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Background Transcranial magnetic stimulation (TMS) is a rapidly expanding technology utilized in research and neuropsychiatric treatments. Yet, conventional TMS configurations affect primarily neurons that are aligned parallel to the induced electric field by a fixed coil, making the activation orientation-specific. A novel method termed rotational field TMS (rfTMS), where two orthogonal coils are operated with a 90° phase shift, produces rotation of the electric field vector over almost a complete cycle, and may stimulate larger portion of the neuronal population within a given brain area. Objective To compare the physiological effects of rfTMS and conventional unidirectional TMS (udTMS) in the motor cortex. Methods Hand and leg resting motor thresholds (rMT), and motor evoked potential (MEP) amplitudes and latencies (at 120% of rMT), were measured using a dual-coil array based on the H7-coil, in 8 healthy volunteers following stimulation at different orientations of either udTMS or rfTMS. Results For both target areas rfTMS produced significantly lower rMTs and much higher MEPs than those induced by udTMS, for comparable induced electric field amplitude. Both hand and leg rMTs were orientation-dependent. Conclusions rfTMS induces stronger physiologic effects in targeted brain regions at significantly lower intensities. Importantly, given the activation of a much larger population of neurons within a certain brain area, repeated application of rfTMS may induce different neuroplastic effects in neural networks, opening novel research and clinical opportunities.

Well-functioning error monitoring of the inner and outer environments is essential for adaptively altering behavior, while malfunction characterizes conditions such as obsessive–compulsive disorder (OCD). The underlying brain processing is manifested as Error-Related Negativity (ERN) signal elicited following error comission, and Perceived Error Related Theta Activity (PERTA) signal elicited following detection of discrepancy in the environment. Yet, while enhanced ERN was repeatedly demonstrated in OCD patients and was found to be potentiated among their unaffected first degree relatives, no comparable observations were reported with regard to PERTA. We recorded EEG activity while OCD patients, OCD patients’ siblings (Family), and healthy controls (HC) performed computerized tasks. For the examination of ERN we used the Stroop task and for the examination of PERTA we presented correct and incorrect mathematical equations. Increased ERN (0–120 ms post response) was observed in both the OCD and Family groups, but only the OCD patients’ signal significantly differed from that of HC's. Similarly, modified PERTA activity was observed in both the OCD and Family groups in the N1 peak (65–125 ms post perceived error), but only for the OCD group this activity significantly differed from that of HC. Both ERN and PERTA's N1 are fast occurring peaks, which suggests that OCD is associate with a constantly over-activated detection system that monitors the inner and outer environment and reacts promptly following detection of a mistake. Furthermore, the modified but non-significantly different activity of the Family group suggests that the pathological condition evolves in vulnerable individuals with neuronal predisposition.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method that is increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help treat addictions, but evaluation is required in a multicenter randomized controlled trial (RCT). METHODS: Here, we tested in chronic smokers whether repeated bilateral rTMS of the lateral prefrontal and insular cortices reduces cigarette craving and consumption and increases quit rates. This multicenter RCT included 14 sites and 262 chronic smokers who received Active or Sham rTMS. Participants received three weeks of daily rTMS sessions following cue-induced craving and were monitored up to four months. The primary outcome was the four-week continuous quit rate (CQR) measured by daily smoking diaries and verified by urine cotinine measures. Secondary outcome measures included changes in cigarette consumption and craving. This trail is registered at ClinicalTrials.gov, number NCT02126124. RESULTS: In the intent to treat analysis set, CQR was 19·4% following Active and 8·7% following Sham rTMS (χ 2 = 5·655, p=0·017). Among completers (N=169), CQR was 28·0% and 11·7%, respectively (χ 2 = 7·219, p=0·007). CQR within the first six weeks was 25·3% (Active) and 6·4% (Sham) (χ 2 = 11·885, p=0·0006), of which 63% (Active) and 50% (Sham) remained abstinent for at least four months (χ 2 =8·46, p=0·003). Significant between-group differences in cigarette consumption and craving emerged as early as two weeks into treatment. CONCLUSIONS: This study establishes a safe treatment protocol that promotes smoking cessation by stimulating the relevant brain circuits. It represents the first large multicenter RCT of brain stimulation for addiction medicine. Funded by: BrainsWay Declaration of Interest: Oscar Morales occasional reports consult work for Brainsway; Dr. Tendler reports personal fees from Brainsway, other from Advanced Mental Health Care Inc./DTMS Center LLC, outside the submitted work; Dr. Roth reports personal fees from Brainsway, outside the submitted work; In addition, Dr. Roth has a patent US 7,407,478 with royalties paid; Mr. Deutsch reports personal fees from Brainsway, during the conduct of the study; personal fees from Brainsway, outside the submitted work; David Feifel reports he is a member of Brainsway's Scientific Advisory Board (non-compensated); Dr. Duffy reports other from Brainsway, during the conduct of the study; other from Alivation Health LLC and Alivation Research LLC, outside the submitted work; Prof. Abraham Zangen is an inventor of Deep TMS coils which were patented by the NIH and other academic institutions where Abraham Zangen worked. These patents were licensed to BrainsWay and Abraham Zangen receives royalties from these patents. In addition Prof. Zangen serves as consultant for BrainsWay and has finanacial insterests in BrainsWay; Dr. Todder reports other from BRAINSWAY, during the conduct of the study; all other authors have nothing to disclose. Ethical Approval:The trial protocol (Supplementary Materials; SM 1.1) was approved by local institutional review boards and was registered at clinicaltrials.gov (NCT02126124). The study was conducted in the United States (12 sites) and Israel (two sites), with active enrollment from August 2014 through August 2019. The trial was supported by industry (BrainsWay).

