Treatment of thalamocortical dysrhythmia

Abstract

To provide a method for treating conditions associated with thalamocortical dysrhythmia.SOLUTION: A method includes applying transcranial low voltage electrical stimulation (TLVES) therapy or transcranial magnetic stimulation (TMS) therapy to a patient, and administering to the patient a dissociative anesthetic during the TLVES therapy or the TMS therapy. A number of conditions including tinnitus, depression and pain can be treated with TLVES or TMS in combination with the dissociative anesthetic, such as an NMADR inhibitor, including ketamine.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Patent Application No. 13 / 826,250, filed March 14, 2013, and U.S. Provisional Patent Application No. 61 / 729,625, filed November 25, 2012, both of which are incorporated by reference in their entireties.

[0002] Neurological disorders affect millions of people worldwide. Several of these various disorders are associated with thalamocortical dysrhythmia, which is usually identified by a set of neurological and psychiatric symptoms resulting from abnormal oscillatory activity in the main neural circuits that connect the thalamus and cortex of the brain. Different symptoms occur depending on the location of the rhythm disruption in the brain, but the neural mechanisms are the same. The abnormal rhythms interfere with normal communication in different areas of the brain, thereby impairing motor and cognitive functions, as well as other neural functions controlled by those areas of the cortex. Symptoms associated with thalamocortical dysrhythmia are among the complex regional pain syndromes (CRPS), also known as RSD, obsessive-compulsive disorder, depression, panic disorder, Parkinson's disease, schizophrenia, rigidity, dystonia, tinnitus, tremor, epilepsy, and major mood disorders. [Background technology]

[0003] Many patients do not respond to conventional treatments for these disorders. For example, STAR-D (Sequenced Treatment Alternatives to Relieve Depression) predicts that only one-third of the 20 million Americans diagnosed with major mood disorders will achieve complete relief, and even after attempts at treatment with various antidepressant trials, many patients remain refractory to pharmacological interventions. See The Numbers Count: Mental Disorders in America, National Institute of Mental Health (2012). Similarly, one-third of the United States suffers from chronic, unrelieved pain. At least 40% of the population experiences chronic pain when combined with physical and psychiatric sequelae. See Institute of Medicine of The National Academies of Science, Report Brief, June 2011.

[0004] The use of novel brain stimulation techniques to treat depression, and potentially other neuropsychiatric disorders, is a new and rapidly developing field. These techniques, such as Transcranial Magnetic Stimulation (TMS) and Transcranial Low Voltage Electrical Stimulation (TLVES), also known as Transcranial Electrical Stimulation (tES), are emerging as promising approaches due to their relative ease of use, safety, and neurobiological effects.

[0005] TLVES involves the use of a weak electrical current (1-4mAmps) passed through brain tissue through electrodes placed on the skull. Effective electrode placements are known for symptoms such as prophylaxis against severe pain, migraines, depression, and hallucinations. tES can be delivered in the form of tDCS (direct current stimulation), tACS (alternating current stimulation), or tRNS (random noise stimulation), which is an intentionally chaotic current. With tES, many parameters can be alternated including frequency (mathematically based on oscillatory waves) and frequency range, waveform, and offset. The stimulation can affect both background electrical states, or occasionally oscillatory states, or alternate neuronal firing. This causes sustained changes in neuronal excitability, as evidenced in physiological studies. This is likely the mechanism by which repeated stimulation can have significant therapeutic effects, as seen in clinical-based studies.

[0006] Depression has also been treated with Transcranial Magnetic Stimulation (TMS), which was first introduced in 1985 to demonstrate relatively painless activation of neuronal systems. In recent years, TMS has been applied to investigate the integrity and effects of electromagnetic stimulation propagated along cortical neuronal systems. More recently, commercial TMS systems have been developed to treat Major Depressive Disorder (MDD). For example, the NEUROSTAR TMS THERAPY® System (Neuronetics, Inc.) is a 37-minute outpatient TMS treatment performed under the supervision of a psychiatrist. It does not require anesthesia or sedation, and the patient remains awake and alert during the treatment. Treatments are typically administered daily for about 4-6 weeks.

