BRAIN STIMULATION: Basic, Translational, and Clinical Research in Neuromodulation - Articles in Press

A neuromodulation experience registry for deep brain stimulation studies in psychiatric research: rationale and recommendations for implementation - Corrected Proof

Matthis Synofzik, Joseph J. Fins, Thomas E. Schlaepfer — 2011-11-07

To the Editor: Responding to the ethical inadequacies of unregulated early psychosurgery, a US National Commission in 1977 issued a recommendation on surgical interventions in neuropsychiatric disorders: “wherever psychosurgery is performed, it should be conducted in a manner that good data will be collected to further the evaluative process . . . the Commission further proposes that a mechanism be set up on the national level to collect data on psychosurgery.”

Rebound symptoms following battery depletion in the NIH OCD DBS cohort: clinical and reimbursement issues - Uncorrected Proof

A.K. Vora, H. Ward, K.D. Foote, W.K. Goodman, M.S. Okun — 2011-11-07

Objective: Deep brain stimulation (DBS) is a promising treatment for medication refractory obsessive compulsive disorder (OCD); however, there may be neuropsychiatric symptoms from unintended battery failure.Background: Previous studies indicated rebound symptoms from impulse generator (IPG) failure in Parkinson’s disease, dystonia, and essential tremor. Unique to OCD is that battery failure may precipitate neuropsychiatric symptoms rather than motor symptoms.Methods: Six patients with medication refractory OCD received implants as part of the previously reported National Institutional Health (NIH) DBS cohort. All available clinical data and adverse event data was reviewed.Results: The average age of cohort was 42.2 years (30-59 years), and the average baseline Y-BOCS score was 33.8 (31-38). All six subjects were observed to have increased OCD symptomatology during IPG failure; however, Y-BOCS scores remained less than pretreatment range, in five subjects. One of the subjects had a Y-BOCS score greater than pretreatment during the period of IPG failure. In addition, Y-BOCS scores improved back to baseline after IPG replacement in five subjects. Other symptoms potentially related to battery failure included: suicidality (n = 1), mood disturbance (n = 2), panic attacks (n = 1), fatigue (n = 2), and a restless sensation in the arms and legs (n = 1). A small number of subjects reported no side effects associated with IPG failure because of preemptive replacement (n = 2).Conclusions: This is a preliminary case series detailing the side effects resulting from IPG failure during OCD DBS. Preemptive battery replacement was an effective strategy for avoiding these issues, and timeliness in insurance reimbursement may be considered in the future. Additionally the use of rechargeable batteries may also help this issue. Clinical Trial Registration Number: NCT00057603

Fundamentals of transcranial electric and magnetic stimulation dose: definition, selection, and reporting practices - Uncorrected Proof

2011-11-03

Background: The growing use of transcranial electric and magnetic (EM) brain stimulation in basic research and in clinical applications necessitates a clear understanding of what constitutes the dose of EM stimulation and how it should be reported.Methods: This paper provides fundamental definitions and principles for reporting of dose that encompass any transcranial EM brain stimulation protocol.Results: The biologic effects of EM stimulation are mediated through an electromagnetic field injected (via electric stimulation) or induced (via magnetic stimulation) in the body. Therefore, transcranial EM stimulation dose ought to be defined by all parameters of the stimulation device that affect the electromagnetic field generated in the body, including the stimulation electrode or coil configuration parameters: shape, size, position, and electrical properties, as well as the electrode or coil current (or voltage) waveform parameters: pulse shape, amplitude, width, polarity, and repetition frequency; duration of and interval between bursts or trains of pulses; total number of pulses; and interval between stimulation sessions and total number of sessions. Knowledge of the electromagnetic field generated in the body may not be sufficient but is necessary to understand the biologic effects of EM stimulation.Conclusions: We believe that reporting of EM stimulation dose should be guided by the principle of reproducibility: sufficient information about the stimulation parameters should be provided so that the dose can be replicated.

