Brain Stimulation

Published by Elsevier
Print ISSN: 1935-861X
Publications
Precise placement of transcranial magnetic stimulation (TMS) coils over target regions is crucial for correct interpretation of TMS effects. Modern frameless stereotaxic systems yield high accuracy, but require extensive equipment and cannot be used in every setting, for example, during functional imaging sessions. The aim of this study was the development of a method for TMS-coil placement based on individual imaging data without the need for external tracking devices. We compared coil positioning over Broca's area using an advanced stereotaxic navigation system with placement according to the surface distance measurements (SDM) method. By using the SDM-method, 3-dimensional renderings adapted from individual T1-weighted magnetic resonance imaging (MRI) data were created to identify Broca's area and Broca's homologue, respectively, and to define anatomic landmarks on the skin's surface. Distances between these landmarks were used to localize the real target on the individual's head. The mean Euclidean distance between surface positions as determined with the two methods was 8.31 mm and the mean difference of estimated virtual electric field intensity at the target point was 7.37 V/m corresponding to 4.01% of maximum field strength. Our findings suggest that, compared with a state-of-the-art frameless stereotaxy system, the SDM-method yields a reasonable accuracy for positioning of a TMS-coil over Broca's area in terms of spatial coordinates.
 
Mean MEP amplitudes (SEM) before and after tACS at 1-, 5-, 10-, 15-, and 30-Hz stimulation
The results of the repeated measures ANOVA of the EEG experiment with tSDCS
Interference with brain rhythms by noninvasive transcranial stimulation that uses weak transcranial alternating current may reveal itself to be a new tool for investigating cortical mechanisms currently unresolved. Here, we aim to extend transcranial direct current stimulation (tDCS) techniques to transcranial alternating current stimulation (tACS). Parameters such as electrode size and position were taken from those used in previous tDCS studies. Motor evoked potentials (MEPs) revealed by transcranial magnetic stimulation (TMS), electroencephalogram (EEG)-power, and reaction times measured in a motor implicit learning task, were analyzed to detect changes in cortical excitability after 2-10 minutes of AC stimulation and sinusoidal DC stimulation (tSDCS) by using 1, 10, 15, 30, and 45 Hz and sham stimulation over the primary motor cortex in 50 healthy subjects (eight-16 subjects in each study). A significantly improved implicit motor learning was observed after 10 Hz AC stimulation only. No significant changes were observed in any of the analyzed frequency bands of EEG and with regard to the MEP amplitudes after AC or tSDCS stimulation. Similarly, if the anodal or cathodal DC stimulation was superimposed on 5, 10, and 15 Hz AC stimulation, the MEP amplitudes did not change significantly. Transcranial application of weak AC current may appear to be a tool for basic and clinical research in diseases with altered EEG activity. However, its effect seems to be weaker than tDCS stimulation, at least in the present context of stimulus intensity and duration. Further studies are required to extend cautiously the safety range and uncover its influence on neuronal circuitries.
 
A minimum of six electroconvulsive therapy (ECT) treatments has to be delivered to achieve sustained improvement in major depression. However, the mechanisms of the therapeutic actions of ECT are still debated. We aimed to study the time course and duration of increased Kv7.2 and Kv11.1 mRNA expression in the hippocampus and piriform cortex (Pir) after electroconvulsive stimulation (ECS). Adult male Sprague-Dawley rats received three ECS per week over 1, 2, or 3 weeks and were decapitated 3 days after the last stimulus. Additional groups of rats receiving nine ECS were sacrificed 7 or 28 days after the last ECS. In situ hybridization was used to measure Kv channel mRNA expression after ECS. Kv7.2 mRNA was increased in the hippocampus and Pir 3 days after both six and nine, but not after three ECS. This was also seen for Kv11.1 mRNA in Pir. These changes lasted for at least 7 days. These results indicate that the changes in Kv7.2 and Kv11.1 channels may contribute to the therapeutic effect of ECT. However, further research needs to be undertaken in this area to extend these findings.
 
While the efficacy of repetitive transcranial magnetic stimulation (rTMS) at 10 Hz over the left prefrontal cortex has been repeatedly demonstrated, it is not clear that the optimal parameters for the treatment of depression have been adequately elucidated. We sought to assess the antidepressant effectiveness of high and low frequency at a higher intensity rTMS compared to sham in patients with moderately treatment resistant depression. The authors conducted a three-week, double-blind, randomized, sham-controlled study of 24 acutely depressed patients given either active 20 Hz (n = 8) or 1 Hz (n = 8) rTMS (at 110% of motor threshold [MT]) or sham treatments (n = 8) over the left prefrontal cortex. Hamilton Depression ratings were analyzed by ANOVA. Patients on both frequencies showed greater improvement than on sham, which was associated with minor increases in depression. During open continuation to allow 7 weeks of active treatment in all individuals, additional improvement was observed. The results seen here using 110% of MT for 3 weeks were more robust than those of previous studies of 1-Hz or 20-Hz rTMS for 2 weeks (at 80% and 100% of MT). The results also raise the possibility that both high and low frequency rTMS over left prefrontal cortex (and not just low frequency over the right prefrontal cortex) exert antidepressant effects, but further work is required to assess what parameters may be most effective in general and for a given individual.
 
