object was positioned within the grid, regardless of its exact location. Stimuli were classified as "new" if an object was dragged into a visually prominent box outside the grid.For stimuli identified as previously learned, participants were also instructed to indicate the exact position of the object during encoding by dragging the object with a joystick to the corresponding box in the grid (spatial context memory). Participants were given ten seconds to respond before the next stimulus appeared.

[0173] High-frequency low-intensity rTMS

[0174] High-frequency, low-intensity rTMS stimulation (<10 mT) was applied to parieto-occipital brain areas. The electrical impulses were delivered to the magnetic coils as burst patterns repeated at 14 Hz. Several studies suggest that the stimulation effect is strongest when the stimulation frequency is at or near the natural frequency (eigenfrequency) of the stimulated brain region (Thut et al., 2011a; Ali et al., 2013). Since posterior cortical regions are considered to generate alpha oscillations (Cuspineda Bravo et al., 2009), stimulation close to the alpha frequency seems reasonable. However, to ultimately distinguish artificial signals of the stimulation frequency from endogenous brain oscillations, stimulation should not occur exactly in the frequency range of interest.For this reason, in the present study, we chose a stimulation frequency of 14 Hz, which corresponds to the upper limit of the alpha band plus 1 Hz. To optimize each participant's response to treatment, the stimulation parameters were individually adjusted, varying the number of pulses per burst (5–20) and the inter-stimulus interval (ISI) within each burst (1.5 to 3 ms). Using quantitative real-time EEG (qEEG), we determined which stimulation parameters elicited the strongest PSD response within the alpha frequency band (8–13 Hz) at the occipital and parietal electrodes. Using the optimal parameters, stimulation was performed throughout the memory paradigm for a total of 25 minutes. For an overview, see Figure 11.

[0175] EEG data acquisition and preprocessing

[0176] Continuous EEG data were recorded for 6–10 minutes in a resting state with eyes closed during baseline (BASE), during the consolidation phase (CON), and after delayed recall (POST). During the experiment, all subjects sat upright in a sound-insulated and electromagnetically shielded room. Participants were instructed in advance to avoid any movements, such as body movements, eye movements, and blinking. To ensure adequate vigilance of the subjects, their condition and the ongoing EEGs were continuously monitored throughout the experiment. The EEG was recorded using the Neurowerk amplifier (Headbox DB26, Neurowerk EEG software V13.19.2.73) from 19 active Ag / AgCl electrodes mounted in an elastic cap. The system is based on the 10–20 electrode placement system. Two additional channels were used for electrooculogram recording.The ground electrode was located on the forehead (Fpz). The Cz channel served as the online reference channel. After careful preparation, the electrode impedance was kept below 5 kΩ. The sampling rate was 512 Hz. The EEG data were exported and converted to EDF format for preprocessing in EEGLAB (version 2021.1). EEG data analysis.

[0177] Preprocessing and analysis of the EEG data were performed using EEGLAB (Delorme & Makeig, 2004) and its Darbeliai plugin (v2019.02.01.1, https: / / github.eom / embar7eeglab_darbeliai / wiki / 0.%20EN), as well as custom MATLAB code (The MathWorks Inc., Natick, MA). First, the EEG data were referenced to a common average reference to interpolate the Cz electrode. The EEG data were filtered with finite impulse response (FIR) filters (0.3–45 Hz). Channels were excluded and interpolated if (1) the channel received no signal for more than 5 seconds, (2) the signal frequency deviated by more than 4 standard deviations from the maximum accepted frequency, or (3) the signal showed only a low correlation with the signal from surrounding channels (r<0.7). On average, 0.98 of the channels were removed and interpolated. The cleaned data were divided into 4-second epochs.The first 15 epochs were removed to allow participants to relax and enter a resting state. Finally, an independent component analysis was calculated, and automatic identification and rejection of noise components was performed using the ICLabel toolbox (Pion-Tonachini et al., 2019), followed by visual inspection. The automated algorithm rejected an average of 1.75 independent components (ICs), and we manually removed an additional 1.72 ICs on average. To calculate spectral power (pV2), the Fast Fourier Transform was performed using the Darbeila plugin in EEGlab. Absolute power was calculated for the frequency range 1–45 Hz with a resolution of 0.1 Hz for each non-overlapping 2-second window of the first 30 artifact-free epochs.Relative power was determined by normalizing the absolute power in each frequency band (delta 1-4 Hz, theta 4-8 Hz, alpha 8-13 Hz, alpha 1 8-11 Hz, alpha 2 11-13 Hz, beta 13-30 Hz, gamma 30-45 Hz) with the total power across the entire frequency spectrum. Relative power analysis was preferred to absolute power analysis because it is more reliable (Duan et al., 2021). Due to the wide range of frequency bands, relative power is not a particularly sensitive measure. Therefore, the PSD (10*log10 (pV2 / Hz)) was additionally determined for each 0.1 Hz step across the entire frequency spectrum and descriptively analyzed. The individual alpha peak frequency (iAPF) was calculated by computationally determining the local peak in the PSD within the alpha frequency band for each resting-state session of both conditions and for each channel. If more than one local peak frequency was found, the peak with the highest power was selected.Since the alpha frequency decreases with age (Kropotov, 2016), the lower limit of the bandwidth was exceeded. If the iAPF was below 8 Hz, the PSD of the entire frequency spectrum was visually inspected by an experienced neurophysiologist, and if necessary, the iAPF was manually corrected. Additionally, the iAPF power (individual alpha peak power, IAPP) was determined. Two participants had to be excluded from the iAPF and iAPP analyses because no peak could be detected in the alpha frequency band (NAD=13, NHC=13'). Statistical analysis of relative power, iAPF, and iAPP was performed using SPSS (IBM SPSS Statistics; Version 28, IBM Corp., Armonk, NY, USA). Due to the stimulation site in the parieto-occipital region and our particular interest in alpha oscillations, which are mainly generated in posterior regions, our analyses focused on the occipital and parietal electrodes.To increase the signal-to-noise ratio for these analyses, the channels of the two brain regions of interest were averaged (parietal: P3, P4, Pz; occipital: O1, O2). To assess pathological changes, relative power during the baseline resting state was compared between groups and frequency bands using ANOVA. To evaluate the neurophysiological effect of rTMS, relative power, iAPF, and iAPP were compared between groups and conditions. Finally, correlation analyses were conducted to examine whether stimulation-induced changes in parieto-occipital alpha band activity were related to memory performance.