Priming does not enhance the efficacy of 1 hertz repetitive transcranial magnetic stimulation for the treatment of auditory verbal hallucinations: results of a randomized controlled study - Corrected Proof

2011-11-02

Background: Low-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the left temporoparietal area (TP) has been investigated as a treatment method for auditory verbal hallucinations (AVH) yielding inconsistent results. In vitro studies have indicated that the effects of low-frequency rTMS can be enhanced by a brief pretreatment phase consisting of high-frequency rTMS (i.e., priming rTMS).Objective: The aim of this single-blind, randomized controlled study was to investigate whether the effects of rTMS on AVH can be enhanced with priming rTMS.Methods: Twenty-three patients with medication-resistant AVH were randomized over two groups: one receiving low-frequency rTMS preceded by 5 minutes of 6 Hertz rTMS; and another receiving low-frequency rTMS without priming. Both treatments were directed at the left TP. The total duration of stimulation was equal in the two groups, namely, 15 sessions of 20 minutes each. The severity of AVH and other psychotic features were measured with the aid of the Auditory Hallucination Rating Scale (AHRS), the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scales (PSYRATS). Results: The severity of AVH and other psychotic symptoms in the group with priming was not significantly lower after 3 weeks of treatment in comparison to baseline. The group treated with standard rTMS showed a trend toward improvement after 3 weeks of treatment. No significant differences were observed on any of the rating scales between the group with and without priming.Conclusions: This study does not provide evidence that priming rTMS is an effective treatment for AVH.

Centromedian thalamic nuclei deep brain stimulation in refractory status epilepticus - Corrected Proof

2011-10-31

Background: Refractory status epilepticus (RSE) is associated with high mortality. We report a potential treatment alternative.Hypothesis: Deep brain stimulation (DBS) of the centromedian thalamic nuclei (CMN) can be effective in the treatment of RSE.Methods: Report of the evolution of RSE after DBS of the CMN in a 27-year-old man.Results: In the course of an encephalopathy of unknown origin, and after a cardiac arrest, the patient developed RSE with myoclonic jerks and generalized tonic-clonic seizures. The EEG showed continuous generalized periodic epileptiform discharges (GPEDS). Five weeks after RSE onset, bilateral DBS of the CMN was started. This treatment was immediately followed by disappearance of tonic-clonic seizures and GPEDS, suggesting a resolution of RSE. The patient continued having multifocal myoclonic jerks, probably subcortical in origin, which resolved after 4 weeks. The patient remained clinically stable for 2 months in a persistent vegetative state.Conclusions: The remission of RSE, the abolition of GPEDS, and the patient survival suggest that DBS of the CMN may be efficacious in the treatment of refractory, generalized status epilepticus.

Alpha EEG guided TMS in schizophrenia - Corrected Proof

2011-10-10

Background: Alpha EEG guided Transcranial Magnetic Stimulation (αTMS) of the dorsolateral prefrontal cortex (DLPFC) has shown promising efficacy for treating the negative symptoms of schizophrenia.Objective/ Hypothesis: The purpose of the current investigation was to test (1) the therapeutic effect in other domains of symptoms of schizophrenia and (2) the specificity of stimulus location. The hypothesis to be tested was that global alpha EEG normalization after αTMS would help improve the clinical symptoms of schizophrenia, regardless of the site of stimulation.Method: Seventy-eight patients with schizophrenia were enrolled in a randomized, double-blind, sham-controlled study with four study groups: frontal αTMS, parietal αTMS, frontal sham, and parietal sham. Patients received daily treatment for 10 days and clinical evaluations at day 5 and 10. The stimulus rate and intensity were determined by individual’s characteristic alpha frequency and motor threshold (80%).Results: Positive and general psychotic symptoms improved significantly after αTMS (P < 0.02). Frontal and parietal αTMS had similar effects (P = 0.48). (3) αTMS with concomitant typical neuroleptics treatment had greater efficacy than atypical neuroleptics (P < 0.04). Degree of EEG normalization as measured by increase in Q factor was highly associated with the improvement in all three domains of symptoms of schizophrenia (P < 0.04).Conclusions: Alpha EEG normalization after treatment with αTMS may directly subserve the processes underlying clinical improvements in schizophrenia. Nonetheless, given the confound of possible unblinding of participants because of an inactive sham control, the current results should be considered preliminary until replicated further.