Electroconvulsive therapy (ECT) and ablative neurosurgical procedures are established interventions for treatment-resistant depression (TRD), but their use may be limited in part by neuropsychological adverse effects. Additional neuromodulation strategies are being developed that aim to match or exceed the efficacy of ECT/ablative surgery with a better neurocognitive side effect profile. In this review, we briefly discuss the neurocognitive effects of ECT and ablative neurosurgical procedures, then synthesize the available neurocognitive information for emerging neuromodulation therapies, including repetitive transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, vagus nerve stimulation, and deep brain stimulation. The available evidence suggests these procedures may be more cognitively benign relative to ECT or ablative neurosurgical procedures, though further research is clearly needed to fully evaluate the neurocognitive effects, both positive and negative, of these novel neuromodulation interventions.
 
Background: Today's brain stimulation methods are commonly traced back historically to surgical brain operations. With this one-sided historical approach it is easy to overlook the fact that non-surgical electrical brain-stimulating applications preceded present-day therapies. Objective/hypothesis: The first study on transcranial electrical brain stimulation for the treatment of severe mental diseases in a larger group of patients was carried out in the 1870s. Methods: Between 1870 and 1878 German psychiatrist Rudolph Gottfried Arndt published the results of his studies in three reports. These are contextualized with contemporary developments of the time, focusing in particular on the (neuro-) sciences. As was common practice at the time, Arndt basically reported individual cases in which electricity was applied to treat severe psychoses with depressive symptoms or even catatonia, hypochondriac delusion and melancholia. Despite their lengthiness, there is frequently a lack of precise physical data on the application of psychological-psychopathological details. Only his 1878 report includes general rules for electrical brain stimulation. Results: Despite their methodological shortcomings and lack of precise treatment data impeding exact understanding, Arndt's studies are pioneering works in the field of electric brain stimulation with psychoses and its positive impacts. Today's transcranial direct current stimulation, and partly vagus nerve stimulation, can be compared with Arndt's methods. Although Arndt's only tangible results were indications for the application of faradic electricity (for inactivity, stupor, weakness and manic depressions) and galvanic current (for affective disorders and psychoses), a historiography of present-day brain stimulation therapies should no longer neglect studies on electrotherapy published in German and international psychiatric and neurological journals and monographs in the 1870s and 1880s.
 
Principle features of tDCS. Schematic drawing of electrode positions suited for tDCS of the primary motor cortex (A), the visual cortex (B), the dorsolateral prefrontal cortex (C), and features of a DC stimulator. Figures A-C show anodal (positively charged electrode, red color) stimulation of the respective cortices according to the 10-20 system. The cathode (blue color) is positioned such that the resulting current flow (from the cathode to the anode) allows an effective modulation of neuronal excitability under the anode. Note that the term reference electrode (the cathode in these examples) does not mean necessarily that this electrode is functionally inert, but that neuronal excitability changes under this electrode are beyond of the scope of interest with regard to a specific experimental setting. The electrodes are connected to a constant current DC stimulator (D). The stimulator should be able to deliver different current intensities (for example, between 1-10 mA), different stimulation durations, and a ramp switch at the beginning and end of stimulation, to allow for protocols inducing short-as well as long-lasting effects of tDCS and to diminish perceptions at the begin and end of stimulation. Current intensity and voltage are controlled online during stimulation. If the voltage needed to deliver a defined current strength is too large because of high resistance, a safety function is activated that terminates stimulation.
Synopsis of tDCS studies performed in humans since 1998
Effects of weak electrical currents on brain and neuronal function were first described decades ago. Recently, DC polarization of the brain was reintroduced as a noninvasive technique to alter cortical activity in humans. Beyond this, transcranial direct current stimulation (tDCS) of different cortical areas has been shown, in various studies, to result in modifications of perceptual, cognitive, and behavioral functions. Moreover, preliminary data suggest that it can induce beneficial effects in brain disorders. Brain stimulation with weak direct currents is a promising tool in human neuroscience and neurobehavioral research. To facilitate and standardize future tDCS studies, we offer this overview of the state of the art for tDCS.
 
