How to Use the H1 Deep Transcranial Magnetic Stimulation Coil for Conditions Other than Depression.

Deep transcranial magnetic stimulation (dTMS) is a relatively new technique that uses different coils for the treatment of different neuropathologies. The coils are made of soft copper windings in multiple planes that lie adjacent to the skull. They are located within a special helmet so that their magnetic fields combine and improve depth penetration. The H1 dTMS coil is designed to stimulate bilateral prefrontal cortices with greater effective stimulation over the left than the right. By positioning the left side of the coil close to the left dorsolateral prefrontal cortex (DLPFC), the H1 coil was used in a multisite study, leading to FDA approval for treatment-resistant depression. In this same position, the H1 coil was also explored as a possible treatment for negative symptoms of schizophrenia, bipolar depression, and migraine. When moved to different positions over the subject's skull, the H1 coil was also explored as a possible treatment for other conditions. Such manipulation of the H1 coil was demonstrated for PTSD and alcohol dependence by positioning it over the medial prefrontal cortex (mPFC), for anxiety by positioning it over the right prefrontal cortex (rPFC), for auditory hallucinations and tinnitus by positioning it over the temporoparietal junction (TPJ), and for Parkinson's and fatigue from multiple sclerosis (MS) by positioning it over the motor cortex (MC) and PFC. Corresponding electrical field diagrams measured with an oscilloscope through a saline-filled head are included.

Prelimbic Stimulation Ameliorates Depressive-Like Behaviors and Increases Regional BDNF Expression in a Novel Drug-Resistant Animal Model of Depression.

BACKGROUND: Approximately one third of all major depression patients fail to respond to conventional pharmacological antidepressants, and brain stimulation methods pose a promising alternative for this population. Recently, based on repeated multifactorial selective inbreeding of rats for depressive-like behaviors, we introduced a novel animal model for MDD. Rats from this Depressive Rat Line (DRL) exhibit inherent depressive-like behaviors, which are correlated with lower levels of brain-derived neurotrophic factor (BDNF) in specific brain regions. In addition, DRL rats do not respond to antidepressant medication but respond to electroconvulsive treatment, and they can thus be utilized to test the effectiveness of brain stimulation on hereditary, medication-resistant depressive-like behaviors. OBJECTIVE: To test the effect of sub-convulsive electrical stimulation (SCES) of the prelimbic cortex, using TMS-like temporal pattern of stimulation, on depressive-like behaviors and regional BDNF levels in DRL rats. METHODS: SCES sessions were administered daily for 10 days through chronically implanted electrodes. Temporal stimulation parameters were similar to those used in TMS for major depression in human patients. Depressive-like behaviors were assayed after treatment, followed by brain extraction and regional BDNF measurements. RESULTS: SCES normalized both the depressive-like behaviors and the reduced BDNF levels observed in DRL rats. Correlation analyses suggest that changes in specific behaviors are mediated, at least in part, by BDNF expression in reward-related brain regions. CONCLUSIONS: Brain stimulation is effective in a drug-resistant, inherited animal model for depression. BDNF alterations in specific regions may mediate different antidepressant effects.

Addiction.

Drug and alcohol addiction is a debilitating disorder characterized by persistent drug-seeking behaviors despite negative physiological, medical, or social consequences. Neurobiological models of addiction propose that the reinforcing effects of addictive drugs are associated with altered neurotransmission within the reward 'mesocorticolimbic' circuitry in the brain. Immense efforts are therefore designed to target the mesocorticolimbic circuitry in attenuating drug dependence and addiction-related behaviors. Yet, to date, most addiction treatments have demonstrated only limited success in reducing addiction-related behaviors. Accumulating and compelling evidence suggests that novel nonsurgical brain stimulation techniques, such as transcranial magnetic stimulation and transcranial direct current stimulation, could serve as promising tools for indexing altered neurotransmission associated with repetitive drug use, and moreover, may hold therapeutic potential for the treatment of drug dependence and addiction-related behaviors. This chapter reviews and discusses the current and potential applications of such techniques in the study and treatment of addiction; we focus on a number of common drugs of abuse, including nicotine, alcohol, cocaine, cannabis, and ecstasy.

Effectiveness of deep transcranial magnetic stimulation combined with a brief exposure procedure in post-traumatic stress disorder--a pilot study.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder induced by traumatic experiences. To date, psychotherapy and drug treatment achieve only partial success, indicating need for further development of treatment strategies. Recent research has found that impaired acquired fear extinction capability serves as an important factor at the pathogenesis of the disorder. Medial prefrontal cortex (mPFC) hypo-activity has been implicated in this extinction impairment, providing insight as to why some trauma exposed individuals will develop PTSD. OBJECTIVE: To test whether fear extinction can be facilitated and therapeutic effect achieved by repeated mPFC deep transcranial magnetic stimulation (DTMS) of PTSD patients resistant to standard treatment. METHODS: In a double-blind study, 30 PTSD patients were enrolled and randomly assigned into 3 treatment groups: A) DTMS after brief exposure to the traumatic event with the script-driven imagery procedure; B) DTMS after brief exposure to a non-traumatic event; C) sham stimulation after brief exposure to the traumatic event. RESULTS: Significant improvement was demonstrated in the intrusive component of the CAPS scale in patients administered DTMS after exposure to the traumatic event script, while patients in the control groups showed no significant improvement. Similar trend was demonstrated in the Total-CAPS score as in the other rating scales. A significant reduction in the HR response to the traumatic script was evident in group A, further supporting the above results. CONCLUSIONS: Combining brief script-driven exposure with DTMS can induce therapeutic effects in PTSD patients. A wide multi-center study is suggested to substantiate these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00517400.