Common and unique responses to dopamine agonist therapy and deep brain stimulation in Parkinson’s disease: an H215O PET study - Corrected Proof

2011-10-05

Background: Dopamine agonist therapy and deep brain stimulation (DBS) of the subthalamic nucleus (STN) are antiparkinsonian treatments that act on a different part of the basal ganglia-thalamocortical motor circuitry, yet produce similar symptomatic improvements.Objective/Hypothesis: The purpose of this study was to identify common and unique brain network features of these standard treatments.Methods: We analyzed images produced by H215O positron emission tomography (PET) of patients with Parkinson’s disease (PD) at rest. Nine patients were scanned before and after injection of apomorphine, and 11 patients were scanned while bilateral stimulators were off and while they were on.Results: Both treatments produced common deactivations of the neocortical sensorimotor areas, including the supplementary motor area, precentral gyrus, and postcentral gyrus, and in subcortical structures, including the putamen and cerebellum. We observed concomitant activations of the superior parietal lobule and the midbrain in the region of the substantia nigra/STN. We also detected unique, treatment-specific changes with possible motor-related consequences in the basal ganglia, thalamus, neocortical sensorimotor cortex, and posterolateral cerebellum. Unique changes in nonmotor regions may reflect treatment-specific effects on verbal fluency and limbic functions.Conclusions: Many of the common effects of these treatments are consistent with the standard pathophysiologic model of PD. However, the common effects in the cerebellum are not readily explained by the model. Consistent deactivation of the cerebellum is interesting in light of recent reports of synaptic pathways directly connecting the cerebellum and basal ganglia, and may warrant further consideration for incorporation into the model.

Top down prefrontal affective modulation of tinnitus with multiple sessions of tDCS of dorsolateral prefrontal cortex - Corrected Proof

Margriet Faber, Sven Vanneste, Felipe Fregni, Dirk De Ridder — 2011-10-05

Most forms of tinnitus are attributable to reorganization and hyperactivity in the auditory central nervous system with coactivation of nonauditory brain structures. One such nonauditory brain area is the dorsolateral prefrontal cortex (DLPFC), which is important for the integration of sensory and emotional aspects of tinnitus. Based on extensive evidence that transcranial direct current stimulation can induce significant effects on DLPFC-related cognitive function, we aimed to investigate whether left or right anodal DLFPC tDCS is associated with modulation of tinnitus. We conducted a double-blind, placebo-controlled cross-over study in which 15 subjects with tinnitus were randomly assigned to receive active and sham anodal tDCS over left (n = 8) or right DLPFC (n = 7) for six sessions in a counterbalanced order; the cathode electrode was placed in the contralateral DLPFC. The results demonstrate that both active conditions—irrespective of the anodal position—can decrease tinnitus annoyance but it is not associated with improvements in tinnitus intensity when comparing pre-tDCS versus post-tDCS as well as comparing sham-tDCS versus real tDCS. Also, we show that the anode electrode placed over the left DLPFC modulates depression when comparing pre-tDCS versus post-tDCS as well as comparing sham-tDCS versus real tDCS. In addition, we also show that the anode electrode placed over the right DLPFC modulates anxiety when comparing pre-tDCS versus post-tDCS. This latter effect does not remain when we compare sham-tDCS versus real tDCS. This study further supports the involvement of the prefrontal cortex in the neural network associated with tinnitus, and also provides initial evidence for a potential brain stimulation site for tinnitus treatment in association with other treatments that can reduce tinnitus intensity.

Cerebral blood flow ratio of the dorsolateral prefrontal cortex to the ventromedial prefrontal cortex as a potential predictor of treatment response to transcranial magnetic stimulation in depression - Corrected Proof

Shinsuke Kito, Takashi Hasegawa, Yoshihiko Koga — 2011-10-05

Background: There is growing evidence that high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex is effective in the treatment of depression. Brain imaging studies have shown that rTMS alters regional brain activity with improvement of depression. However, a predictor of treatment response to rTMS has not yet been identified.Objective: The aim of this study was to estimate regional cerebral blood flow in the frontal regions and investigate the correlation with treatment response to high-frequency rTMS over the left dorsolateral prefrontal cortex in depression.Methods: Twenty-four patients with depression received high-frequency rTMS over the left dorsolateral prefrontal cortex and were assessed with the Hamilton Depression Rating Scale. Brain scans were acquired before rTMS using 99mTc-ethyl cysteinate dimer single photon emission computed tomography (SPECT), and cerebral blood flow in 16 brain regions was estimated using a fully automated region of interest (ROI) analysis software. Two principal components were extracted from cerebral blood flow in 16 brain regions by factor analysis with maximum likelihood method and Promax rotation with Kaiser normalization.Results: Sixteen brain regions were divided into two groups: dorsolateral prefrontal cortex (superior frontal, medial frontal, middle frontal, and inferior frontal regions); ventromedial prefrontal cortex (anterior cingulate, subcallosal, orbital, and rectal regions). Treatment response to rTMS was correlated with cerebral blood flow ratio of the dorsolateral prefrontal cortex to the ventromedial prefrontal cortex (DLPFC/VMPFC CBF ratio, r = −0.60, P = 0.002).Conclusions: The findings of this study suggest that depressed patients with a lower DLPFC/VMPFC CBF ratio may show a better response to high-frequency rTMS over the left dorsolateral prefrontal cortex.