The effect of various drugs was investigated by using transcranial magnetic stimulation (TMS) both in healthy subjects and patients, and the results indicated an influence of antidepressant drugs (ADs) on motor excitability. The aim of our study was to analyze the effects of two ADs, the tricyclic (TCA) clomipramine and the serotoninergic antidepressant (SSRI) citalopram on the motor cortex excitability in major depressed patients with TMS. Thirty affected subjects were placed into three groups: two received an intravenous dose of 25 mg clomipramine or 40 mg citalopram, and one received an injection of a placebo. Motor cortex excitability was studied by single and paired TMS before and after 3.5, 8, and 24 hours from administration of the drugs and placebo. Motor cortical excitability was measured using different TMS parameters: resting motor threshold (RMT), motor-evoked potential (MEP) amplitude, intracortical inhibition (ICI), and intracortical facilitation (ICF). The results indicated a temporary but significant increase of RMT and ICI and a decrease of ICF after the administration of both drugs, with a longer inhibition for the clomipramine rather than the citalopram. MEP amplitude was not significantly affected by the antidepressant injections. Our findings highlight that a single intravenous dose of clomipramine or citalopram exerts a significant but transitory suppression of motor cortex excitability in depressed patients. TMS represents a useful research tool in assessing the effects of motor cortical excitability of drugs used in the treatment of mental disorders.
 
Currently, the underlying neurobiological mechanism as to how repetitive transcranial magnetic stimulation (rTMS) can alter depressive states remains unclear. Animal data suggest that its influence could occur at the neurotransmitter level, such as modulation of the serotonin system. Twenty-one antidepressant-free medication-resistant unipolar depressed patients, and 21 age- and gender-matched healthy subjects were studied. We examined the neurobiologic impact of 10 high-frequent (HF)-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC) on postsynaptic 5-HT(2A) receptor binding indices (BI) measured with ¹²³I-5-I-R91150 single photon emission computed tomography (SPECT) only in patients. Compared with the control group, patients displayed significantly less bilateral dorsolateral prefrontal cortical and significantly higher left hippocampal baseline 5-HT(2A) receptor BI. Successful HF-rTMS treatment correlated positively with 5-HT(2A) receptor BI in the DLPFC bilaterally and correlated negatively with right hippocampal 5-HT(2A) receptor uptake values. Our results indicate that HF-rTMS treatment affect the serotonergic system. Our data also suggest that this kind of treatment affects 5-HT(2A) receptor BI in the DLPFC and in the hippocampus in different ways.
 
The International 10-20 system is a method for standardized placement of electroencephalogram (EEG) electrodes. The 10-20 system correlates external skull locations with the underlying cortical areas. This system accounts for variability in patient skull size by using certain percentages of the circumference and distances between four basic anatomical landmarks. This 10-20 system has recently been used in transcranial magnetic stimulation (TMS) research for locating specific cortical areas. In the treatment of depression (and some types of pain), the desired placement of the TMS coil is often above the left dorsalateral prefrontal cortex (DLPFC) which corresponds to the F3 location given by the 10-20 system. However, for an administrator with little experience with the 10-20 system, the numerous measurements and calculations can be excessively time-consuming. Additionally, with more measurements comes more opportunity for human error. For this reason we have developed a new, simpler and faster way to find the F3 position using only three skull measurements. In this paper, we describe and illustrate the application of the new F3 location system, provide the formulas used in the calculation of the F3 position, and summarize data from 10 healthy adults. After using both the International 10-20 system and this new method, it appears that the new method is sufficiently accurate; however, future investigations may be warranted to conduct more in dept analyses of the method's utility and potential limitations. This system requires less time and training to find the optimal position for prefrontal coil placement and it saves considerable time compared to the 10-20 EEG system.
 
In Transcranial Magnetic Stimulation (TMS), the Motor Threshold (MT) is the minimum intensity required to evoke a liminal response in the target muscle. Because the MT reflects cortical excitability, the TMS intensity needs to be adjusted according to the subject's MT at the beginning of every TMS session. Shorten the MT estimation process compared to existing methods without compromising accuracy. We propose a Bayesian adaptive method for MT determination that incorporates prior MT knowledge and uses a stopping criterion based on estimation of MT precision. We compared the number of TMS pulses required with this new method with existing MT determination methods. The proposed method achieved the accuracy of existing methods with as few as seven TMS pulses on average when using a common prior and three TMS pulses on average when using subject-specific priors. Our adaptive Bayesian method is effective in reducing the number of pulses to estimate the MT.
 