[0007] During NeuroStar TMS treatment, magnetic field pulses are generated and directed at the left prefrontal cortex, an area of ​​the brain that has been demonstrated to function abnormally in patients with depression. These TMS magnetic fields are of the same type and strength as those used in magnetic resonance imaging (MRI) machines. The magnetic field pulses travel freely through hair, skin, and the skull to the brain.

[0008] Inside the brain, the magnetic field pulses are thought to induce electrical changes in the affected neural networks. The amount of electrical potential generated is very small and not felt by the patient, but it is thought to be capable of altering neural tissue activity, leading to the release of neurotransmitter chemicals such as serotonin, norepinephrine and dopamine. Regional Cerebral Blood Flow (rCBF) can also be directly altered by TMS.

[0009] One of the major drawbacks of TMS is that it requires several weeks of strictly scheduled treatments, which equates to a large human burden in terms of time, money and inconvenience, and is often subject to patient non-compliance.

[0010] Aside from techniques such as TLVES and TMS, there are many pharmaceuticals currently available to treat neurological disorders. These include, but are not limited to, anticonvulsants, antiepileptics, barbiturates, barbituric acid derivatives, anesthetics, tinnitus treatments, selective serotonin reuptake inhibitors, antidepressants, neuroleptics, antihypertensives, antipsychotics, calcium channel blockers, ACE inhibitors and beta blockers, mood stabilizers and stimulants, and hallucinogens. However, many of these drugs are limited by their effectiveness and their side effects. For example, many of these drugs are known to cause drowsiness, depression, insomnia, weight changes, sexual dysfunction, cognitive dysfunction, weakness, fatigue, hallucinations, and other side effects that severely limit their use in clinical practice.

[0011] In recent years, interest has been focused on the use of NMDA receptor antagonists to treat neuropsychiatric disorders. NDMA inhibitors are a class of psychopharmacological drugs that function by antagonizing or inhibiting the action of NMDA-type glutamate receptors (NMDARs). They are commonly used as anesthesia in animals and humans. The state of anesthesia they induce is called dissociative anesthesia. Some synthetic opioids also function as NMDAR antagonists, such as meperidine, dextropropoxyphene, tramadol, and ketobemidone. Some NMDA receptor antagonists, including but not limited to ketamine, dextromethorphan, phencyclidine, and nitric oxide, are known for their dissociative, hallucinogenic, and / or euphoric properties.

[0012] Ketamine, a specific NMDA inhibitor, has been shown to be effective in treating depression in patients with bipolar illness who are unresponsive to antidepressants. See Preskorn, Biol. Psychiatry (2012) 72:522-23. In patients with major depressive disorder and bipolar depression, ketamine can produce a rapid-acting antidepressant effect, working within 2 hours versus the weeks that typical antidepressants often require to function. When used alone, ketamine appears to provide 4 to 7 days of relief from suicidal ideation. However, ketamine does not appear to provide sustained relief from suicidal ideation in depression. Summary of the Invention [Problem to be solved by the invention]

[0013] Thus, the inventors have identified a need for a treatment for symptoms associated with thalamocortical dysrhythmia that provides more robust and more consistent improvement. Such a treatment would also provide a greater likelihood of sustained success. Moreover, the treatment would preferably reduce the undesirable effects of drug therapy.

[0014] The following statements in this section are not prior art to the claims of this application and are not admitted to be prior art by inclusion in this section. [Means for solving the problem]

[0015] In one aspect, the present disclosure relates to a method of treating a condition associated with thalamocortical dysrhythmia in a patient, the method comprising administering transcranial low voltage electrical stimulation (TLVES) or transcranial magnetic stimulation (TMS) therapy to the patient in combination with administering a dissociative anesthetic to the patient during the TLVES or TMS therapy.

[0016] In various aspects of the present disclosure, conditions associated with thalamocortical dysrhythmia are known as tinnitus, pain including complex regional pain syndrome or reflex sympathetic dystrophy, and forms of depression including bipolar depression.