Contact dermatitis after transcranial direct current stimulation - Corrected Proof

Philipp Riedel, Stefan Kabisch, Patrick Ragert, Katharina von Kriegstein — 2011-10-03

Transcranial direct current stimulation (tDCS) is used for the exploration of human brain function and is a potential tool for the treatment of medical conditions. Safety guidelines have recently been established to prevent adverse effects. In this study, we report the appearance of maculopapular erythemata after single application of tDCS that adhered to the safety guidelines.

Investigating the relationship between cognitive change and antidepressant response following rTMS: a large scale retrospective study - Uncorrected Proof

Kate E. Hoy, Rebecca A. Segrave, Zafiris J. Daskalakis, Paul B. Fitzgerald — 2011-09-23

Background: The use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression has been studied extensively over the last 15 years. In this time the vast majority of trials included assessment of cognition to determine whether the technique is cognitively safe. However, recent evidence suggests that the assessment of cognition could also have an important role to play in the prediction of antidepressant response.Objectives: The current study conducted a post hoc analysis of the cognitive data from four clinical trials of rTMS for treatment resistant depression, with an aim to investigate the relationship between early cognitive changes and eventual depression improvement.Method: Data from 137 patients were included in the analysis (62 male and 75 female, mean ages 41.86 ± 11.68 years). The primary outcome measure for all four studies was the Montgomery Asberg Depression Rating Scale (MADRS). Clinical and cognitive assessments were undertaken at baseline, a midtime point, and at endpoint after 4 or 6 weeks of treatment.Results: There was no cognitive deterioration after a treatment course of rTMS across the four depression trials. Initial improvements in performance on immediate visuospatial memory were significantly related to eventual reduction of depression severity, with visuospatial improvement being a significant predictor of degree of eventual improvement in a near significant regression model.Conclusions: Traditionally cognitive batteries in rTMS trials are designed to provide a broad assessment of neuropsychological functioning across numerous cognitive domains; however, there is growing evidence that cognition may have a very important role to play as an early indicator of antidepressant response.

Transcranial alternating stimulation in a high gamma frequency range applied over V1 improves contrast perception but does not modulate spatial attention - Corrected Proof

Bence Laczó, Andrea Antal, Robert Niebergall, Stefan Treue, Walter Paulus — 2011-09-19

Spatial visual attention enhances information processing within its focus. Vision at an attended location is faster, more accurate, of higher spatial resolution, and has an enhanced sensitivity for fine changes. Earlier hypotheses suggest that the neuronal mechanisms of these processes are based on the interactions among different neuronal groups by means of cortical oscillations in the gamma range. The aim of the current study was to modulate these oscillations externally, using a new technique called transcranial alternating current stimulation (tACS). We investigated the effect of covert spatial attention within and outside its focus by probing contrast sensitivity and contrast discrimination at high resolution across the visual field of 20 healthy human subjects. While applying 40, 60, and 80 Hz tAC stimulation over the primary visual cortex (V1), subjects’ contrast-discrimination thresholds were obtained using two different conditions: in the first condition we presented a black disc as a peripheral cue that automatically attracted the subject’s attention, whereas there was no cue in the second condition. We found that the spatial profile of contrast sensitivity was not affected by the stimulation. Contrast-discrimination thresholds on the other hand decreased significantly during 60 Hz tACS, whereas there was no effect of 40 and 80 Hz stimulation. These results suggest that attention plays an important role in contrast discrimination based on V1 activities that are influences by gamma range tACS stimulation.