Subthalamic nucleus deep brain stimulation (STN DBS) is an effective therapeutic option for advanced Parkinson's disease (PD). Nevertheless, some patients develop gait disturbances despite a persistent improvement of PD segmental symptoms. Recent studies reported that stimulation of STN with low frequencies produced a positive effect on gait disorders and freezing episodes. To evaluate the effects of 80 Hz stimulation frequency on gait in PD patients undergoing STN DBS and to determine whether such effects are maintained over time. We evaluated 11 STN DBS treated PD patients who had developed gait impairment several years after surgery. Gait was assessed by means of the Stand-Walk-Sit (SWS) test. Motor symptoms and activities of daily living were evaluated through the Unified PD Rating Scale (UPDRS). The stimulation frequency was switched from 130 Hz to 80 Hz, adapting the voltage to maintain the same total delivered energy. Patients were assessed at baseline and 3 hours after switching the stimulation frequency to 80 Hz. Follow-up evaluations were carried out after 1, 5, and 15 months. The clinical global improvement scale was rated at every follow-up visit. A significant improvement of gait (SWS test) was evident immediately after switching the stimulation frequency to 80 Hz, with no deterioration of PD segmental symptoms. However, gait improvement was no longer detectable by the SWS test at follow-up evaluations 1, 5, and 15 months later. Three patients were switched back to 130 Hz because of unsatisfactory control of motor symptoms. Of the eight patients maintained at 80 Hz up to 15 months, five showed a global improvement and three showed no change. Stimulation frequency at 80 Hz has an immediate positive effect on gait in STN DBS treated patients; however, the objective gait improvement is not maintained over time, limiting the use of this frequency modulation strategy in the clinical setting.
 
Repetitive transcranial magnetic stimulation (rTMS) has been identified as a potentially valuable tool for the rehabilitation of language impairment after left hemisphere (LH) stroke, in populations of persons with chronic aphasia. Applied to a homologue to Broca's area, rTMS is posited to modulate bilateral language networks, promoting measurable behavioral language change, in accordance with theories of transcallosal disinhibition arising from the damaged LH. The current investigation is an open-label study, presenting detailed case and group presentations on a population of seven nonfluent aphasic participants. Behavioral language performance is presented on expressive and receptive language measures up to 8 months after a 10-day protocol of 1 Hz stimulation. This research aims to provide longitudinal behavioral language outcomes for persons with aphasia, subsequent to rTMS and supplement previous studies to inform the clinical efficacy of rTMS. In accordance with previous investigations, significant improvements in picture naming, spontaneous elicited speech and auditory comprehension were found. Time of testing was identified as a significant main effect. Significant improvements in picture naming accuracy and decreases in picture naming latency were also identified. The results demonstrate sustained language improvements up to 8 months subsequent to TMS application. The results of this investigation are consistent with the findings of previous research studies, reporting behavioral language changes after rTMS in nonfluent aphasia. Additional evidence is provided to demonstrate that rTMS may facilitate retrieval mechanisms involved in picture naming.
 
Methamphetamine abuse and addiction can lead to impaired cognition and psychosis, and there is no effective treatment for methamphetamine-induced mental illnesses. The aim of this study was to test whether repeated electroconvulsive shock (ECS) treatment has a therapeutic effect on methamphetamine-induced abnormal behavior in mice. To test the effects of ECS on methamphetamine-induced psychosis, ICR mice were randomly assigned to administration with either chronic methamphetamine or saline injection, and then both groups underwent post-treatment with either six once-daily ECS treatments or parallel sham controls. Prepulse inhibition (PPI), the novel object recognition test (NORT) and behavioral sensitization were performed for behavioral evaluation between the groups. To test the effects of ECS on methamphetamine addiction, methamphetamine-induced conditioned place preference (CPP) was examined after ECS and drug-primed reinstatement in the other set of experiments. The animals receiving repeated ECS following pretreatment with methamphetamine showed significant improvement in PPI and NORT, but not in behavioral sensitization. In the CPP study, the ECS-treated animals achieved extinction of place preference, but relapsed after a low-dose reinstatement of methamphetamine. The results indicated that repeated ECS treatments can ameliorate impairment to the sensorimotor gating and recognition memory elicited by methamphetamine, and temporarily suppress the reinforcement induced by methamphetamine in mice. Our findings suggest electroconvulsive therapy (ECT) may have potential applications with regard to the treatment of methamphetamine psychosis and addiction.
 
Background: Responsive deep brain stimulation (rDBS) has been recently proposed to block epileptic seizures at onset. Yet, long-term stability of brain responses to such kind of stimulation is not known. Objective: To quantify the neural adaptation to repeated rDBS as measured by the changes of anti-epileptic efficacy of bilateral DBS of the substantia nigra pars reticulata (SNr) versus auditory stimulation, in a rat model of spontaneous recurrent absence seizures (GAERS). Methods: Local field potentials (LFP) were recorded in freely moving animals during 1 h up to 24 h under automated responsive stimulations (SNr-DBS and auditory). Comparison of seizure features was used to characterise transient (repetition-suppression effect) and long-lasting (stability of anti-epileptic efficacy, i.e. ratio of successfully interrupted seizures) effects of responsive stimulations. Results: SNr-DBS was more efficient than auditory stimulation in blocking seizures (97% vs. 52% of seizures interrupted, respectively). Sensitivity to minimal interstimulus interval was much stronger for SNr-DBS than for auditory stimulation. Anti-epileptic efficacy of SNr-DBS was remarkably stable during long-term (24 h) recordings. Conclusions: In the GAERS model, we demonstrated the superiority of SNr-DBS to suppress seizures, as compared to auditory stimulation. Importantly, we found no long-term habituation to rDBS. However, when seizure recurrence was frequent, rDBS lack anti-epileptic efficacy because responsive stimulations became too close (time interval < 40 s) suggesting the existence of a refractory period. This study thus motivates the use of automated rDBS in patients having transient seizures separated by sufficiently long intervals.
 