[0017] In another embodiment, the dissociative anesthetic is an NMDA-type glutamate receptor (NMDAR) antagonist, such as ketamine, and can be administered for about 30-60 minutes of treatment. When the NMDAR antagonist is ketamine, the dose can be about 50-500 mg. Comparable therapeutic doses of other NMDAR antagonists can be used instead.

[0018] In yet another embodiment, the TLVES therapy or the TMS therapy is applied before, during and after the administration of the NMDAR antagonist.In particular, the method may include a priming procedure before the application of the TMS therapy combined with a dissociative anesthetic.

[0019] Yet another embodiment of the present disclosure includes repeating the method of treatment at least five times at intervals of 3-7 days.

[0020] These and alternatives, together with other aspects and advantages, will become apparent to those of ordinary skill in the art from a reading of the following detailed description, appropriately taken with reference to the accompanying drawings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Exemplary systems and methods are described herein. It should be understood that the word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment or feature described herein as "exemplary" or "example" is not necessarily to be construed as preferred or advantageous over other embodiments or features. The exemplary embodiments described herein are not meant to be limiting. It will be expressly understood that certain aspects of the disclosed systems and methods can be arranged or combined in a wide variety of different configurations, all of which are contemplated herein.

[0022] In various aspects, the present disclosure relates to a method of treating a thalamocortical dysrhythmia disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a dissociative anesthetic in combination with transcranial electrical or magnetic stimulation, e.g., TMS or transcranial low-voltage electrical stimulation (TLVES).

[0023] Non-limiting examples of neurological disorders associated with thalamocortical dysrhythmia include depression, chronic depression, bipolar depression, neuropathic or central pain, complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD), obsessive-compulsive disorder, panic disorder, rigidity, dystonosis, tinnitus, tremor, epilepsy, petit mal epilepsy, absence epilepsy, autism, Parkinson's disease, obsessive-compulsive disorder (OCD), schizophrenia, schizoaffective disorder, migraine, restless legs syndrome, etc. Also, users of various drugs of abuse, such as heroin, opiates, cocaine, stimulants, alcohol, and tranquilizers, are known to have thalamocortical dysrhythmia.

[0024] TMS involves creating and applying a fluctuating magnetic field in a controlled manner. The flux created by the expansion and contraction of the magnetic field creates electrical changes in the patient's tissue delivered by the TMS head coil. Some results are believed to depolarize neurons and generate action potentials. Another possible result is believed to be the modification of the electrical state of cells delivered by magnetic stimulation. One key advantage of TMS over TLVES is that TMS can be delivered to the brain in a more spatially focused manner, especially when using a figure-of-eight shaped coil. One parameter in the TMS treatment described herein is the electromagnetic frequency used to effect stimulation of brain tissue. For example, stimulation frequencies of 1 Hz or less may be used with the TMS treatment described herein. Stimulation frequencies of 1 Hz or less are also referred to as single-pulse TMS, although this term is generally used to describe TMS delivered every few seconds at random intervals. TMS delivered at higher frequencies may be used with the TMS treatment described herein, although such TMS treatments delivered at higher frequencies may also be described as repetitive TMS (rTMS). The inhibitory and excitatory effects of TMS are hypothesized to be akin to long-term potentiation and long-term depression. Another approach delivers bursts of repeated stimulation, also known as theta-burst stimulation (TBS), where an early stimulation primes the system for a later stimulation.

[0025] Transcranial electrical stimulation, delivered at low voltage (usually less than about 20 volts), takes several forms, including fixed current DC stimulation (tDCS), alternating current stimulation (tACS), or random (noise) current generation (tRNS). The dosage associated with transcranial low voltage electrical stimulation (TLVES) can be defined in terms of the size and location of the electrodes on the skull, as well as the duration, frequency, and intensity of the current (mAmps). Currents less than about 4 mAmps are commonly used with these techniques. In some embodiments, commercially available computer-controlled DC stimulators may be used.

