Transcranial Magnetic and Direct Current Stimulation in Children.

Promising results in adult neurologic and psychiatric disorders are driving active research into transcranial brain stimulation techniques, particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), in childhood and adolescent syndromes. TMS has realistic utility as an experimental tool tested in a range of pediatric neuropathologies such as perinatal stroke, depression, Tourette syndrome, and autism spectrum disorder (ASD). tDCS has also been tested as a treatment for a number of pediatric neurologic conditions, including ASD, attention-deficit/hyperactivity disorder, epilepsy, and cerebral palsy. Here, we complement recent reviews with an update of published TMS and tDCS results in children, and discuss developmental neuroscience considerations that should inform pediatric transcranial stimulation.

Persistent uncrossed corticospinal connections in patients with intractable focal epilepsy.

Corticospinal connections may be bilateral at birth, but a predominantly unilateral and crossed pattern develops by the toddler years. Acquired injury can alter the normal development of laterality such that uncrossed corticospinal connections persist, particularly if the injury is early in life and involves the motor system. Whether other developmental insults, such as childhood epilepsy, affect the development of crossed laterality in the motor system is unknown, although this topic has relevance for understanding the broader impact of epilepsy on brain development. Accordingly, in a cohort of children with intractable focal epilepsy, we tested by neuronavigated transcranial magnetic stimulation (nTMS) whether childhood epilepsy is associated with persistent uncrossed corticospinal connections. Specifically, we hypothesized that in contrast to early-life neuroclastic corticospinal tract injury that induces preservation of uncrossed corticospinal connections in the contralesional hemisphere, uncrossed corticospinal connections will be preserved in the epileptic hemisphere where the corticospinal tract is intact, but overstimulated by ongoing seizures and epileptic interictal discharges. Motor cortex mapping was performed by nTMS as part of a clinical presurgical evaluation, and the analysis was limited to patients with radiographically intact motor cortices and corticospinal tracts. Given that foot motor cortex representation is often bilateral, we focused on the lateralization for the tibialis anterior muscle cortical motor representation and its relation to the seizure focus. We demonstrate preserved uncrossed corticospinal connections for the tibialis anterior region of the hemisphere affected by the epilepsy. These findings indicate a pathologically preserved immature motor lateralization in patients with epilepsy and suggest that developmental processes associated with hemispheric lateralization are affected by epilepsy.

Bursts of high-frequency repetitive transcranial magnetic stimulation (rTMS), together with lorazepam, suppress seizures in a rat kainate status epilepticus model.

BACKGROUND: Status epilepticus (SE) is a condition of prolonged or recurrent and often drug-resistant seizures where nonsedating SE therapy remains an important unmet need. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a means to suppress seizures but has not been extensively studied in models. OBJECTIVES: We aimed to test the antiepileptic potential of high-frequency rTMS in SE. As a step toward eventual coupling of rTMS with antiepileptic pharmacotherapy, we also tested whether high-frequency rTMS in combination with a low (ineffective but less likely to cause a side effect) lorazepam dose is as effective as a full lorazepam dose in suppressing seizures in a rat SE model. METHODS: EEG was recorded to measure epileptic spike frequency in the rat kainate SE model. Epileptic spikes were counted before, during, and after either high-frequency rTMS treatment alone or high-frequency rTMS treatment in combination with lorazepam, a firstline SE treatment. RESULTS: We found that rTMS alone decreases epileptic spike frequency only acutely. However, combinatory treatment with half-dose lorazepam together with rTMS was as effective as a full lorazepam dose. CONCLUSION: We report that high-frequency rTMS has modest antiepileptic potential alone but acts in complement with lorazepam to suppress seizures.

Inherited behaviors, BDNF expression and response to treatment in a novel multifactorial rat model for depression.

Major depressive disorder (MDD) is a common and devastating mental illness behaviorally characterized by various symptoms, including reduced motivation, anhedonia and psychomotor retardation. Although the etiology of MDD is still obscure, a genetic predisposition appears to play an important role. Here we used, for the first time, a multifactorial selective breeding procedure to generate a distinct 'depressed' rat line (DRL); our selection was based upon mobility in the forced swim test, sucrose preference and home-cage locomotion, three widely used tests associated with core characteristics of MDD. Other behavioral effects of the selection process, as well as changes in brain-derived neurotrophic factor (BDNF) and the response to three antidepressant treatments, were also examined. We show that decreased mobility in the forced swim test and decreased sucrose preference (two directly selected traits), as well as decreased exploration in the open field test (an indirectly selected trait), are hereditary components in DRL rats. In addition, lower BDNF levels are observed in the dorsal hippocampus of DRL rats, complying with the neurotrophic hypothesis of depression. Finally, electroconvulsive shocks (ECS) but not pharmacological treatment normalizes both the depressive-like behavioral impairments and the BDNF-related molecular alterations in DRL rats, highlighting the need for robust treatment when the disease is inherited and not necessarily triggered by salient chronic stress. We therefore provide a novel multifactorial genetic rat model for depression-related behaviors. The model can be used to further study the etiology of the disease and suggest molecular correlates and possible treatments for the disease.