Deep brain stimulation of the ventral striatum is an effective treatment for a variety of treatment refractory psychiatric disorders yet the mechanism of action remains elusive. We examined how five days of stimulation affected rhythmic brain activity in freely moving rats in terms of oscillatory power within, and coherence between, selected limbic regions bilaterally. Custom made bipolar stimulating/recording electrodes were implanted, bilaterally, in the nucleus accumbens core. Local field potential (LFP) recording electrodes were implanted, bilaterally in the prelimbic and orbitofrontal cortices and mediodorsal thalamic nucleus. Stimulation was delivered bilaterally with 100 μs duration constant current pulses at a frequency of 130 Hz delivered at an amplitude of 100 μA using a custom-made stimulation device. Synchronized video and LFP data were collected from animals in their home cages before, during and after stimulation. Signals were processed to remove movement and stimulation artifacts, and analyzed to determine changes in spectral power within, and coherence between regions. Five days stimulation of the nucleus accumbens core yielded temporally dynamic modulation of LFP power in multiple bandwidths across multiple brain regions. Coherence was seen to decrease in the alpha band between the mediodorsal thalamic nucleus and core of the nucleus accumbens. Coherence between each core of the nucleus accumbens bilaterally showed rich temporal dynamics throughout the five day stimulation period. Stimulation cessation revealed significant "rebound" effects in both power and coherence in multiple brain regions. Overall, the initial changes in power observed with short-term stimulation are replaced by altered coherence, which may reflect the functional action of DBS.
 
Background: The stimulus-response (S-R) curve is a well accepted constituent in transcranial magnetic stimulation (TMS) studies. However, it has been suggested that parameters of the S-R curve differ when stimuli are provided in a "ramped" (measured steps from low to high intensity), or "random" fashion. Hypothesis: We hypothesized that there would be no difference in the parameters of the S-R curve between either methodologies. Methods: Using a randomised cross-over design, 10 healthy participants (29.6 ± 6.4 yrs, 3 f) completed "ramped" or "random" curves in biceps brachii (BB) and first dorsal interosseous (FDI) muscles of both limbs. Curves were compared using mixed-factor ANOVA and correlated between limbs and methodologies. Results: No differences (P > 0.05) and high correlations (range 0.71-0.97; P < 0.001) were observed in BB and FDI data between curves. Conclusions: This study demonstrated that either methodology provides similar parameters of the S-R curve in healthy participants.
 
Transcranial magnetic stimulation is frequently used to construct stimulus response (SR) curves in studies of motor learning and rehabilitation. A drawback of the established method is the time required for data acquisition, which is frequently greater than a participant's ability to maintain attention. The technique is therefore difficult to use in the clinical setting. To reduce the time of curve acquisition by determining the minimum acquisition time and number of stimuli required to acquire an SR curve. SR curves were acquired from first dorsal interosseous (FDI) and abductor digiti minimi (ADM) at 6 interstimulus intervals (ISI) between 1.4 and 4 s in 12 participants. To determine if low-frequency rTMS might affect the SR curve, MEP amplitudes were monitored before and after 3 min of 1 Hz rTMS delivered at 120% of resting motor threshold in 12 participants. Finally, SR curves were acquired from FDI, ADM and Biceps Brachii (BB) in 12 participants, and the minimum number of stimuli was calculated using a sequential MEP elimination process. There were no significant differences between curves acquired with 1.4 s ISI and any other ISI. Low frequency rTMS did not significantly depress MEP amplitude (P = 0.87). On average, 61 ± 18 (FDI), 60 ± 16 (ADM) and 59 ± 16 (BB) MEPs were needed to construct a representative SR curve. This study demonstrates that reliable SR curves may be acquired in less than 2 min. At this rate, SR curves become a clinically feasible method for assessing corticospinal excitability in research and rehabilitation settings.
 