[0026] Although the transcranial electrical and magnetic stimulation described herein may be consistent across a relatively wide range of individuals, it should be understood that there are differences in individual responses to electrical or electromagnetic stimulation for a given individual. One way in which the intensity of stimulation is calibrated for a given individual is to test the person to obtain the minimum intensity of stimulation applied to the motor cortex (often also referred to as MI) that evokes a motor response. This motor threshold is generally reported as the minimum intensity required to effect stimulation and may be defined in terms of a percentage of the available power of the device, or alternatively, in terms of the strength of the magnetic field measurement, i.e., in Tesla units. In any case, the degree to which stimulation effects treatment in a particular patient is influenced by the stimulation frequency, the repetition frequency of treatment (including pretreatment as described below), and the personal response characteristics of the particular patient. These and similar individual variabilities in response are believed to be attributable to individual physiology and chemistry, and are at least in part genetically determined. Specific TMS parameters include the inter-train interval (the time between trains of stimulation), the number of trains per session, and the duration of the session. The most common discomforts are headache, scalp pain, nausea, and temporary hearing loss, and these factors also affect how patients respond to treatment. Thus, it should be understood that implementing the methods described herein on any patient requires the practitioner to exercise a certain amount of experience and judgment to adjust to the individual sensitivity of the patient. For example, when a clinician has identified a medical or psychological weakness in a patient that would previously suggest that the patient is not a good candidate for TMS, or when the patient wishes to avoid TMS treatment, tES treatment provides an alternative and effective approach. tES treatment provides important clinical benefits for patients who are not good candidates for TMS treatment. tES can also be important as an effective switching treatment for patients who are sensitive to the drug side effects of TMS treatment.

[0027] NMDA receptor antagonists are a class of dissociative anesthetics that function by antagonizing or inhibiting the action of NMDA-type glutamate receptors (NMDARs). They are used as anesthetics for animals and are less commonly used in humans. The anesthetic state they induce is called dissociative anesthesia. NMDA receptors are ionotropic receptors that allow the movement of electrical signals between neurons in the brain and the spinal column. To allow electrical signals to pass, NMDA receptors must be open. To stay open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated."

[0028] Ketamine ((RS)-2-(2-chlorophenyl)-2-methylaminocyclohexanone) is a drug used in human and veterinary medicine. Ketamine is primarily used for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (especially in emergency medicine), and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, increased blood pressure, and bronchodilation, and maintains perfusion of brain and cardiac tissue.

[0029] Ketamine has been shown to be effective in treating depression in bipolar patients who do not respond to antidepressants. In particular, it has been shown to reduce suicidal thoughts. In people with major depressive disorder, it produces a rapid antidepressant effect, working within two hours, whereas typical antidepressants take several weeks to work.

[0030] Ketamine has also been used as an experimental and controversial treatment for complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD). CRPS / RSD is a severe chronic pain condition characterized by sensory, autonomic, motor and dystrophic signs and symptoms. CRPS pain is continuous, often worsens over time, and is usually disproportionate to the severity and duration of the inciting event. Ketamine-infused patients with obsessive-compulsive disorder (OCD) have more limited benefit than those above. (Pittenger, et al., Biol Psychiatry (2012) 72:964-970.)

[0031] Other NMDA receptor antagonists include adamantane derivatives, amantadine, memantine, rimantadine, allylcyclohexylamine, dieticyclidine, esketamine, eticyclidine, gacyclidine, methaphyte, methoxetamine, neramexane, phencyclidine, phenylhexylcyclopyrrolidine, rolicyclidine, tenocyclidine, tiletamine, methoxydine (4-MeO-PCP), morphinan, dextromethorphan, dextrorphan, methophan, morphanol, 2-MDP, 8A-PDHQ, aptiganel, dexoxadrol, diethyl ether, dizocilpine, ethoxadrol, ibogaine (Tabemanthe These include: iboga), Midafotel, NEFA, Nitrous Oxide, Norivocaine, Perzinfotel, Remacemide, Selfotel and Xenon.