Football gambling three arm-controlled study: gamblers, amateurs and laypersons.

BACKGROUND: Football (soccer) betting, as a strategic form of betting, became one of the favorite wagers for pathological gamblers. Previous studies demonstrated the psychological and biological significance of the 'illusion of control' (personal control) and 'near miss' results in gambling. In our study, we explored whether knowledge and expertise of pathological sports gamblers can ensure a successful bet. SAMPLE AND METHODS: Participants were divided into three groups of individuals - pathological gamblers, amateurs and laypersons - and were asked to predict in advance the general result and the exact result of football matches in the European Champions League Round of 16. RESULTS: The 165 participants included 53 pathological sports gamblers (52 males and 1 female), 78 laypersons (45 females and 33 males) and 34 amateurs (all males). After a thorough statistical analysis, we found no significant differences between the groups, no matter what kind of previous knowledge they had acquired. CONCLUSION: This study demonstrates that the 'illusion of control' of pathological gamblers, attained by knowledge of the game and its latest data and information (especially in a strategic gamble as football betting), has no factual background. Moreover, our study demonstrates without a doubt that there is no significant difference between the male pathological sports gamblers group and the male/female laypersons group.

Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.

Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.

Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: differential outcomes in anesthetized and awake animals.

Long-term effects of repetitive transcranial magnetic stimulation (rTMS) have been associated with neuroplasticity, but most physiological studies have evaluated only the immediate effects of the stimulation on neurochemical markers. Furthermore, although it is known that baseline excitability state plays a major role in rTMS outcomes, the role of spontaneous neural activity in metaplasticity has not been investigated. The first aim of this study was to evaluate and compare the long-term effects of high- and low-frequency rTMS on the markers of neuroplasticity such as BDNF and GluR1 subunit of AMPA receptor. The second aim was to assess whether these effects depend on spontaneous neural activity, by comparing the neurochemical alterations induced by rTMS in anesthetized and awake rats. Ten daily sessions of high- or low-frequency rTMS were applied over the rat brain, and 3 d later, levels of BDNF, GluR1, and phosphorylated GluR1 were assessed in the hippocampus, prelimbic cortex, and striatum. We found that high-frequency stimulation induced a profound effect on neuroplasticity markers; increasing them in awake animals while decreasing them in anesthetized animals. In contrast, low-frequency stimulation did not induce significant long-term effects on these markers in either state. This study highlights the importance of spontaneous neural activity during rTMS and demonstrates that high-frequency rTMS can induce long-lasting effects on BDNF and GluR1 which may underlie the clinical benefits of this treatment in neuroplasticity-related disorders.

Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study.

BACKGROUND: About 25% of schizophrenia patients with auditory hallucinations are refractory to pharmacotherapy and electroconvulsive therapy. We conducted a deep transcranial magnetic stimulation (TMS) pilot study in order to evaluate the potential clinical benefit of repeated left temporoparietal cortex stimulation in these patients. The results were encouraging, but a sham-controlled study was needed to rule out a placebo effect. METHODS: A total of 18 schizophrenic patients with refractory auditory hallucinations were recruited, from Beer Yaakov MHC and other hospitals outpatient populations. Patients received 10 daily treatment sessions with low-frequency (1 Hz for 10 min) deep TMS applied over the left temporoparietal cortex, using the H1 coil at the intensity of 110% of the motor threshold. Procedure was either real or sham according to patient randomization. Patients were evaluated via the Auditory Hallucinations Rating Scale, Scale for the Assessment of Positive Symptoms-Negative Symptoms, Clinical Global Impressions, and Quality of Life Questionnaire. RESULTS: In all, 10 patients completed the treatment (10 TMS sessions). Auditory hallucination scores of both groups improved; however, there was no statistical difference in any of the scales between the active and the sham treated groups. CONCLUSIONS: Low-frequency deep TMS to the left temporoparietal cortex using the protocol mentioned above has no statistically significant effect on auditory hallucinations or the other clinical scales measured in schizophrenic patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00564096.

Translational neuromodulation: approximating human transcranial magnetic stimulation protocols in rats.