Acute vagal nerve stimulation displaces [ 11 C]yohimbine binding to the a2 adrenoceptors in minipig brain. Parametric maps of the average binding potential of the 6 pigs at baseline (middle) and after 30 min of acute stimulation (right) are shown. The left column shows the corresponding MRI images.
Binding potential change during acute vagal nerve stimulation as a function of baseline binding potentials in six minipig brains. Abscissa: Average binding potential (ratio) of brains at baseline. Ordinate: Average binding potential decline (ratio) from baseline to acute vagal nerve stimulation. Points show average binding potentials of 9 brain regions calculated from volumes of distribution of tracer yohimbine as described in Methods. Error bars represent the standard deviation. Slope of regression line is significantly greater than zero at P < 0.01.
Vagal nerve stimulation (VNS) emerged as an anti-epileptic therapy, and more recently as a potential antidepressant intervention. We hypothesized that salutary effects of VNS are mediated, at least in part, by augmentation of the inhibitory effects of cortical monoaminergic neurotransmission at appropriate receptors, specifically adrenoceptors. Our objective was to measure the effect of acute VNS on α2 adrenoceptor binding. Using positron emission tomography (PET), we measured changes in noradrenaline receptor binding associated with acute VNS stimulation in six anesthetized Göttingen minipigs. We used the selective α2 adrenoceptor antagonist [(11)C]yohimbine, previously shown to be sensitive to competition from the receptor's endogenous ligands, as a surrogate marker of monoamine release. PET records were acquired 4-6 weeks after the implant of a VNS electrode in minipigs before and within 30 min of the initiation of 1 mA stimulation. Kinetic analysis with the Logan graphical linearization generated tracer volumes of distribution for each condition. We used an averaged value of the distribution volume of non-displaceable ligand (VND), to calculate binding potentials for selected brain regions of each animal. VNS treatment markedly reduced the binding potential of yohimbine in limbic, thalamic and cortical brain regions, in inverse correlation with the baseline binding potential. The result is consistent with release of noradrenaline by antidepressant therapy, implying a possible explanation for the antidepressant effect of VNS. Copyright © 2015 Elsevier Inc. All rights reserved.
 
Positioning the shoulder joint from 30 degrees adduction (anterior [ANT]) to 30 degrees abduction (posterior [POST]) in the horizontal plane modifies the corticospinal output to hand and forearm muscles in humans. We investigated the mechanisms by which the central nervous system (CNS) maintains force output under conditions of increased effort and reduced corticospinal activity. Ten healthy subjects were studied with the shoulder joint fully supported and passively kept either in ANT or POST. Changes in motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS), intracortical inhibition (ICI), intracortical facilitation (ICF), H-reflex and F-waves were studied at force levels corresponding to 10% maximum voluntary contraction (MVC) of abductor digiti minimi (ADM) in ANT for both shoulder positions. In addition, premovement changes in ADM MEP size were assessed in a choice reaction time paradigm in the two shoulder positions. ADM MEPs were larger in POST than in ANT either during or before ADM voluntary contraction, pointing to increased corticospinal excitability in both conditions. ICI and ICF were increased and decreased, respectively, indicating a general disfacilitation on primary motor cortical (M1) output to ADM in POST. F-waves and H-reflexes were increased and decreased, respectively, indicating postsynaptic facilitation and increased presynaptic inhibition at spinal cord level in POST. A larger cortical output is produced in POST to maintain the same force levels as in ANT. A contributory role of premotor regions is hypothesized.
 
Transcranial magnetic stimulation (TMS) is a non-invasive technique used recently to treat different neuropsychiatric and neurodegenerative disorders. Despite its proven value, the mechanisms through which TMS exerts its beneficial action on neuronal function remain unclear. Recent studies have shown that its beneficial effects may be at least partly due to a neuroprotective effect on oxidative and cell damage. This study shows that TMS can modulate the Nrf2 transcriptor factor in a Huntington's disease-like rat model induced by 3-nitropropionic acid (3-NP). Western blot analysis demonstrated that 3-NP caused a reduction in Nrf2 in both cytoplasm and nucleus, while TMS applied to 3-NP-treated rats triggered an increase in cytoplasm and nucleus Nrf2 levels. It was therefore concluded that TMS modulates Nrf2 expression and translocation and that these mechanisms may partly explain the neuroprotective effect of TMS, as well as its antioxidant and cell protection capacity.
 
Over the last two decades, deep brain stimulation (DBS) has become a recognized and effective clinical therapy for numerous neurological conditions. Since its inception, clinical DBS technology has progressed at a relatively slow rate; however, advances in neural engineering research have the potential to improve DBS systems. One such advance is the concept of current steering, or the use of multiple stimulation sources to direct current flow through targeted regions of brain tissue. The goals of this study were to develop a theoretical understanding of the effects of current steering in the context of DBS, and use that information to evaluate the potential utility of current steering during stimulation of the subthalamic nucleus. We used finite element electric field models, coupled to multi-compartment cable axon models, to predict the volume of tissue activated (VTA) by DBS as a function of the stimulation parameter settings. Balancing current flow through adjacent cathodes increased the VTA magnitude, relative to monopolar stimulation, and current steering enabled us to sculpt the shape of the VTA to fit a given anatomical target. These results provide motivation for the integration of current steering technology into clinical DBS systems, thereby expanding opportunities to customize DBS to individual patients, and potentially enhancing therapeutic efficacy.
 