[0178] Analysis of behavioral data

[0179] Performance in the memory task during the rTMS-EEG experiment was analyzed with regard to item memory and spatial context memory. Item memory was defined as a d-prime (z[hit] - z[false alarm]) according to signal detection theory, taking response bias into account. Spatial context memory was operationalized as the positioning error, measured by the distance between the position of each stimulus indicated by the participant in the retrieval task and the position at which the stimulus was presented in the learning task. The distance was calculated as the square root of the sum of the squared distances (measured in pixels) on the horizontal and vertical axes. The lower the value, the better the spatial context memory.To investigate the pathologically impaired memory performance in the AD group and the stimulation effect on memory performance, item memory and spatial context memory were compared between groups and stimulation conditions for both initial and delayed retrieval. The interaction between delay (initial and delayed retrieval) and stimulation condition (stimulation, sham) was used to assess a stimulation effect during the consolidation phase.

[0180] Behavioral results

[0181] For item memory, a significant group effect was found for both stimulation conditions and both retrieval tasks, with lower memory performance in AD compared to HC, F (l,26) = 10.86, p = .003, pp = .30. However, there was no significant effect of condition (stimulation vs. sham stimulation), no significant effect of delay (initial vs. delayed retrieval), and no significant interaction effects, all > .05. Descriptive information can be found in Figure 12. For spatial context memory, a significant main effect of group was found, with more positioning errors in AD than in HC (A(l,26) = 17.80, p<.001, / 7 2=.41) and a significant main effect of delay, with more positioning errors in delayed than in initial retrieval (A(l,26) = 12.50, p=.002, qp2=.33'). In addition, the ANOVA revealed a significant interaction effect of group × delay (F(l,26)=6.63, p=.016, qp2=.2O) as well as a significant interaction effect Conditions x Delay x Group (A(l,13) = 4.43, p = .045, r / p2 = .15). Post-hoc ANOVAs within groups showed a significant main effect of delay only for AD (A(l,13) = 10.96, p = .006, r / p2 = .23). AD patients made more positioning errors during delayed retrieval than during initial retrieval, i.e., they forgot spatial context information over time. Furthermore, the interaction Condition x Delay showed a non-significant trend (A(l,13) = 3.79, p = .074, r / p2 = .23), suggesting that forgetting of spatial context information was more pronounced in AD patients under stimulation than under sham stimulation. There were no significant effects for HC. Relative performance.

[0182] For relative power during baseline, averaged across all channels, an ANOVA revealed a significant group × frequency band interaction effect (A(6,156) = 3.90, χ = .001, χ2 = .13). Post-hoc t-tests revealed significant group differences in the theta (p = .01), alpha (p = .041), and alpha 2 bands (p = .028), with increased relative theta and decreased relative alpha power in AD compared to HC (see Figure 13). An ANOVA revealed no effect of stimulation on relative power within the alpha frequency band at the occipital or parietal electrodes. Regardless of the stimulation condition and the group, relative power differed between sessions (occipital: A(2,50)=4.01, =.O24, qp2=.14; parietal: A(2,50)=4.6, =.O15, pp2=.16) with an increase in relative alpha power from baseline to the second resting state during the consolidation phase (occipital: =.O52, parietal: =.O28) and from baseline to post (occipital: =.O28, parietal: = O35, see Figure 14). Differential analyses of Alphai and Alpha2 also showed no effect of stimulation.