OBJECTIVE: Transcranial magnetic stimulation (TMS) is a well-established clinical protocol with numerous potential therapeutic and diagnostic applications. Yet, much work remains in the elucidation of TMS mechanisms, optimization of protocols, and in development of novel therapeutic applications. As with many technologies, the key to these issues lies in the proper experimentation and translation of TMS methods to animal models, among which rat models have proven popular. A significant increase in the number of rat TMS publications has necessitated analysis of their relevance to human work. We therefore review the essential principles for the approximation of human TMS protocols in rats as well as specific methods that addressed these issues in published studies. MATERIALS AND METHODS: We performed an English language literature search combined with our own experience and data. We address issues that we see as important in the translation of human TMS methods to rat models and provide a summary of key accomplishments in these areas. RESULTS: An extensive literature review illustrated the growth of rodent TMS studies in recent years. Current advances in the translation of single, paired-pulse, and repetitive stimulation paradigms to rodent models are presented. The importance of TMS in the generation of data for preclinical trials is also highlighted. CONCLUSIONS: Rat TMS has several limitations when considering parallels between animal and human stimulation. However, it has proven to be a useful tool in the field of translational brain stimulation and will likely continue to aid in the design and implementation of stimulation protocols for therapeutic and diagnostic applications.

Moderators of the response to deep TMS for smoking addiction.

Introduction: Deep repetitive transcranial magnetic stimulation (Deep TMS™) was recently cleared by the FDA as a short-term treatment for smoking cessation. However, it is unknown which participants are more likely to benefit from the treatment. Methods: We evaluated the data from the published randomized controlled trial of 262 participants 22-70 years old that led to the FDA clearance to characterize demographic and smoking history factors that moderate Deep TMS treatment efficacy. The current analysis included 75 completers in the active TMS group and 94 completers in the sham TMS group. Results: We found that participants younger than 40 had four times the quit rate than those older than 40. Additionally, participants who quit following treatment smoked 10 years less than non-quitters. Moreover, Caucasian participants had two times the quit rate than African-American participants. Strikingly, participants with more than 12 years of education had 7 times the quit rate than participants with less education. Conclusion: Three weeks of Deep TMS has a higher smoking addiction quit rate in participants who are younger, more educated, Caucasian and with less extensive smoking history. Participants who are older, with less education and more extensive smoking history may need a longer treatment course and/or combined treatment modalities. Potential reasons may be related to the challenges of inducing neuronal modifications in those with greater physical and psychological dependence. Further investigation is warranted.

Preliminary Report of the Safety and Tolerability of 1 Hz Repetitive Transcranial Magnetic Stimulation in Temporal Lobe Epilepsy.

Background: Low frequency (≤1 Hz) repetitive transcranial magnetic stimulation (rTMS) has been shown to suppress cortical excitability and is beginning to be trialed for the treatment of refractory epilepsy. Purpose: As a step toward a larger trial, the current pilot study was aimed to test the tolerability and safety of temporal lobe rTMS using H-coil for the treatment of temporal lobe epilepsy (TLE). Research Design: 1800 pulses of active or sham rTMS were applied 5  days a week for 2 weeks over the temporal lobe of the affected hemisphere. Results: Nine participants were enrolled and randomized to verum or sham stimulation. One participant dropped out from the sham group after 5 rTMS sessions. In-session, 3 patients had typical seizures during sham stimulation. One patient had seizures also during active stimulation (albeit fewer than during sham). Minor reported adverse events during stimulation otherwise included transient neck pain and headache, and were reported in equal numbers in both groups. Major adverse events were not reported. Our results indicate that H-coil rTMS was well-tolerated. Conclusion: Given the relatively high prevalence of individuals with TLE who are treatment-resistant and the preliminary results of this study, we suggest that a larger safety and efficacy trial of 1 Hz rTMS for the treatment of TLE is warranted.

Transcranial magnetic stimulation tracks subminute changes in cortical excitability during propofol anesthesia.

Automated anesthesia systems that continuously monitor cortical excitability (CE) changes to govern drug infusion rates, are desirable. Paired-pulse transcranial magnetic stimulation (ppTMS), with electromyography (EMG), provides noninvasive CE measures. We tested whether, and with what temporal resolution, ppTMS-EMG detects dose-dependent CE in rats anesthetized with continuous intravenous propofol. Motor-evoked potentials (MEPs) were recorded every 20 seconds as either propofol bolus or change in infusion rate was applied. ppTMS-derived measures varied in direct proportion to propofol dose with subminute temporal resolution. We conclude that ppTMS-EMG enables real-time markers of target engagement by anesthetics that may be incorporated into an automated device.

Age-dependent effects of chronic stress on brain plasticity and depressive behavior.

Exposure to chronic mild stress (CMS) is known to induce anhedonia in adult animals, and is associated with induction of depression in humans. However, the behavioral effects of CMS in young animals have not yet been characterized, and little is known about the long-term neurochemical effects of CMS in either young or adult animals. Here, we found that CMS induces anhedonia in adult but not in young animals, as measured by a set of behavioral paradigms. Furthermore, while CMS decreased neurogenesis and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of adult animals, it increased these parameters in young animals. We also found that CMS altered alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor GluR1 subunit levels in the hippocampus and the nucleus accumbens of adult, but not young animals. Finally, no significant differences were observed between the effects of CMS on circadian corticosterone levels in the different age groups. The substantially different neurochemical effects chronic stress exerts in young and adult animals may explain the behavioral resilience to such stress young animals possess.