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become the surgical therapy of choice for medically intractable Parkinson's disease. However, quantitative understanding of the interaction between the electric field generated by DBS and the underlying neural tissue is limited. Recently, computational models of varying levels of complexity have been used to study the neural response to DBS. The goal of this study was to evaluate the quantitative impact of incrementally incorporating increasing levels of complexity into computer models of STN DBS. Our analysis focused on the direct activation of experimentally measureable fiber pathways within the internal capsule (IC). Our model system was customized to an STN DBS patient and stimulation thresholds for activation of IC axons were calculated with electric field models that ranged from an electrostatic, homogenous, isotropic model to one that explicitly incorporated the voltage-drop and capacitance of the electrode-electrolyte interface, tissue encapsulation of the electrode, and diffusion-tensor based 3D tissue anisotropy and inhomogeneity. The model predictions were compared to experimental IC activation defined from electromyographic (EMG) recordings from eight different muscle groups in the contralateral arm and leg of the STN DBS patient. Coupled evaluation of the model and experimental data showed that the most realistic predictions of axonal thresholds were achieved with the most detailed model. Furthermore, the more simplistic neurostimulation models substantially overestimated the spatial extent of neural activation.
 
Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCWM) is an experimental therapy for major depressive disorder (MDD). The specific axonal pathways that mediate the anti-depressant effects of DBS remain unknown. Patient-specific tractography-activation models (TAMs) are a new tool to help identify pathways modulated by DBS. TAMs consist of four basic components: 1) anatomical and diffusion-weighted imaging data acquired on the patient; 2) probabilistic tractography from the brain region surrounding the implanted DBS electrode; 3) finite element models of the electric field generated by the patient-specific DBS parameter settings; and 4) application of the DBS electric field to multi-compartment cable models of axons, with trajectories defined by the tractography, to predict action potential generation in specific pathways. This study presents TAM predictions from DBS of the SCCWM in one MDD patient. Our findings suggest that small differences in electrode location can generate substantial differences in the directly activated pathways.
 
In paired-pulse (conditioned-test) transcranial magnetic stimulation (TMS) protocols, the effect of the conditioning pulse on the test response can be substantial. Epidural recordings indicate that this is mediated through modulation of late indirect (I-) wave volleys. It is not well understood how strong effect sizes could arise from the later, and usually weaker, I-wave volleys. To formulate a model of I-wave summation at the spinal level to explore the contribution of late I-waves to the activation of the α-motoneuronal pool and to paired-pulse TMS measures of intracortical inhibition and facilitation. I-wave recruitment curves were modeled for the first three I-waves. A series of steps converted I-wave inputs to α-motoneuronal activation. The role of I₃ in activating the α-motoneuronal pool was investigated by manipulating the amplitude of the I₃ volley. For all TMS intensities, I₃ made a contribution to the firing of the α-motoneuronal pool that was disproportional to its contribution to the descending volley. At its most influential, I₃ increased the descending volley by 23.5% but increased the proportion of motoneurons that fired by 567%. There was a U-like relationship to stimulus intensity with inhibition of I₃, and an inverted-U relationship for facilitation of I₃, in keeping with empirical observation. Changes in spinal excitability disproportionally influenced α-motoneuronal recruitment. Late I-waves have a pivotal role in determining the response to paired-pulse TMS. The spinal transfer function that converts I-wave input to α-motoneuron activation can amplify the role of late I-waves and potentially influence paired-pulse TMS measures of intracortical inhibition and facilitation.
 
Background: When using transcranial magnetic stimulation, a stimulation intensity defined as a certain level above the threshold for activation of a hand muscle is commonly used, disregarding the fact that the areas of activation for different muscles may have varying response characteristics intra- and interindividually. Objective: To study the response characteristics of different muscles and compare them within and between individuals. Also to investigate the effect of varying stimulation intensity (defined in two different ways) and amplitude criterion for response, on the sizes of the activation areas for different muscles. Methods: A system of transcranial magnetic stimulation with navigation capacity where the stimulation intensity can be defined in terms of the electric field strength in the tissue was used. Four different muscles were investigated in healthy adults. The threshold for activation at rest (RMT) of the different muscles and their respective areas of activation were quantified using three different stimulus intensities (100, 110 and 120% RMT) and two criteria for response amplitude (20 and 50 μV). Results: Responses could readily be determined using 20 μV as response limit. The RMTs for different muscles varied within and between individuals. The degree to which the area depended on stimulation intensity differed between muscles intra- and interindividually. All results were statistically significant (P < 0.05 or less). Conclusions: The response characteristics vary between muscles within an individual and between individuals for a certain muscle. Thus, for optimal accuracy when delineating the activation area, the investigation should be adapted to each particular muscle.
 