Chronic treatment resistant depression takes a substantial toll on patients' quality of life and alternative treatment options are limited. This prospective multicenter study evaluated the safety, tolerability and efficacy of four weeks of thrice-a-week deep transcranial magnetic stimulation (dTMS) in combination with selective serotonin reuptake inhibitors (SSRIs).Forty patients who failed to respond during a 16-week double-blind placebo controlled (DBPC) trial of dTMS or sham dTMS as monotherapy were screened and started a treatment of previously tolerable but ineffective SSRI. After ten days of medication, high frequency dTMS was added three times a week for four weeks.dTMS combined with SSRIs was well tolerated, with only headaches as a related adverse event (n = 4), which did not cause drop outs. Six patients were excluded from analysis: 1 was missing screening data and 5 received less than 10 sessions. Out of 34 patients included in this study, 12 (35.3%) patients remitted (HDRS-21 10). No significant differences were found between patients who had received sham or active dTMS in the earlier DBPC multicenter trial.This was a small scale open study of dTMS with SSRIs in patients that failed to respond during a DBPC dTMS trial, although a carryover effect cannot be excluded. Comparative efficacy of dTMS with and without SSRIs and specific dosing and protocol parameters warrant specifically-designed large-scale controlled studies.Thrice weekly dTMS at 120% motor threshold(MT), 10 HZ, 3‑s trains, 20‑s intervals, 2400 daily pulses, can augment formerly ineffective SSRI treatment.