Alternate day dTMS combined with SSRIs for chronic treatment resistant depression: A prospective multicenter study.

INTRODUCTION: 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). METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: Thrice weekly dTMS at 120% motor threshold(MT), 10 HZ, 3­s trains, 20­s intervals, 2400 daily pulses, can augment formerly ineffective SSRI treatment.

Alterations in the Timing of Huperzine A Cerebral Pharmacodynamics in the Acute Traumatic Brain Injury Setting.

Traumatic brain injury (TBI) may affect the pharmacodynamics of centrally acting drugs. Paired-pulse transcranial magnetic stimulation (ppTMS) is a safe and noninvasive measure of cortical gamma-aminobutyric acid (GABA)-mediated cortical inhibition. Huperzine A (HupA) is a naturally occurring acetylcholinesterase inhibitor with newly discovered potent GABA-mediated antiepileptic capacity, which is reliably detected by ppTMS. To test whether TBI alters cerebral HupA pharmacodynamics, we exposed rats to fluid percussion injury (FPI) and tested whether ppTMS metrics of cortical inhibition differ in magnitude and temporal pattern in injured rats. Anesthetized adult rats were exposed to FPI or sham injury. Ninety minutes post-TBI, rats were injected with HupA or saline (0.6 mg/kg, intraperitoneally). TBI resulted in reduced cortical inhibition 90 min after the injury (N = 18) compared to sham (N = 13) controls (p = 0.03). HupA enhanced cortical inhibition after both sham injury (N = 6; p = 0.002) and TBI (N = 6; p = 0.02). The median time to maximum HupA inhibition in sham and TBI groups were 46.4 and 76.5 min, respectively (p = 0.03). This was consistent with a quadratic trend comparison that projects HupA-mediated cortical inhibition to last longer in injured rats (p = 0.007). We show that 1) cortical GABA-mediated inhibition, as measured by ppTMS, decreases acutely post-TBI, 2) HupA restores lost post-TBI GABA-mediated inhibition, and 3) HupA-mediated enhancement of cortical inhibition is delayed post-TBI. The plausible reasons of the latter include 1) low HupA volume of distribution rendering HupA confined in the intravascular compartment, therefore vulnerable to reduced post-TBI cerebral perfusion, and 2) GABAR dysfunction and increased AChE activity post-TBI.

Huperzine A: A promising anticonvulsant, disease modifying, and memory enhancing treatment option in Alzheimer's disease.

Alzheimer's disease (AD) is the most frequent cause of dementia. Besides cognitive deterioration, patients with AD are prone to seizures - more than 20% of patients diagnosed with AD experience at least one unprovoked seizure and up to 7% have recurrent seizures. Although available antiepileptic drugs (AEDs) may suppress seizures in patients with AD, they may also worsen cognitive dysfunction and increase the risk of falls. On the basis of preclinical studies, we hypothesize that Huperzine A (HupA), a safe and potent acetylcholinesterase (AChE) inhibitor with potentially disease-modifying qualities in AD, may have a realistic role as an anticonvulsant in AD.

Construction and Evaluation of Rodent-Specific rTMS Coils.

Rodent models of transcranial magnetic stimulation (TMS) play a crucial role in aiding the understanding of the cellular and molecular mechanisms underlying TMS induced plasticity. Rodent-specific TMS have previously been used to deliver focal stimulation at the cost of stimulus intensity (12 mT). Here we describe two novel TMS coils designed to deliver repetitive TMS (rTMS) at greater stimulation intensities whilst maintaining spatial resolution. Two circular coils (8 mm outer diameter) were constructed with either an air or pure iron-core. Peak magnetic field strength for the air and iron-cores were 90 and 120 mT, respectively, with the iron-core coil exhibiting less focality. Coil temperature and magnetic field stability for the two coils undergoing rTMS, were similar at 1 Hz but varied at 10 Hz. Finite element modeling of 10 Hz rTMS with the iron-core in a simplified rat brain model suggests a peak electric field of 85 and 12.7 V/m, within the skull and the brain, respectively. Delivering 10 Hz rTMS to the motor cortex of anaesthetized rats with the iron-core coil significantly increased motor evoked potential amplitudes immediately after stimulation (n = 4). Our results suggest these novel coils generate modest magnetic and electric fields, capable of altering cortical excitability and provide an alternative method to investigate the mechanisms underlying rTMS-induced plasticity in an experimental setting.

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.