[0183] Power spectral density

[0184] Descriptively, an increase in PSD at the mean peak frequency (~9.5 Hz) was observed in HC and even more so in AD under active stimulation during the consolidation phase. This result was observed for all channels. Due to the stimulation site in the parieto-occipital region, as well as our particular interest in alpha oscillations, which are primarily generated in occipital regions, the following metrics and the figure focus on data from occipital electrodes. Compared to baseline, the PSD at the mean peak frequency increased by 16.57% (MBASE=5.25, MCON=6.12) in HC under stimulation and by 1.94% (MBASE=6.19, MCON=6.31) under sham stimulation. In AD, the PSD at the mean peak frequency increased by 56.97% (MBASE=2.58, MCON=4.05) under stimulation and by 4.26% (MBASE=3.05, MCON=3.18) under sham stimulation.In HC, the PSD increase was maintained even after stimulation (Mpost=6.35), whereas in AD the PSD decreased immediately (Mpost=2.66), see Figure 15.

[0185] Individual alpha peak frequency (iAPF) An ANOVA for the iAPF at the occipital electrodes revealed significant interaction effects stimulation × session (F(2,48)=3.90, Greenhouse-Geisser corrected p=.041, / 7 2=.15) and group × session (F(2,48)=7.45, p=.002, pp2=.25'). Further within-group analyses revealed no significant differences at baseline, consolidation, or post between stimulation and sham stimulation for either AD or HC, see Figure 16. An ANOVA for the iAPF at the parietal electrodes revealed no significant main or interaction effects.

[0186] Individual Alpha Peak Power (iAPP)

[0187] An ANOVA on iAPP revealed no significant effect of stimulation and no significant interaction effects, neither occipital nor parietal. However, further within-group analyses revealed a significantly higher iAPP value under stimulation (consolidation phase) compared to sham stimulation in the AD group, both occipital (t(12)=2.25, p=0.046, 95%CI [0.24, 2.93]),

[0188] Cohen's d = .65) and parietal (t(12)=2.24, p=.047, 95%CI[0.15, 2.27],

[0189] Cohen's d = .65) by 26.64% and 24.26%, respectively. There were no significant differences in iAPP scores at baseline and after simulation. No significant simulation-related changes in iAPP were observed in the HC group, see Figure 17.

[0190] IAPP at occipital and parietal electrodes during the consolidation phase under stimulation and sham stimulation is positively correlated with item memory in delayed recall (sham: occipital: r=.57, =.004, 95%CI[0.20, 0.80]; parietal: r=.48, =.017, 95%CI[0.19,0.74]; forehead: occipital: r=.35, =.093, 95%CI[0.06, 0.59]; parietal: r=.31, p=.141, 95%CI[-0.5, 0.58]). Within-group correlation analyses show a trend towards a positive association between iAPP and item memory for AD (sham: occipital: r=.596, =.053, 95%CI[0.03, 0.88]; parietal: r=.54, =.09, 95%CI[0.00, 0.95]; stim: occipital: r=.399, =.244, 95%CI[-0.11, 0.75]; parietal: r=.35, p=.29, 95%CI[-0.25, 0.77]; see Figure 18), but not for HC.