[0032] In one embodiment, the present disclosure relates to a method for treating symptoms associated with thalamocortical dysrhythmia. The method includes treating a patient with transcranial electrical or electromagnetic stimulation, such as TMS or TLVES, in combination with a dissociative anesthetic. In one embodiment, the dissociative anesthetic is an NMDAR inhibitor, such as ketamine. The use of electrical or electromagnetic stimulation in combination with a dissociative anesthetic, such as ketamine, often results in improved therapeutic response, with reduced dosage of the dissociative anesthetic compared to the dosage normally required for treatment without stimulation. For example, when used in combination with TMS, the dosage of ketamine can be about 10 mg to about 500 mg, which is delivered in standard commercial formulations during the course of TMS treatment. More specifically, the ketamine dose can range from about 20 mg to about 400 mg, specifically from about 50 mg to about 350 mg, more specifically from about 100 mg to about 350 mg, and even more specifically from about 200 mg to about 300 mg.

[0033] The combined treatment (i.e., stimulation combined with anesthesia) may extend from about 20 seconds to about 120 seconds at appropriate dosage levels. In particular, the stimulation period may extend from about 20 seconds to about 100 seconds, from about 30 seconds to about 90 seconds, from about 40 seconds to about 100 seconds, or more specifically, from about 20, 30, 50, 60, 70, 80, 90, 110, or 120 seconds. In one particular embodiment, a ketamine dose of between about 50 and 350 mg is injected in a treatment of TMS treatment extended for about 20-60 seconds. Longer injection times may also provide a gentler delivery of ketamine to the patient, generally resulting in a better feeling and fewer side effects.

[0034] During the combined procedure, the electrical or electromagnetic stimulation is administered at the time of administration of the anesthetic agent, or before and / or after administration of the anesthetic agent. For example, administration of the anesthetic agent may be preceded by a stimulation period ranging from about 1 to 15 minutes, more specifically about 3 to 10 minutes, or even more specifically about 5 minutes. Following the preceding stimulation period, administration of the anesthetic agent begins, and stimulation may continue at the time of administration. Following administration of the anesthetic agent, stimulation may then be continued for a period ranging from about 1 to 15 minutes, more specifically about 3 to 10 minutes, or even more specifically about 5 minutes.

[0035] During combined treatment with TMS, the TMS head coil is directed at the anterior cingulate region for treatment of the majority of disorders related to thalamocortical dysrhythmia. When treating tinnitus, stimulation of the association cortex may be appropriate. As more is known in the future about which brain regions are involved in various additional health conditions, it will become clearer which brain regions should be the focus of stimulation for the treatment of such additional health conditions.

[0036] The appropriate dose for TMS treatment may be about 80% to 120% of the patient's motor threshold. As understood by those skilled in the art, the patient's motor threshold reflects the amount of TMS power output at which the patient's thumb begins to twitch when TMS is directed to the relevant area of ​​the voluntary motor cortex. This relates to brain stimulation as providing one simple way to operate within safe parameters achieved. More specifically, the appropriate dose for TMS treatment is about 90 to 120%, 100% to 120%, or 105% to 115% of the patient's motor threshold. One example of the appropriate dose for TMS treatment is 110% of the patient's motor threshold. Generally, the frequency of the dose is 1 Hz, and stimulation is continued during the combined treatment described herein.

[0037] Similar methods are known to those skilled in the art to achieve the appropriate degree and location of stimulation for TLVES. For example, with TLVES, electrode placement can be anterior-posterior (e.g., center of forehead and center of back of head or Oz). Typically, a patient can be treated with 1,000 to 2,500 mAmps for 10-50 minutes, e.g., about 1,000, 1,200, 1,300, 1,500, 2,000 or 2,500 mAmps for about 15, 25, 25 or 45 minutes. Stimulation may include an offset of about 800 to about 1200 mAmps, e.g., about 1000 mAmps. TLVES may be continuous during combined treatment as described herein. TLVES may also be initiated prior to the start of infusion of the dissociative anesthetic, e.g., about 1-15 minutes prior to the start of infusion, more specifically, e.g., about 1, 2, 5, 10 or 15 minutes prior to the start of infusion. The TLVES may continue for a finite amount of time once the injection is complete.