Background Dorsolateral prefrontal cortex (DLPFC) is critically involved in mood and alcohol use disorders. Objective : We aimed to investigate the safety of intervention with add-on bilateral prefrontal high-frequency deep transcranial magnetic stimulation (dTMS) and between-group differences in treatment response in patients with different types of depressive episodes, including major depressive episodes in the course of major depressive disorder (MDD), bipolar disorder, type I (BD-I), and MDD with alcohol use disorder (MDAUD). Methods We conducted a 6-month open-label study, involving 82 patients with DSM-5 Depressive Episode. Of these, 41 had diagnosis of MDD, 20 BD-I, and 21 MDAUD. All patients received standard drug treatment and add-on dTMS over the bilateral DLPFC with left prevalence for four weeks, with five sessions in each week. We rated mood state with the Hamilton Depression Rating Scale (HDRS) at baseline, one-month, and six-month follow-up visits. Results Mean total HDRS scores dropped from 22.8 (SD = 5.9) at baseline to 10.4 (SD = 3.6) at 1 month, to 10.0 (SD = 4.5) at 6 months, while response/remission were 70.73% ( N = 58) and 19.51% ( N = 16) at 1 month and 76.83% ( N = 63) and 32.93% (27) at 6 months, respectively, with no between-group differences. No patient experienced any side effects. Conclusions High-frequency DLPFC dTMS was well tolerated and did not significantly differ on improvement of depression in MDD, BD-I, and MDAUD.

Background Obsessive Compulsive Disorder (OCD) is a chronic and disabling disorder with poor response to pharmacological treatments. Converging evidences suggest that OCD patients suffer from dysfunction of the cortico-striato-thalamo-cortical (CSTC) circuit, including in the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC). Objective To examine whether modulation of mPFC-ACC activity by deep transcranial magnetic stimulation (DTMS) affects OCD symptoms. Methods Treatment resistant OCD participants were treated with either high-frequency (HF; 20 Hz), low-frequency (LF; 1 Hz), or sham DTMS of the mPFC and ACC for five weeks, in a double-blinded manner. All treatments were administered following symptoms provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive Scale (YBOCS). Results Interim analysis revealed that YBOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (n = 18) was significantly higher than that of the sham group (n = 15) for at least one month following the end of the treatment. Notably, the clinical response in the HF group correlated with increased Error Related Negativity (ERN) in the Stroop task, an electrophysiological component that is attributed to ACC activity. Conclusion HF DTMS over the mPFC-ACC alleviates OCD symptoms and may be used as a novel therapeutic intervention. Notwithstanding alternative explanations, this may stem from DTMS ability to directly modify ACC activity.

Objective Here we bring a neurophysiological diagnostic tool, based on pathophysiologically-relevant brain region, that is critical for reducing the variability between clinicians, and necessary for quantitative measures of ADHD severity. Methods 54 healthy and 57 ADHD adults participated in the study. Electroencephalography (EEG) was recorded when combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex and also recorded during the Stop Signal task. Results TMS evoked potentials (TEPs) and the event related potential (ERP) components in the Stop Signal task were found to be significantly reduced in ADHD relative to the matched healthy controls. Stop signal reaction time (SSRT) and stopping accuracy was found to correlate with the ERP signal, and ADHD severity correlated with the TEP signal. Cortical activity (early TEP and Stop Signal ERP) diagnostic model yielded accuracy of 72%. Conclusion TEPs and ERPs reveal that right PFC excitability was associated with ADHD severity, and with behavioral impulsivity – as a hallmark of ADHD pathology. This electrophysiological biomarker supports the potential of objective diagnosis for ADHD. Significance Such tools would allow better assessment of treatment efficacy and prognosis, may advance understanding of the pathophysiology of the disease and better the public's attitudes and stigma towards ADHD. Trial Registration: Trial to Evaluate the Efficacy of the HLPFC Coil Deep Transcranial Magnetic Stimulation System in Treating Attention Deficit and Hyperactivity Disorder (ADHD) in Adults, https://clinicaltrials.gov/ct2/show/NCT01737476 , ClinicalTrials.gov number NCT01737476

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.

Low frequency repetitive TMS (rTMS) of a cortical seizure focus is emerging as an antiepileptic treatment. While conventional rTMS stimulators activate only superficial cortical areas, reaching deep epileptic foci, for example in temporal lobe epilepsy (TLE), is possible using specially designed H-coils. We report the results of rTMS in a young adult with pharmacoresistant bilateral TLE who underwent three courses (of 10, 15, and 30 daily sessions) of unilateral rTMS over the hemisphere from which seizures originated most often. Seizure frequency was assessed before and after each block of rTMS sessions, as was the tolerability of the procedure. Seizure frequency declined significantly, by 50 to 70% following each rTMS course. All sessions were well-tolerated.