Brain stimulation in the study and treatment of addiction.

Addiction is a devastating and chronically relapsing disorder. Repeated drug administration induces neuroadaptations associated with abnormal dopaminergic activity in the mesocorticolimbic circuitry, resulting in altered cortical neurotransmission and excitability. Electrical stimulation of specific brain regions can be used in animal models and humans to induce local activation or disruption of specific circuitries or alter neuronal excitability and cause neuroadaptations. Non-surgical stimulation of specific brain regions in human addicts can be achieved by transcranial magnetic stimulation (TMS). TMS is used for transient stimulation or disruption of neural activity in specific cortical regions, which can be used to assess cortical excitability, and to induce changes in cortical excitability. Moreover, it is suggested that repeated stimulation can cause long-lasting neuroadaptations. Therefore, TMS paradigms were used in some studies to assess the presence of altered cortical excitability associated with chronic drug consumption, while other studies have begun to assess the therapeutic potential of repetitive TMS. Similarly, transcranial direct current stimulation (tDCS) is used to modulate neuronal resting membrane potential in humans and alter cortical excitability. The current review describes how these brain stimulation techniques have recently been used for the study and treatment of addiction in animal models and humans.

Consensus: New methodologies for brain stimulation.

We briefly summarized several new stimulation techniques. There are many new methods of human brain stimulation, including modification of already known methods and brand-new methods. In this article, we focused on theta burst stimulation (TBS), repetitive monophasic pulse stimulation, paired- and quadri-pulse stimulation, transcranial alternating current stimulation (tACS), paired associative stimulation, controllable pulse shape TMS (cTMS), and deep-brain TMS. For every method, we summarized the state of the art and discussed issues that remain to be addressed.

Behavioral analysis during the forced swimming test using a joystick device.

The behavioral test described by Porsolt in 1977 for screening potential antidepressant drugs is extensively used both in basic research and in the pharmaceutical industry. The measured behavior is the immobility time during the swimming test (preformed in rodents), which decreases upon acute antidepressant treatment. Several research groups have suggested some modifications on the original Porsolt paradigm and its analysis. Nevertheless, there are still inaccuracies resulting from either undefined intermediate behaviors or from considering the movement of the whole body as one unit without analyzing the motion of the limbs. Herein, we propose a novel and simple scoring method, based on continuous measurement of the limbs motion, using a joystick, a computer screen and simple software. We validated the method, using antidepressant drugs and studied examples of false positives and false negatives of the traditional Porsolt paradigm. The proposed method is easy to use, it accounts for all range of movements and the analysis is relatively fast. Moreover, the results obtained using this analysis method show a normal Gaussian distribution in a population of rats (while the traditional Porsolt analysis does not) which allows selective breeding of 'motivated' and 'depressed' lines of animals.

Nucleus accumbens beta-endorphin levels are not elevated by brain stimulation reward but do increase with extinction.

Beta-endorphin is an endogenous opioid peptide implicated in reward processes, but the brain sites directly involved in its putative role in reward have not been identified. Here we used in vivo microdialysis in rats to study the effect of a potent reinforcer, lateral hypothalamus self-stimulation (LHSS), on the extracellular levels of beta-endorphin in the nucleus accumbens (NAS). The NAS is involved in the reinforcing effects of natural and artificial rewards, has high density of opioid receptors and is innervated by arcuate nucleus beta-endorphin neurons. LHSS had no effect on extracellular levels of beta-endorphin in the NAS. Surprisingly, extinction of the self-stimulation behaviour induced a rapid increase in NAS beta-endorphin levels. In a subsequent experiment in rats previously trained to self-administer heroin for 10 days, beta-endorphin levels also were increased during a test for extinction of the heroin-reinforced behaviour. Finally, the increase in extracellular beta-endorphin levels in the NAS was also observed during exposure to an aversive stimulus, intermittent footshock (20 min). These results indicate a possible role for increased levels of NAS beta-endorphin in the organism's adaptive response to stress and frustration.

Endomorphin-1 and -2 immunoreactive cells in the hypothalamus are labeled by fluoro-gold injections to the ventral tegmental area.

Endomorphin-1 and -2 (EM1, EM2) are endogenous opioids with high affinity and selectivity for the mu-opioid receptor. Cells expressing EM-like immunoreactivity (EM-LI) are present in the hypothalamus, and fibers containing EM-LI project to many brain regions, including the ventral tegmental area (VTA). The VTA is one of the most sensitive brain regions for the rewarding and locomotor effects of opioids. It contains mu-opioid receptors, which are thought to mediate gamma-aminobutyric acid-dependent disinhibition of dopamine transmission to the nucleus accumbens. We investigated whether hypothalamic EM-LI cells project to the VTA, where they could play a natural role in this circuitry. The retrograde tracer Fluoro-Gold (FG) was microinjected into the anterior or posterior VTA in rats. Nine days later, colchicine was injected, and 24 hours later, the animals were perfused and processed for fluorescence immunocytochemistry. Numerous FG-labeled cells were detected in the hypothalamus. Both EM1-LI and EM2-LI cells were present in the periventricular nucleus, between the dorsomedial and ventromedial hypothalamus and between the ventromedial and arcuate nuclei. Subpopulations of EM1-LI and EM2-LI cells were labeled by FG. Injections of FG to the anterior and posterior VTA were both effective in producing double-labeled cells, and an anterior-posterior topographical organization between the VTA and hypothalamus was observed. The results support the idea that some endomorphin-containing neurons in the hypothalamus project to the VTA, where they may modulate reward and locomotor circuitry.