Currently, it is difficult to predict precise regions of cortical activation in response to transcranial magnetic stimulation (TMS). Most analytical approaches focus on applied magnetic field strength in the target region as the primary factor, placing activation on the gyral crowns. However, imaging studies support M1 targets being typically located in the sulcal banks. To more thoroughly investigate this inconsistency, we sought to determine whether neocortical surface orientation was a critical determinant of regional activation. MR images were used to construct cortical and scalp surfaces for 18 subjects. The angle (θ) between the cortical surface normal and its nearest scalp normal for ∼50,000 cortical points per subject was used to quantify cortical location (i.e., gyral vs. sulcal). TMS-induced activations of primary motor cortex (M1) were compared to brain activations recorded during a finger-tapping task using concurrent positron emission tomographic (PET) imaging. Brain activations were primarily sulcal for both the TMS and task activations (P < 0.001 for both) compared to the overall cortical surface orientation. Also, the location of maximal blood flow in response to either TMS or finger-tapping correlated well using the cortical surface orientation angle or distance to scalp (P < 0.001 for both) as criteria for comparison between different neocortical activation modalities. This study provides further evidence that a major factor in cortical activation using TMS is the orientation of the cortical surface with respect to the induced electric field. The results show that, despite the gyral crown of the cortex being subjected to a larger magnetic field magnitude, the sulcal bank of M1 had larger cerebral blood flow (CBF) responses during TMS.
 
Background: Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD). Objective: We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD. Methods: In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 μs pulse width), MEDIUM (0.5-1.0 mA, 250 μs), or HIGH (1.25-1.5 mA, 250 μs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase). Results: VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose. Conclusions: TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.
 
Comparison of all measurements between the real tDCS and sham groups
Comparison of baseline and final values of autonomic parameters, including data from both sham and real tDCS groups.
Neuromodulatory techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have been increasingly studied as possible treatments for many neurological and psychiatric disorders. tDCS is capable of inducing changes in regional cerebral blood flow in both cortical and subcortical structures, as shown by positron emission tomography studies, and might conceivably affect hypothalamic and autonomic nervous system functions. However, it remains unknown whether acute changes in autonomic or hypothalamic functions may be triggered by conventional tDCS protocols. To verify whether tDCS, when performed with a bipolar cephalic montage, is capable of inducing acute changes in autonomic or hypothalamic functions in healthy subjects. Fifty healthy volunteers were studied. tDCS was performed with the anode over the C3 position and the cathode over the right supraorbital region. Subjects received either real or sham tDCS. Parameters assessed before and after a 20-minute session included blood pressure, tympanic thermometry, hand skin temperature, heart rate and ventilatory rate. Plasma concentrations of cortisol were also measured in a sub-set of 10 participants. A repeated-measures, mixed-design ANOVA showed significant changes in hand skin temperature (P = .005) and cortisol levels (P < .001) after both real and sham stimulation. There were no statistically significant changes in any of the other measurements. The changes in hand temperature and cortisol levels, having occurred in both the sham and experimental groups, probably reflect a non-specific stress response to a new procedure. There were no significant changes in autonomic functions, ventilation rate or core body temperature that can be attributed to conventional tDCS applied to healthy volunteers.
 
Background: Tobacco smoking is the leading cause of preventable deaths worldwide, but many smokers are simply unable to quit. Psychosocial and pharmaceutical treatments have shown modest results on smoking cessation rates, but there is an urgent need to develop treatments with greater efficacy. Brain stimulation methods are gaining increasing interest as possible addiction therapeutics. Objectives: The purpose of this paper is to review the studies that have evaluated brain stimulation techniques on tobacco addiction, and discuss future directions for research in this novel area of addiction interventions. Methods: Electronic and manual literature searches identified fifteen studies that administered repetitive transcranial magnetic stimulation (rTMS), cranial electrostimulation (CES), transcranial direct current stimulation (tDCS) or deep brain stimulation (DBS). Results: rTMS was found to be the most well studied method with respect to tobacco addiction. Results indicate that rTMS and tDCS targeted to the dorsolateral prefrontal cortex (DLPFC) were the most efficacious in reducing tobacco cravings, an effect that may be mediated through the brain reward system involved in tobacco addiction. While rTMS was shown to reduce consumption of cigarettes, as yet no brain stimulation technique has been shown to significantly increase abstinence rates. It is possible that the therapeutic effects of rTMS and tDCS may be improved by optimization of stimulation parameters and increasing the duration of treatment. Conclusion: Although further studies are needed to confirm the ability of brain stimulation methods to treat tobacco addiction, this review indicates that rTMS and tDCS both represent potentially novel treatment modalities.
 
Top-cited authors
Michael A Nitsche
  • Leibniz Research Center for Working Enviroment and Human Factors
Alvaro Pascual-Leone
  • Harvard Medical School, Boston, MA, United States
Marom Bikson
  • City College of New York
Walter Paulus
  • Universitätsmedizin Göttingen
Felipe Fregni
  • Spaulding Rehabilitation Hospital