Objectives Repetitive transcranial magnetic stimulation (rTMS), using standard coils, provided modest symptomatic benefits in patients with Parkinson's disease (PD). In our previous exploratory studies, using the newly developed Hesed coil (providing deeper rTMS; rDTMS) high frequency (HF), excitatory rDTMS over the primary motor cortex (M1), did not achieve sufficient beneficial effect for PD symptoms, while low frequency (LF) inhibitory stimulation, was mildly beneficial. To further investigate the optimal rDTMS stimulation parameters for PD patients, and to assess whether there is an added value for dual stimulation, consisting of HF rDTMS over the prefrontal cortex (PFC) along with LF M1 rDTMS. The rational for the selection of the current stimulation parameters and sites lies on the previous studies that demonstrated an inhibitory effect of 1 Hz rTMS on the increased cortical activity in PD as well as dopamine release by PFC stimulation. Patients and methods An open comparative active study of one month duration (12 sessions) of LF rDTMS over M1 alone (n = 9) or combined with HF PFC rDTMS (M1-PFC, n = 10). Outcome measures included the total and motor Unified Parkinson's Disease Rating Scale scores (T-UPDRS and M-UPDRS) and other variables, were collected at baseline and on days 30 and 60. Results For the M1 + PFC group, T-UPDRS score improved from baseline to day 30, by 15% (median: 52 points, decreased to 44, p = 0.02, effect size: 0.51) and M-UPDRS score improved by 24% (median: 37 points decreased to 28, p = 0.04, effect size: 0.47). The corresponding results for the M1 group were insignificant. Additionally, the between groups comparison, was insignificant. Conclusion rDTMS, consisting of M1 excitation with PFC inhibition improved PD motor symptoms but was not significantly superior to M1 rDTMS alone. rDTMS stimulation protocols for M1 should be further evaluated in larger scale controlled studies.

The current study investigated the anxiolytic properties of the deep transcranial magnetic stimulation (DTMS) in unipolar major depression using a systematic literature review and meta-analysis. Compared to baseline, large anxiolytic and antidepressant outcomes were obtained after 20 daily sessions of high-frequency DTMS according to data from six open-label studies with 95 patients. Unlike the antidepressant effect, the anxiolytic effect was more heterogeneous among studies and did not depend on concurrent treatment with antidepressants.

OCD is a chronic and disabling disease with a lifetime prevalence of 2%-3%. About 40-60% of these patients do not adequately respond to pharmacotherapy and CBT. Deep transcranial magnetic stimulation (dTMS) was shown to be safe and effective as a treatment alternative for OCD and recently received regulatory approvals. Yet it is unclear whether patients who failed numerous medications and/or CBT can still benefit from dTMS. Here, we analyzed recent data from a double-blind multicenter dTMS study and found efficacy of this novel treatment even in OCD patient cohorts who previously failed to respond to multiple medications and CBT.

The sense of self has always been a major focus in the psychophysical debate. It has been argued that this complex ongoing internal sense cannot be explained by any physical measure and therefore substantiates a mind-body differentiation. Recently, however, neuro-imaging studies have associated self-referential spontaneous thought, a core-element of the ongoing sense of self, with synchronous neural activations during rest in the medial prefrontal cortex (PFC), as well as the medial and lateral parietal cortices. By applying deep transcranial magnetic stimulation (TMS) over human PFC before rest, we disrupted activity in this neural circuitry thereby inducing reports of lowered self-awareness and strong feelings of dissociation. This effect was not found with standard or sham TMS, or when stimulation was followed by a task instead of rest. These findings demonstrate for the first time a critical, causal role of intact rest-related PFC activity patterns in enabling integrated, enduring, self-referential mental processing.