[0191] Discussion: To our knowledge, this study is the first to combine rTMS and EEG during a memory paradigm in Alzheimer's disease patients. The aim of this study was to investigate the underlying neurophysiological mechanisms of high-frequency, low-intensity rTMS over parieto-occipital brain regions and its effect on memory performance in Alzheimer's disease patients and cognitively healthy elderly individuals. We demonstrated that even a single rTMS session leads to increased alpha power compared to sham treatment. In Alzheimer's disease patients, the stimulation protocol used appears to be beneficial with regard to the pathologically altered alpha band. During stimulation, the individual alpha peak power in Alzheimer's disease patients increased by approximately 25 percent compared to sham treatment, suggesting a therapeutic effect of the stimulation.Interestingly, this effect was not observed in age-matched healthy elderly subjects, whose alpha power was comparable under stimulation and sham stimulation. This difference in reactivity between Alzheimer's patients and age-matched healthy elderly subjects could be explained by differences in baseline neuronal activity, as Alzheimer's patients exhibit pathologically reduced alpha oscillations. According to the principle of state dependence, NIBS must consider not only the properties of the stimulus but also the baseline neuronal activity. It is assumed that different brain states imply different susceptibility to the stimulation effect (Silvanto et al., 2008).Accordingly, the results of the current study show a stronger stimulation effect on the alpha band in AD patients with pathologically reduced alpha at baseline than in healthy controls with comparatively high alpha at baseline. A complementary correlation analysis further confirmed the principle of state dependence. The lower the individual alpha power at baseline, the higher the increase in alpha from baseline to consolidation (A iAPP consolidation - baseline) under stimulation (r=-.473, = .015, 95%CI [-.665, -.151]). Several studies have systematically investigated this effect on NIBS by inducing different brain states in the form of different baseline alpha values ​​under two different conditions: open and closed eyes (Neuling et al., 2013a; Ruhnau et al., 2016).Occipital alpha represents the waking resting state, characterized by aversion to external stimuli, including blocking visual inputs, and focusing on internal representations. Accordingly, alpha oscillations synchronize when the eyes are closed and desynchronize when the eyes are open (Kropotov, 2016). The two states "open eyes" and "closed eyes" thus represent different brain states with lower and higher alpha power, respectively. Studies have shown that stimulation with alpha-tACS over parieto-occipital brain regions had a significantly stronger effect on the alpha band when participants kept their eyes open than when they kept their eyes closed.In summary, the studies show a stronger response to alpha-band stimulation at lower baseline alpha levels, which is consistent with the results of the current study (Neuling et al., 2013a; Ruhnau et al., 2016). There are two main hypotheses regarding the underlying mechanisms of frequency-controlled noninvasive brain stimulation (rhythmic TMS and tACS). The first hypothesis states that the stimulation effect is primarily due to the entrainment of natural oscillations by the stimulation frequency. The stimulation frequency serves as a kind of clock. The stimulation effect is caused by the synchronization of the natural oscillations with an external source—the stimulation frequency. Accordingly, the power increase is expected to be centered at the stimulation frequency, i.e., 14 Hz in the present study. An effect at the intrinsic natural frequency for the alpha band (iAPF), however, is not expected.The second hypothesis, however, states that the stimulation effect is due to spike-timing-dependent plasticity. According to this assumption, an alpha enhancement would be observed at the intrinsic eigenfrequency for the alpha band (iAPF) (Vossen et al., 2015). Our results show a significant increase in PSD at the stimulation frequency (14 Hz) and its harmonics (28 Hz, 42 Hz; Figure 5). However, AD patients show an equally significant increase in PSD at the iAPF (on average by 9.5 Hz). Thus, stimulation did not lead to an equalization of the spontaneous alpha frequency, which is also confirmed by our results for the iAPF, according to which no stimulation-induced difference in the iAPF was found in either AD or HC. Furthermore, the observed effects at the stimulation frequency (14 Hz) could be artificially induced rather than endogenous brain oscillations.Even if, according to the entrainment hypothesis, an oscillatory brain response was triggered by stimulation at this frequency, it could not be distinguished from an artificially generated signal. Conversely, this also means that the effects in iAPF most likely did not result from an artificial signal. Our results thus support the plasticity hypothesis and confirm the systematic investigation by Vossen et al. (2015) as well as numerous studies on long-lasting aftereffects of stimulation that could not be explained by entrainment as the underlying mechanism (Zaehle et al., 2010; Neuling et al., 2013b; Kasten et al., 2016). Regarding our secondary outcome variables, item and spatial memory performance, no positive stimulation effect was found for either Alzheimer's patients or healthy elderly individuals.A ceiling effect seems most likely in the healthy elderly, as almost all participants in both conditions, both before and after the delay, remembered all items and the spatial context very accurately. In contrast, AD patients showed even greater forgetting of spatial context information under stimulation than under sham stimulation. Since the increase in alpha power did not lead to an improvement in overall memory performance, one might assume that, contrary to our expectations, memory performance is not related to alpha power and that a stimulation-induced increase in alpha power does not lead to an improvement in memory performance in AD patients. However, this assumption contradicts our results, which show a significant correlation between alpha power during the consolidation phase and item memory.Interestingly, this correlation appears to be more pronounced under sham stimulation than under stimulation. Thus, stimulation appears to disrupt the relationship between alpha power during consolidation and episodic memory. One possible explanation could be the differential influence of increased alpha power during different memory processes. An increase in alpha power could be beneficial during the consolidation phase, a period of waking rest without sensory input and focused on internal representations. On the other hand, alpha power should be reduced during encoding or retrieval, as the focus is on external stimuli with strong visual input. Alpha synchronization is widely considered a process of active inhibition (e.g., Klimesch et al., 1999, 2000; Sauseng et al., 2005).Alpha is synchronized in brain regions irrelevant to the current task, leading to the inhibition of these brain regions to enable efficient processing in the relevant brain regions where alpha is desynchronized. Accordingly, studies have frequently found alpha desynchronization, or a decrease in alpha power, in memory-relevant brain regions, including parietal regions, during encoding and retrieval tasks. A recent study by Martin-Buro et al. (2020) even found that alpha power gradually decreased when moving from an object recognition task to a non-object recognition task, representing a gradual accumulation of memory performance.Accordingly, we would expect alpha power to be reduced during encoding and retrieval in brain areas associated with these memory processes, such as the precuneus. A stimulation-induced artificial increase in alpha power during encoding and retrieval in parietal brain areas would impair the underlying cognitive processes and could negatively impact memory performance. This assumption is consistent with the results of Gonzalez-Rosa et al. (2015). They found a stimulation-induced increase in alpha power that led to a longer reaction time in a visual recognition task, rather than, as the authors expected, a shortened RT and thus improved performance.Such an inhibitory effect of the stimulation-induced alpha increase during encoding and retrieval on memory performance could explain the disturbed relationship between alpha power during the consolidation phase and item memory in Alzheimer's patients found in the current study. A positive effect of stimulation during consolidation and a negative effect of stimulation during encoding and retrieval may have counteracted each other, resulting in neither a significant improvement nor a deterioration in memory performance under stimulation compared to sham stimulation. However, the present study does not conclusively clarify in which phase of memory formation stimulation of the alpha frequency band has positive effects on memory performance.Further studies using a standardized stimulation protocol are needed to stimulate different memory processes at different time points. In summary, this study has expanded existing knowledge on the underlying mechanisms of non-invasive brain stimulation. Our results demonstrate that rTMS delivered to parieto-occipital brain areas at the alpha frequency level can modulate pathological brain activity in Alzheimer's patients, even at low intensities. Thus, the stimulation protocol used in this study represents a novel, safe, and cost-effective therapeutic approach for home treatment. Future research is needed to investigate the sustained therapeutic effect when stimulation is applied regularly over several weeks or months (Perera et al., 2016; Koch et al., 2022).To achieve a sufficient sample size for this purpose, a multicenter study is recommended.