[0038] Dissociative anesthetics may be delivered to a patient by conventional delivery methods, including intravenous, intramuscular, oral, intranasal, and, where appropriate, inhalation. Depending on the anesthetic, its half-life, delivery method, and absorption rate, the stimulation time during the combined procedure may be adjusted to ensure that the anesthetic is present in a therapeutically effective amount at the time of stimulation. When the anesthetic is delivered intravenously, the patient experiences its effect virtually immediately. If the anesthetic is delivered orally, additional time may be added to the stimulation to ensure that stimulation occurs while the anesthetic is therapeutically effective. The pharmacokinetics of ketamine and other dissociative anesthetics have been relatively well studied by others in the art, and the understanding derived from those studies provides a good basis for predicting the time, method, and amount of drug administration to time the anesthetic to enter the bloodstream and become available for treatment of the patient's tissues.

[0039] Prior to the combined treatment, the patient may receive a priming stimulation treatment of about 10 to 80 seconds. For example, when TMS is used in the combined treatment, the TMS head coil is directed to the left and right dorsolateral prefrontal cortex during a priming treatment of about 10 to 40 seconds, respectively. The frequency for the priming stimulation treatment may be about 1 Hz for the right prefrontal cortex and about 1 Hz for the left prefrontal cortex. The combined treatment may follow immediately after the completion of the priming TMS treatment, or the combined treatment may continue up to one day after the priming treatment, depending on the patient's tolerance and compliance. Priming with other forms of electrical or electromagnetic stimulation may also be used, depending on the patient's needs and tolerance.

[0040] In yet another alternative, the patient may be pretreated with electrical or electromagnetic stimulation for weeks or days prior to the combined treatment. For pretreated patients, no priming is required. Thus, the combined treatment may begin after a series of pretreatments, for example, the next day. When the combined treatment uses TMS, the pretreatment typically includes TMS treatment with a therapeutic regimen every day (about 6 days out of 7) for about 3 days to 2 weeks. For example, the pretreatment may include up to 4 TMS treatment sessions per day of 1.5 hours, with 45 minutes between treatment sessions. As an example, the pretreatment session includes stimulation at 1 Hz directed to the dorsolateral prefrontal cortex (left), stimulation at 10 Hz directed back to the left prefrontal cortex, stimulation at 20 Hz to the right prefrontal cortex, and stimulation at 20 Hz to the area overlying the anterior cingulate region.

[0041] Some patients may be apprehensive and fearful about the ketamine procedure, so the use of an anti-anxiety medication such as Valium (diazepam) or Versed (midazolam) may be appropriate, as may an anti-emetic such as Zofran (ondansetron).

[0042] Great positive outcomes have been associated with the combination of TMS treatment + ketamine when the combination is performed on a weekly or biweekly basis. Another alternative includes treatments every 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21 days or more. In some cases, patients stopped treatment for various reasons, but resumed after a few weeks or months. Positive outcomes can be expected with about 2-20, more specifically about 5-15 treatments, with a regular interval of about 3-11 days, more specifically about one week. Positive outcomes can also be achieved at longer or shorter intervals, which may be sporadic due to the patient's schedule and compliance issues. In certain embodiments, depression may be successfully treated with at least about 5 treatment sessions, more particularly about 6-8 treatment sessions, while chronic pain may require several additional treatment sessions to achieve the desired outcome, particularly if the pain is accompanied by severe depression and / or addiction. In some instances, patients may be given ongoing infrequent treatment (e.g., every 1 to 4 months) for maintenance purposes.

[0043] The use of TMS alone is reported to be effective in about 20-30% of patients for mild treatment to relieve depression. TMS is also reportedly effective in treating severe depression. Studies suggest that using ketamine alone to treat depression results in about 60-70% success rate. However, to achieve this success with ketamine alone, the dose of ketamine is reportedly 5-15 times higher than the dose required when ketamine is used in combination with TMS as described herein. Also, relief with ketamine alone is very transient in ketamine alone studies.