Background Tobacco smoking is the leading cause of preventable death in developed countries. Our previous studies in animal models and humans suggest that repeated activation of cue-induced craving networks followed by electromagnetic stimulation of the dorsal prefrontal cortex (PFC) can cause lasting reductions in drug craving and consumption. We hypothesized that disruption of these circuitries by deep transcranial magnetic stimulation (TMS) of the PFC and insula bilaterally can induce smoking cessation. Methods Adults ( N = 115) who smoke at least 20 cigarettes/day and failed previous treatments were recruited from the general population. Participants were randomized to receive 13 daily sessions of high-frequency, low-frequency or sham stimulation following, or without, presentation of smoking cues. Deep TMS was administered using an H-coil version targeting the lateral PFC and insula bilaterally. Cigarette consumption was evaluated during the treatment by measuring cotinine levels in urine samples and recording participants' self-reports as a primary outcome variable. Dependence and craving were assessed using standardized questionnaires. Results High (but not low) frequency deep TMS treatment significantly reduced cigarette consumption and nicotine dependence. The combination of this treatment with exposure to smoking cues enhanced reduction in cigarette consumption leading to an abstinence rate of 44% at the end of the treatment and an estimated 33% 6 months following the treatment. Conclusions This study further implicates the lateral PFC and insula in nicotine addiction and suggests the use of deep high-frequency TMS of these regions following presentation of smoking cues as a promising treatment strategy.

Objectives To assess the efficacy of high-frequency (20Hz) brain stimulation on lower limb motor function in subjects with chronic (>6mo) subcortical stroke. Design Double-blind, placebo-controlled crossover study. Setting University hospital. Participants Right-handed subjects (N=10) affected by a first-ever subcortical stroke in the territory of the middle cerebral artery were included in this study. Interventions Repetitive transcranial magnetic stimulation (rTMS) was delivered with the H-coil, specifically designed to target deeper and larger brains regions. Each subject received both real and sham rTMS in a random sequence. The 2 rTMS cycles (real or sham) were composed of 11 sessions each, administered over 3 weeks and separated by a 4-week washout period. Main Outcome Measures Lower limb functions were assessed by the lower limb Fugl-Meyer scale, the 10-m walk test, and the 6-minute walk test before and 1 day after the end of each treatment period, as well as at a 4-week follow-up. Results Real rTMS treatment was associated with a significant improvement in lower limb motor function. This effect persisted over time (follow-up) and was significantly greater than that observed with sham stimulation. A significant increase in walking speed was also found after real rTMS, but this effect did not reach statistical significance in comparison with the sham stimulation. Conclusions These data demonstrated that 3 weeks of high-frequency deep rTMS could induce long-term improvements in lower limb functions in the chronic poststroke period, lasting at least 1 month after the end of the treatment.

Objective To compare the ability of an H-coil and figure-8 coil to stimulate different motor cortex regions. Methods The resting (rMT) and active (aMT) motor thresholds were measured for the right hand APB and leg AHB muscles in 10 subjects, using an H-coil and a figure-8 coil. The electric field distribution induced by the coils was measured in a head model. The combination of the hand and leg MTs with the field measurements was used to determine the depth of hand and leg motor areas via the intersection points. Results The rMT and aMT of both APB and AHB were significantly lower for the H-coil. The ratio and difference between the leg and hand rMT and aMT were significantly lower for the H-Coil. Electric field measurements revealed significantly more favorable depth profile and larger volume of stimulation for the H-coil. The averaged intersection for the APB was at a distance from coil of 1.83 ± 0.54 cm and at an intensity of 97.8 ± 21.4 V/m, while for the AHB it was at a distance of 2.73 ± 0.44 cm and at an intensity of 118.6 ± 21.3 V/m. Conclusion The results suggest a more efficient activation of deeper motor cortical regions using the H-coil. Significance The combined evaluation of MTs by H- and figure-8 coils allows measurement of the individual depth of different motor cortex regions. This could be helpful for optimizing stimulation parameters for TMS treatment.