[0192] Use of r-TMS for HRV regulation

[0193] The peripheral autonomic nervous system

[0194] The autonomic nervous system is a communication system for the exchange of information between the individual organs of the body. It innervates the smooth muscles of all organs and organ systems, as well as the heart and glands. Vital functions such as respiration, circulation, digestion, metabolism, glandular secretion, body temperature, and reproduction are controlled by this system. In contrast to the endocrine system, the autonomic nervous system is able to intervene more quickly. The activities of the autonomic nervous system are largely beyond voluntary control. The task of this system is to maintain the body's internal environment within limits that are optimal for cellular function. To this end, the autonomic nervous system has two structures: the sympathetic and parasympathetic nervous systems, which are interconnected via centers in the brainstem and hypothalamus.

[0195] Noradrenaline is released as a neurotransmitter at the sympathetic nerve endings that run to all body organs. Through this pathway, sympathetic activation can be selectively and locally limited to very specific organs. The second pathway is hormonal. Here, the release of adrenaline in the adrenal medulla is stimulated via sympathetic nerve pathways. The released hormone simultaneously reaches the body's organs via the bloodstream and can thus trigger generalized sympathetic activation that extends to all organs.

[0196] The development of suitable methods for assessing autonomic cardiac rhythm regulation has led to widespread diagnostic applications, for example, in stress medicine, which finds the variability measure a dependent parameter for mental health. Heart rate variability, called HRV, is an expression of sympathetic and parasympathetic activity. HRV is determined via an ECG measurement.

[0197] Permanently elevated stress with corresponding sympathetic tone manifests itself in predominantly long-wave fluctuations. The neurovegetative regulatory system is then only limitedly able to adapt to internal and external stresses. This can be recognized, for example, by disturbed sleep rhythms, as has been demonstrated in fibromyalgia, for example, by desynchronized REM phases of nighttime sleep. The autonomic balance of the autonomic nervous system is shifted toward the sympathetic nervous system; this is increasingly transmitted to the autonomic heart rhythm, while vagal activity is simultaneously weakened. Hypertension, coronary disease, cardiac arrhythmias, heart attacks, heart failure, diabetes, burnout, anxiety disorders, psychosomatic and immune diseases can result from chronic overactivation.

[0198] The parasympathetic nervous system: a protective mechanism against stress-related health risks and a guarantor of physical fitness.

[0199] As outlined above, chronic sympathetic overactivation is associated with numerous disease risks. In the past, it was assumed that this hyperactivation of the sympathetic system was the sole determining factor for an increased risk of disease. However, based on numerous empirical studies, the view has recently emerged that the pathogenetic relevance of sympathetic overactivation is highly dependent on the activation state of the parasympathetic system, and that parasympathetic hypoactivity plays a far greater role in the development of disease and disease risk.

[0200] On the one hand, this means that the parasympathetic nervous system, under normal circumstances, plays an absolutely central role as a protective mechanism in the regulation of health-relevant bodily processes. On the other hand, however, it also means that dysfunctions and impairments of the parasympathetic control mechanisms are associated with serious consequences for human health. Regulation of the autonomic nervous system using pulsating magnetic fields: Using individually determined magnetic fields (these must always be determined individually), the two branches of the autonomic nervous system are brought into a harmonious oscillation pattern.