[0044] In comparison, the percentage of patients completing treatment with the TMS+ketamine combination who achieve positive outcomes is higher than the reported success rates for either TMS alone or ketamine alone. Patients who have positive outcomes from treatment with the TMS+ketamine combination, as described herein, also tend to achieve more robust, i.e., longer-lasting, positive results and less adverse side effects. Positive outcomes include returning to work, returning to a broken job, returning to college, getting married, reconciling a broken relationship, reliable abstinence from substance abuse, and a dramatic reduction in destructive doses of opioid narcotics. Also, many patients who achieve positive outcomes after undergoing the combination treatment described herein have previously failed all other treatments for their symptoms. These treatments included rTMS, VNS, TLVES, ECT, hyperbaric oxygen treatment, medications including infusions of ketamine (only), and other medications such as homeopathies.

[0045] Thus, the described procedures provide superior outcomes using less anesthetic in combination with TMS or TLVES. With less anesthetic required, the procedures have fewer side effects. Also, less need for TMS or TLVES results in better patient compliance, which itself contributes to more positive outcomes. In fact, patients who initially experience relief from a procedure tend to be motivated to undergo another procedure that provides lasting benefits.

[0046] TLVES / ketamine treatment offers clinical benefits for patients who would not be good candidates for TMS / ketamine treatment. In particular, clinicians may know in advance that certain patients are not good candidates for TMS. For example, patients may benefit more from TLVES / ketamine because they are exhausted by the strong effects of TLVES / ketamine on the overall cerebral blood flow, or patients may become agitated and require special care to stay in place for prolonged TMS / ketamine sessions. TLVES / ketamine treatment offers a valid alternative approach. It may also be important as a transitional treatment for patients who are sensitive to the side effects of TLVES / ketamine treatment. TLVES / ketamine may be less taxing on those who are less robust and may be an excellent option for those who are already on track for a stable recovery.

[0047] In another embodiment, the present disclosure relates to a method of reducing side effects associated with treating a condition associated with thalamocortical dysrhythmia with a dissociative anesthetic. For example, side effects can be minimized or reduced by using a lower dose of anesthetic in the treated patient. In this method, the dissociative anesthetic is administered in combination with TMS or TLVES. Similarly, in another embodiment, the present disclosure relates to a method of reducing the dose of a dissociative anesthetic for treating a condition associated with thalamocortical dysrhythmia. In these embodiments, the dose of the anesthetic can be reduced by about 2-20 times the amount normally administered for treating the condition. In another embodiment, the dose can be reduced by 5-15 times, more specifically 10-15 times, and even more specifically 5, 10, or 15 times. In a particular embodiment where the dissociative anesthetic is ketamine, the dose for treating the condition is about 20 mg to about 400 mg, about 50 mg to about 350 mg, more specifically about 100 mg to 350 mg, and even more specifically about 200 mg to about 300 mg. In another embodiment where the dissociative anesthetic is ketamine, the dosage for treating the condition is about 0.1-6.0 mg / kg, more specifically about 0.5-5.0 mg / kg, and even more specifically about 1.0-4.0 mg / kg. EXAMPLES

[0048] Example 1: TMS / Ketamine Treatment Thirty-five patients were treated with a combination of ketamine and TMS. All 28 patients who completed the treatments identified in Table 1 had positive outcomes with the treatment regimen identified in Table 2 (Tables 1 and 2 are presented at the end of the detailed description of the invention, before the claims). To simplify the description of Table 2, patients who received treatments more than once a week are indicated as having received treatments once a week. Also, intervals are rounded to the nearest week.

[0049] Some patients received pretreatment (PT) consisting of daily TMS treatment for 3 days to 2 weeks (usually 6 or 7 days) (shown as "PT days" or "PT weeks" in Table 2). Other patients received a priming TMS treatment before the combined treatment. Some patients received neither pretreatment nor priming, but many patients received one or the other. Because the priming treatment is less rigorous than a few days of pretreatment, all patients receiving pretreatment were eventually switched to receiving either priming or nothing. Pretreatment and / or priming treatment was administered based on the disease and patient compliance. Patients suffering from chronic pain responded well when pretreatment or priming was administered, but no clear differences were reported for depressed patients.