Introduction Obsessive compulsive disorder (OCD) is a disabling disease with an annual prevalence of 1.2%. Currently approved medications only result in a reduction of symptoms for 40-60% of patients leaving most patients significantly affected. Symptom severity is correlated to the degree of hyperconnectivity in the cortico-stiriato-thalamic circuit and increased glucose metabolism in the anterior cingulate cortex during symptom provocation and at rest. Methods Ninety-four OCD patients who met inclusion/exclusion criteria (age 22-68, YBOCS≥20 despite SSRI treatment and/or CBT, stable on medications or therapy for at least two months) were randomized to receive active or sham treatment for twenty-nine sessions over six weeks. Deep transcranial magnetic stimulation(dTMS) was applied over the medial prefrontal(mPFC) and anterior cingulate cortices(ACC) using the H7 dTMS coil. Once the coil was in the treatment position, the patient’s symptoms were provoked using an individualized script tailored to the patient’s obsessions and compulsions. Subsequently, dTMS was administered for eighteen minutes at 100% resting motor threshold of the foot, 20HZ pulse frequency, in 2 second trains, with a 20 second inter-train interval totaling 2000 pulses. The sham coil was designed to have the same sound, scalp and facial sensation of the real coil without stimulating the brain directly. Results The mean age of the subjects was 38.7 (±11.75), 58.7%male, 78.8% Caucasian, mean age of onset was 13, 98% had failed medications approved for OCD and 68.7% had failed CBT. At the end of week 6 (the primary endpoint) the YBOCS decreased by 5.7 points (95% CI: [3.3;8.2]) in the dTMS arm and by 3.0 points (95% CI: [0.7;5.4]) in the control arm (p-value: 0.0157). Response (≥30% decrease/20% decrease in the YBOCS) rates were dTMS 38.10% in the dTMS arm and 11.11% in the sham arm (p-value:0.0033). Partial response rates were (≥20% decrease in the YBOCS) 54.76 in the dTMS arm and 26.67% in the sham arm (p-value: 0.0076). At week 10 (follow up) the YBOCS decreased by 6.2 points (95% CI: [3.6;8.7]) in the dTMS arm and by 3.8 points (95% CI: [1.4;6.2]) in the control arm (p-value: 0.0459). There were no serious adverse events related to the treatment. The most frequent adverse event, headache, did not differ in frequency between the two arms. Conclusions High frequency dTMS of the ACC was found to be an effective treatment for OCD. This approach is an additional intervention in the toolbox for treating OCD.

Background Impaired neuronal plasticity and, specifically, altered expression of brain-derived neurotrophic factor (BDNF) were shown to play a critical role in depressive behavior and the mechanism of various antidepressant treatments including electroconvulsive therapy (ECT). Interestingly, opposing roles were suggested for BDNF in the hippocampus and the ventral tegmental area (VTA), while interactions between these regions were shown on various levels. Here, we evaluated whether BDNF plays an essential role in the antidepressant-like effects of ECT and performed a direct comparison between BDNF manipulations in the VTA and the hippocampus. Methods Knockdown or overexpression of BDNF was induced in hippocampus or VTA of rats by microinjection of specific lentiviral vectors. The effects of these manipulations on antidepressant outcomes of ECT were evaluated by the forced swim test and by sucrose preference measurements, and BDNF expression levels were assessed in other reward-related brain regions. Results Here, we show that whereas ECT increased hippocampal BDNF expression, induction of hippocampal BDNF knockdown did not block its antidepressant-like effect. Importantly, we found that ECT caused a robust reduction in VTA BDNF levels. Moreover, VTA BDNF knockdown alone was sufficient to induce an antidepressant-like effect, and VTA BDNF overexpression blocked the antidepressant-like effect of ECT. Conclusions While neuroplastic alterations, as expressed by changes in BDNF expression within different brain regions, are induced by ECT, the antidepressant-like effect of ECT in an animal model depends on reduction of VTA BDNF expression but not on the elevation of hippocampal BDNF expression.