[0201] The autonomic nervous system controls heart rate variability through the afferent sympathetic and parasympathetic nervous systems. This control can be demonstrated for the sympathetic branch in the lower frequency range, 0.04–0.15 Hz, and for the parasympathetic or vagal branch in the higher frequency band (0.15–0.4 Hz) of the autonomic nervous system. Analysis of the heart rate variability spectra revealed changes in the power ratio from "low band" to "high band."

[0202] By stimulating the autonomic nervous system with an individually determined magnetic field frequency, the overactive sympathetic nervous system is downregulated (dampened) and, at the same time—and this is the very special effect of the magnetic field—strengthens the parasympathetic nervous system. This logically leads to outstanding relief of the cardiac system, enabling the patient to respond appropriately to stressors.

[0203] The exact mechanism remains unknown. Nevertheless, pulsating magnetic fields influence the autonomic nervous system. They induce electrical currents and potentials in the body. This alters the naturally occurring electrical gradients and influences the movement of ions through ion channels. This can even lead to nerve stimulation.

[0204] Various studies have demonstrated that pulsating magnetic fields (depending on field strength and frequency) cause changes in the activity patterns of the autonomic nervous system. These effects have been documented using HRV technology. A highly significant effect of pulsating magnetic fields on the autonomic nervous system has been demonstrated.

[0205] This ingenious strategy can thus be successfully utilized for optimal and healthy stress management. A proprietary magnetic field therapy system was developed and tested for its effects on the autonomic nervous system. Three examples demonstrate the extraordinary positive effects of this therapy system on the nervous system.

[0206] Measurement method

[0207] The ECG electrodes are arranged as shown in Figure 19. The measurement was performed in a soundproof room. The subjects were rested and awake. The measurement was performed with their eyes open.

[0208] In the present case (subject 3), the application of a pulsating magnetic field occipitally with 4 coils at a frequency of 14 Hz induced a significant improvement in the HRV profile - better than with the frequencies 2 Hz & 19 Hz. Thus, the subject can show an optimal response to internal and / or external stressors.

[0209] Summary: It can be clearly demonstrated that pulsating magnetic fields have a regulatory effect on both branches of the autonomic nervous system. The significant improvement in the autonomic regulation index (ARI) indicates significantly improved stress management. A reduced alpha level is particularly evident in people with dementia, which is significant for dementia. Since the fields definitely influence alpha activity, a positive effect on memory can also be achieved with stimulation at the back of the head, as is necessary for HRV.

[0210] It is therefore of great interest to develop concepts that aim at a stabilizing, regulating or corrective effect on the autonomic nervous system as well as an increase in alpha activity in the EEG.

[0211] Well-established results of psychophysiological research demonstrate that emotional reactions as a result of automatic, cognitive-affective evaluation processes in the brain are always accompanied by changes in specific physiological functions, mediated by the activation of the autonomic nervous system (ANS).

[0212] Negative emotions are associated with stronger reactions than positive emotions. Activation of the ANS leads to specific physical functional changes via sympathetic and parasympathetic nerve pathways, such as increased sweat gland activity, arteriolar constriction, and increased or decreased cardiac and respiratory activity. The connection between these physiological reactions and basic emotions such as anger, fear, and disgust has been repeatedly confirmed in numerous studies. For example, the mere anticipation of an aversive event proved to be an effective stressor, resulting in increased sweat production and thus an increase in skin conductance. Various studies have shown that skin conductance and skin resistance reactions, in particular, can be used as reliable indicators of the effectiveness of emotional stress stimuli.

[0213] As an exemplary example, we consider the cardiovascular system as the most common source of morbidity and mortality, so the protective effect of efficient parasympathetic innervation becomes particularly clear:

[0214] ■ Reduction of cardiac work and oxygen demand

[0215] ■ Reducing the risk of fatal ventricular arrhythmias.

[0216] ■ Protection against pathogenetic increases in blood pressure

[0217] ■ Direct inhibition of sympathetic nerve activity

[0218] ■ Protection against atheromatous changes in the vessel walls.

[0219] depression

[0220] Depression is one of the most common mental illnesses and is classified as a type of affective disorder. Despite a wealth of research, the pathogenesis of depression and the involvement of psychophysiological processes and specific brain areas in the development and maintenance of depressive symptoms are not yet sufficiently understood.

[0221] Hemispheric asymmetries have been discussed as a possible diathesis for the development of depressive disorders for several decades. Initial evidence for this comes from observations of patients with brain lesions, who showed different emotional reactions depending on the hemisphere affected by the lesion. Evidence has been found that left-hemispheric lesions are more strongly associated with negative emotional expressions such as crying, anxiety, or depressed mood, while right-hemispheric lesions are more likely to be characterized by indifferent or positive affect. Numerous research studies support the assumed relationship between left-hemispheric lesions and negative affect.