[0050] Based on the lack of success reported in previous studies using ketamine alone, TMS alone, or TLVES alone, the positive outcomes shown in Table 1 suggest a synergistic effect of combination therapy with ketamine and TMS. Additionally, patients receiving combination therapy had sustained benefits not previously reported with ketamine alone, and required much lower doses of ketamine than previously known.

[0051] Example 2: TLVES / Ketamine Treatment Three patients were pre-treated with TMS / Ketamine as described above and improved significantly, however these patients were sicker and less robust than other members of the cohort.

[0052] Patients were treated with tACS or tRNS by defining the anode at F3 and the cathode at F8 in terms of net current. Electrical stimulation of the electrodes was applied for 20 min. Ketamine was started after 5 min and was continuously infused for 15-50 min at a total dose of 0.5-5.0 mg per kg. For tACS, the parameters were 1200 μAmps without offset or 1200 μAmps with an offset of 1000 μAmps. For tRNS, the parameters were 1300 or 2000 μAmps with an offset of 1000 μAmps. With TLVES / ketamine, all three patients were able to obtain similar therapeutic effects as TMS / ketamine with less post-procedure fatigue.

[0053] While various aspects and embodiments are disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims. [Table 1] [Table 2-1] [Table 2-2] [Table 2-3]

Claims

1. 1. A method of treating a condition associated with thalamocortical dysrhythmia in a patient, comprising: administering transcranial low voltage electrical stimulation (TLVES) or transcranial magnetic stimulation (TMS) therapy to the patient; and administering a dissociative anesthetic to the patient during the TLVES therapy or the TMS therapy.

2. 2. The method of claim 1, wherein the dissociative anesthetic is an NMDA-type glutamate receptor (NMDAR) antagonist.

3. The method of claim 2 , wherein the NMDAR antagonist is ketamine.

4. 2. The method of claim 1, wherein the TLVES therapy or the TMS therapy is administered before, during, or after administration of the NMDAR antagonist.

5. The method of claim 1 further comprising a priming step.

6. 10. The method of claim 1, wherein the method is repeated at intervals of 3 to 7 days.

7. 2. The method of claim 1, wherein the symptom associated with thalamocortical dysrhythmia is tinnitus.

8. The method of claim 1 , wherein the condition associated with thalamocortical dysrhythmia is substance abuse.

9. 1. A method of treating pain in an individual, the method comprising: administering transcranial low voltage electrical stimulation (TLVES) therapy or transcranial magnetic stimulation (TMS) therapy to the individual; and administering an NMDA-type glutamate receptor (NMDAR) antagonist to the patient during the TLVES therapy or the TMS therapy.

10. 10. The method of claim 9, wherein the TLVES therapy or the TMS therapy is administered before, during, or after administration of the NMDAR antagonist.

11. 10. The method of claim 9, wherein the NMDAR antagonist is ketamine at a dose of about 50-500 mg.

12. 12. The method of claim 11, wherein the ketamine is infused for about 30 to 60 seconds.

13. The method of claim 9 further comprising a priming step.

14. 10. The method of claim 9, wherein the method is repeated at least five times at intervals of 3 to 7 days.

15. 10. The method of claim 9, wherein the pain is associated with complex regional pain syndrome or reflex sympathetic dystrophy.

16. 1. A method for treating depression, comprising: applying transcranial low voltage electrical stimulation (TLVES) therapy or transcranial magnetic stimulation (TMS) therapy to a patient suffering from depression; and administering an NMDA-type glutamate receptor (NMDAR) antagonist to the patient during the TLVES therapy or the TMS therapy.

17. 17. The method of claim 16, wherein the TLVES therapy or the TMS therapy is administered before, during, or after administration of the NMDAR antagonist.

18. 17. The method of claim 16, wherein the NMDAR antagonist is ketamine at a dose of about 50-500 mg.

19. 20. The method of claim 18, wherein the ketamine is infused for about 30 to 60 seconds.

20. 20. The method of claim 16, further comprising a priming step.

21. 17. The method of claim 16, wherein the method is repeated at least five times at intervals of 3 to 7 days.

22. 17. The method of claim 16, wherein the depression is bipolar depression.

Images