Objective repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for the treatment of post-stroke motor deficits. Since the crucial role of non-primary motor cortices and contralesional brain areas is emerging for motor recovery in chronic stroke; we assessed safety and efficacy of bilateral rTMS over the motor areas associated to physical training (PT) on upper extremity (UE) motor function. Methods double-blind, placebo-controlled trial on 20 patients with chronic stroke conditioning moderate to mild upper limb motor impairment. Eleven sessions of high frequency rTMS were delivered with the H-coil over the motor areas bilaterally. Subjects were randomly allocated to the real rTMS plus PT or the placebo (sham) rTMS plus PT. UE impairment was evaluated by the Fugl-Meyer assessment for UE (FM-UE), Modified Ashworth Scale (MAS) and hand grip strength at baseline (T0), after treatment (T1) and one-month follow-up (T2). Results no serious adverse events were reported. At T1 FM-UE significantly improved in both groups, while at T2 the improvement was significant only for the real group. The improvement was significantly higher in the real compared with the sham group. In the real group, greater improvement in FM-UE was found in patients moderately impaired compared with less impaired at baseline. Spasticity and hand grip strength also significantly improved in the real group at T1 and amelioration of spasticity persisted also at T2. Conclusion bilateral high-frequency rTMS with H-coil associated with PT is safe and enhances the effect of PT alone. Although plegic patients were not included, subjects with moderate rather than mild motor impairment may mainly benefit from this stimulation protocol.

Background Transcranial magnetic stimulation (TMS) enables non-surgical activation of specific brain areas. TMS over the prefrontal cortex (PFC) is emerging as a significant tool that can augment or replace non/partially effective antidepressant medications. Deep TMS (DTMS) utilizes newly developed coils that enable effective stimulation of deeper cortical layers involved in the pathophysiology of depression. Objectives We aimed to assess the H1-DTMS coil as an add-on to antidepressants in treating patients with major depression. We also intended to evaluate whether the antidepressant outcome of DTMS treatment is affected by a cognitive–emotional procedure performed during stimulation. Methods 57 patients were enrolled in the study that included 4 weeks of daily 20 Hz stimulation sessions and additional 4 weekly sessions as a short maintenance phase. Two subgroups of patients received either positive or negative cognitive–emotional reactivation along with the stimulation sessions. Results 21 of 46 patients (46%) who received at least 10 stimulation sessions achieved response (improvement of ≥ 50% in the Hamilton Depression Rating Scale (HDRS)) and 13 of them (28%) achieved remission (HDRS-24 ≤ 10) by the end of the daily treatment phase. Improvements were smaller in the negatively reactivated group and Beck Depression Inventory scores were not significantly improved in this group. Conclusions DTMS over the PFC proved to be safe and effective in augmenting antidepressant medications. Negative cognitive–emotional reactivation can disrupt the therapeutic effect of DTMS. A large sham controlled study is required to further establish the effectiveness of DTMS as an augmentation treatment and the role of cognitive reactivation during stimulation.

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.

Background Electroconvulsive therapy (ECT) is a very effective treatment for major depression. This method involves robust nonfocal stimulation of the brain and can normalize both neurochemical alterations and depressive behavior in animal models. We hypothesized that short stimulation sessions of specific reward-related brain sites might induce similar effects. Methods In the present study we compared behavioral and neurochemical effects produced by ECT and by repeated stimulation of reward-related brain sites, in a widely used rat model for depressive behavior induced by chronic mild stress (CMS). Different groups of rats received 10 sessions of either electroconvulsive shocks or subconvulsive electrical stimulation (SCES) of specific brain sites with an implanted electrode. The SCES temporal parameters were similar to those used in transcranial magnetic stimulation studies in humans. A battery of behavioral tests and measurements of brain-derived neurotrophic factor (BDNF) levels were used to assess the effectiveness of these treatments relative to sham treatments. Results Repeated SCES of either the nucleus accumbens (NAC) or the ventral but not the dorsal prelimbic cortex (PLC) reversed the main behavioral deficit and the reduction of BDNF levels in the hippocampus that were induced by CMS. The ECT was more effective because it also normalized a behavioral deficit associated with anxiety but produced a learning and memory impairment. Conclusions This study implicates the ventral PLC and the NAC in the pathophysiology of depressive behavior and suggests that local intermittent SCES can induce an antidepressant effect similar to that of ECT, without the cognitive impairment caused by the convulsive treatment.