[0222] However, studies have shown that not all lesions of the left hemisphere consistently lead to depressive mood, but that the location of the lesion within the hemisphere is crucial. For example, a computed tomography study demonstrated that lesions near the frontal pole of the left hemisphere are particularly associated with negative affect.

[0223] To measure brain electrical activity, the low-frequency alpha band, which lies between 8 Hz and 13 Hz, is typically analyzed in asymmetry research. Alpha activity, or alpha power, is inversely related to cortical activity: the higher the proportion of alpha activity, the lower the activity in the corresponding brain area. Imaging techniques confirm this inverse relationship. When examining anterior brain regions, the medial-frontal electrode positions F3 and F4, as well as F7 and F8 in the medial-lateral region, are usually recorded.

[0224] A possible explanation for this demonstrated asymmetry could be a predominant perfusion disorder of the frontal brain. Various studies have shown that mathematical computations (percent power fraction (PPF) of the individual frequency ranges) can calculate and detect evidence of central perfusion disorders. Furthermore, alterations in beta and theta power profiles have been associated with existing depression. Various studies have shown that patients with depression can also exhibit significantly slowed alpha and theta waves. These investigations demonstrate that depression-specific signals must be present in the EEG. Over the past 20 years, NeuroNet has succeeded in identifying typical EEG patterns in patients with depression. As can be clearly seen, the frontal brain sections display a striking distribution profile of theta and alpha waves.In this context, the possible significance of delta and beta waves in this clinical picture still needs to be determined. Furthermore, the significance of higher-amplitude, rhythmic slow brain waves (delta and / or theta waves) in this condition needs to be clarified. It should be investigated whether this is an intermittent, bilateral anterior (IBA) or an intermittent, left anterior (ILA) phenomenon.

[0225] Recently, various studies have shown that strong magnetic fields are suitable for treating severe depression. These generate a strong magnetic field 100 times per second, thereby triggering a seizure in the brain.

[0226] Electroconvulsive therapy (ECT), used for more than 75 years, works similarly. However, the seizure is triggered by electrical impulses. Many patients with depression experience improvement after ECT—the reasons for this are still unclear. Even in patients who do not respond to any other treatment method, the success rate is 50 to 70 percent. However, this improvement lasts for more than six months in only half of those. Nevertheless, the method far outperforms currently available medications, as well as psychotherapy and behavioral therapies.

[0227] The relatively new magnetic seizure therapy appears to be significantly gentler according to initial studies. Nevertheless, in this context, the question remains as to the extent to which a very strong magnetic field is necessary to treat depression. Our studies on patients have shown evidence that even pulsating magnetic fields with low field strengths have an impact on the human EEG.

[0228] Based on these results, it makes sense to also examine and treat patients with depression using this technology. For this, a quantitative EEG recording is required. This serves to determine which pulsating magnetic field has a positive effect on the depressed patient's EEG profile. Use of r-TMS in Asperger's syndrome

[0229] Asperger's syndrome: symptoms in children

[0230] Typical Asperger syndrome symptoms usually only become noticeable after the age of three. Before then, however, children already exhibit abnormalities in their communication and language skills. Despite normal language development, they have difficulty communicating with others. Motor development is also sometimes delayed, but not always.

[0231] Nevertheless, Asperger's syndrome is often not diagnosed in children until preschool or school age. Those affected have problems with social interactions, which is evident, for example, when playing with peers. For example, they have difficulty empathizing with the thoughts and feelings of others and have great difficulty adapting to other people and social situations. They have difficulty correctly interpreting the facial expressions, gestures, and tone of voice of others. They often barely display any facial expressions themselves.

[0232] Children with Asperger's syndrome are often unable to engage in a two-way conversation. They talk whenever they want and about topics that interest them, without adapting to their listeners. They don't understand subtle signals from the other person, such as changing the subject or ending the conversation. People with Asperger's syndrome often also talk to themselves.

[0233] Children with Asperger's syndrome also often don't know how to build friendships. Some even have no interest in social interactions or friendships at all.

[0234] In addition, Asperger's autism sometimes exhibits sensory perception disorders. Some affected individuals react very sensitively to certain smells, sounds, surfaces, or touch stimuli. This can lead to a veritable sensory overload for those affected in everyday situations. People with Asperger's autism are sometimes clumsy when walking and lack motor coordination. Stereotypical behaviors also occur. These can include repetitive hand movements, for example, in stressful situations.

[0235] Asperger's syndrome: symptoms in adults

[0236] The unusual behaviors associated with Asperger's autism are often less noticeable in adult patients than they were in childhood. However, even adults usually have a grammatically correct, polished style of speech and a detailed narrative style, although they barely distinguish between important and unimportant details.