Objective: The H-coils are a new development in transcranial magnetic stimulation (TMS) research, allowing direct stimulation of deeper neuronal pathways than does standard TMS. This study assessed possible health risks, and some cognitive and emotional effects, of two H-coil versions designed to stimulate deep portions of the prefrontal cortex, using several stimulation frequencies. Methods: Healthy volunteers (n = 32) were randomly assigned to one of four groups: each of two H-coil designs (H1/H2), standard figure-8 coil, and sham-coil control. Subjects were tested in a pre–post design, during three increasing (single pulses, 10 Hz, and 20 Hz) stimulation sessions, as well as 24–36 h after the last stimulation. Results: The major finding of the present study is that stimulation with the novel H-coils was well tolerated, with no adverse physical or neurological outcomes. Computerized cognitive tests found no deterioration in cognitive functions, except for a transient short-term effect of the H1-coil on spatial recognition memory on the first day of rTMS (but not in the following treatment days). On the other hand, spatial working memory was transiently improved by the H2-coil treatment. Finally, the questionnaires showed no significant emotional or mood alterations, except for reports on ‘detachment’ experienced by subjects treated with the H1-coil. Conclusions: This study provides additional evidence for the feasibility and safety of the two H-coil designs (H1/H2). Significance: The H-coils offer a safe new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions. � 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Although the monoamine theory of depression is well studied, regarding childhood depression it is poorly supported. Antidepressant treatments affecting the monoaminergic system fail to ameliorate childhood depression in the same manner that they affect adult depression. The present study used the Flinders sensitive line (FSL) rat, a well-investigated genetic animal model of depression and Sprague–Dawley (SD) rats as controls. We co-measured monoamines and dehydroepiandrosterone (DHEA) levels in the nucleus accumbens on postnatal day 1, in prepubertal rats (35 days), and adult rats (4 months) in order to examine developmental characteristics in the monoamine systems. The results suggest that there are different ontogenetic patterns of monoaminergic activity in FSL and SD rats. While monoamine levels were different only in adulthood, FSL rats exhibited lower DHEA levels already in prepubertal childhood. These differences may be relevant to the poor response to antidepressant drugs observed in depressed children and suggest DHEA as a new marker for childhood depression.

Cannabinoids are widely abused drugs. Our goal was to identify genes modulated by Δ 9 -tetrahydrocannabinol (Δ 9 -THC) treatment. We found that chronic administration of Δ 9 -THC (1.5 mg/kg/day, i.p.; 7 days) to rats, downregulates the expression of oxytocin-neurophysin (OT-NP) mRNA and of OT and oxytocin-associated NP (NP OT ) immunoreactivity in nucleus accumbens (NAc) and ventral tegmental area (VTA), brain areas involved in reward and addiction. Real-time PCR revealed a 60% and 53% reduction of OT-NP mRNA in NAc and VTA, respectively, under chronic treatment, while no changes were observed in NAc after 24 h. Immunohistochemistry showed a large decrease in number of OT and NP OT -stained fibers in NAc (by 59% and 52%, respectively) and VTA (by 50% and 56%, respectively). No changes in cell staining were observed in the paraventricular nucleus and supraoptic nucleus. As OT is known to inhibit development of drug tolerance and attenuate withdrawal symptoms, we suggest that OT downregulation could play a role during the establishment of the chronic effects of Δ 9 -THC.

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.