[0237] Just as in children, Asperger's syndrome can lead to restricted facial expressions and avoidance of eye contact in adults. Many affected individuals react little or not at all to a smile or a humorous remark.

[0238] Difficulties in social interaction sometimes also affect relationships. Those affected often appear cold and selfish. Many find it difficult to establish contact with potential partners. If a relationship does work out, many find it difficult to meet their partner's demands for intensive communication and involvement.

[0239] Asperger's syndrome can have two consequences for professional life: Some patients quickly become overwhelmed when dealing with colleagues or customers, easily offend others with their very direct, seemingly rude manner, and are hardly able to adapt flexibly to different requirements.

[0240] In other cases, however, Asperger syndrome in adults has a positive impact on professional development. This is especially true when those affected can utilize their distinctive special interests in their work. Furthermore, many people with Asperger syndrome are able to successfully achieve professional and personal goals thanks to their often high cognitive abilities. Other possible applications

[0241] ■ Sleep disorders

[0242] ■ Dizziness ■ Raynaud's disease

[0243] ■ Burnout

[0244] ■ Aggression

[0245] ■ motor disorders

[0246] ■ Panic / Anxiety ■ Dyslexia

[0247] ■ ADHD

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Claims

Patent claims 1. Arrangement with an EEG device, in particular a QEEG device and a head part which has at least two applicators which generate a low-frequency electromagnetic field of an application frequency in a frequency range of 1 Hz to 100 Hz, preferably up to 300 Hz and with a field strength of less than 20 mT, for use in the treatment of dementia, depression, HRV regulation, Raynaud's disease, Asperger's syndrome, migraine, dizziness, sleep disorders, burnout, ADHD, muscular and / or joint pain or autism.

2. Arrangement according to claim 1, characterized in that the field strength of a coil is less than 10 mT, in particular less than 1 mT, preferably less than 0.2 mT and particularly preferably less than 0.1 mT.

3. Arrangement according to one of the preceding claims, characterized in that the applicator has at least a first coil and a second coil which are arranged next to one another and can be fastened to a headband in such a way that they are located on the head of a patient on the forehead in the region of the frontal lobe, in particular in the region of the prefrontal cortex, in particular on both sides of the longitudinal fissura.

4. Arrangement according to one of the preceding claims, characterized in that the applicator has at least a third coil and a fourth coil, which are arranged next to one another and can be aligned and arranged in such a way that they are located at the back of the head of a patient in the region of the occipital lobe or in the region of the cerebellum, in particular on both sides of the longitudinal fissura.

5. Arrangement according to one of the preceding claims, characterized in that the applicator has at least a fifth coil and a sixth coil, which are arranged diametrically opposite one another and can be aligned and can be arranged so that they sit on the side of a patient's head in the area of ​​the temporal lobe.

6. Arrangement according to claims 3, 4 and 5, characterized in that the third, fourth, fifth and sixth coils are arranged in a head shell, the head shell having a back and two side parts extending on two opposite sides of the back part perpendicular to the latter and parallel to one another, the third and fourth coils being arranged in the back part and the fifth and sixth coils each being arranged in a side part.

7. Arrangement according to one of the preceding claims, characterized in that the application frequency is individually adaptable, in particular can be determined by a measurement with the QEEG.

8. Arrangement according to claim 7, characterized in that the EEG frequency spectrum is generated by measuring the EEG during stimulation with different frequencies.

9. Arrangement according to claim 8, characterized in that the frequency spectrum with the lowest or the pattern with the best alpha is used as therapy.

10. Arrangement according to claim 9, characterized in that The evaluation is based on the following criteria: - Alpha amplitude: the higher the alpha maximum, the better - Right-left shift of the alpha maximum, right shift is better, brain activity is faster - Delta: the lower the value of the maximum, the better - Beta: the lower the value of the maximum, the better 11. Arrangement according to one of the preceding claims 7 to 10, characterized in that the application frequency when using the arrangement for the treatment of Dementia: 14 Hz, 20 Hz, 40 Hz, 80 Hz, 100 Hz-150 Hz or n times the harmonics of 14 Hz with 1-10 bursts HRV: 14 Hz with 7 and / or 8 bursts Raynaud's disease: 14 Hz with 10 bursts Asperger's Syndrome: 14Hz with 8 bursts Pain: 2 Hz with 10-20 bursts.

12. Arrangement according to one of the preceding claims, characterized in that the first and second coils are designed as round or cross-wound coils and / or the third and fourth coils are designed as round or cross-wound coils and / or the fifth and sixth coils are designed as round or cross-wound coils.

13. Use of a device according to claim 10 for the treatment of dementia, depression, HRV regulation, Raynaud's disease, Asperger's syndrome, migraine, dizziness, sleep disorders, burnout, ADHD, muscular and / or joint pain or autism.

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