Central cholinergic dysfunction measured “in vivo” correlates with different behavioral disorders in Alzheimer’s disease and dementia with Lewy body - Corrected Proof

2011-09-19

Background: Cholinergic deficits have been largely correlated to behavioral disorders in dementia. However, cholinergic deficits are not homogeneous and they are distributed differently in the basal forebrain and brainstem among Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). The different cholinergic networks involved suggest different patterns of behavior symptomatology in the two groups.Objective: To correlate the deficit of cholinergic activity, measured in vivo by the short latency afferent inhibition (SAI) technique, with the behavioral symptoms in patients affected by DLB and AD.Methods: Behavioral and neuropsychologic tests including Neuropsychiatric Inventory (NPI), mini-mental status examination (MMSE), and an extensive neuropsychologic investigation were administered to 18 DLB patients and 18 one-to-one matched AD patients. SAI data were compared with those from a control group of age-matched healthy individuals and the level of SAI in patients was correlated with behavioral measures.Results: AD tended to be more impaired than DLB on long-term memory, whereas DLB were more impaired than AD on constructional praxis tasks. NPI total score was similar but with a different behavioural pattern in DLB and AD. In particular, delusions and hallucinations prevailed in DLB patients, whereas affective disturbances prevailed in AD patients. SAI was significantly reduced both in AD and DLB patients when compared with controls; SAI correlated with hallucinations in DLB patients and with euphoric manic state and disinhibition in AD patients.Conclusions: Reduction of cholinergic activity as evaluated by SAI measurement correlates with different behavior disorders in AD and DLB patients.

Transcranial direct current stimulation in treatment resistant depression: a randomized double-blind, placebo-controlled study - Corrected Proof

2011-09-08

Background: Anodal transcranial direct current stimulation (tDCS) of the prefrontal cortex has been proposed as therapeutic intervention in major depression. According to clinical needs, this study addresses the question whether tDCS is effective in treatment resistant major depressive episodes.Methods: Twenty-two patients with a major depressive episode were randomly assigned to a cross-over protocol comparing tDCS and placebo stimulation add-on to a stable antidepressant medication. The parameters of active tDCS were: 1 or 2 mA for 20 minutes/day, anode over the left dorsolateral prefrontal cortex, cathode over the contralateral supraorbital region. Active and placebo tDCS was applied for 2 weeks using indistinguishable DC stimulators. Patients, raters, and operators were blinded to treatment conditions.Results: There was no significant difference in depression scores after 2 weeks of real compared with 2 weeks of sham tDCS. Scores on the Hamilton Depression Rating Scale were reduced from baseline by 14.7% for active tDCS and 10% for placebo tDCS. In contrast, subjective mood ratings showed an increase in positive emotions after real tDCS compared with sham tDCS.Conclusions: Anodal tDCS, applied for 2 weeks, was not superior to placebo treatment in patients with treatment resistant depression. However, secondary outcome measures are pointing to a positive effect of tDCS on emotions. Therefore, modified and improved tDCS protocols should be carried out in controlled pilot trials to develop tDCS towards an efficacious antidepressant intervention in therapy-resistant depression.

Impaired long-term depression in schizophrenia: a cathodal tDCS pilot study - Corrected Proof

2011-09-07

Background: Neural plasticity involves the reorganization of synaptic connections and represents the ability of the brain to adjust its function in response to challenge. Disturbed cortical plasticity has been linked to the pathophysiology of schizophrenia, with indirect evidence for disturbed plasticity in the disease state having been provided by postmortem studies and various animal models. However, glutamate-dependent long-term depression (LTD)-like cortical plasticity has not yet been investigated.Objective: To investigate LTD-like cortical plasticity after transcranial direct current stimulation (tDCS) in schizophrenia patients.Methods: Using excitability-diminishing cathodal tDCS, we performed the first in vivo assessment of glutamate-dependent LTD-like cortical plasticity in 21 schizophrenia patients and 21 matched healthy control subjects. To reveal the physiologic basis of the hypothesized plasticity deficits, we tested different inhibitory and excitatory neuronal circuits with transcranial magnetic stimulation (TMS).Results: Cathodal tDCS failed to reduce motor-evoked potential amplitudes in schizophrenia patients, indicating abolished LTD-like plasticity. Furthermore, schizophrenia patients had a prolonged GABAB-dependent cortical silent period (CSP) at baseline and tDCS failed to modulate the duration of CSP in the patient group. Finally, schizophrenia patients presented an elevated resting-motor threshold at baseline in comparison to healthy controls.Conclusions: The pattern of our results provides evidence for a specific plasticity deficit in schizophrenia patients, which might be associated with a hyperglutamatergic state. These findings may reflect a reduced signal-to-noise ratio and a disturbed filter function in schizophrenia patients. An increase of GABAB-activity may be a compensatory mechanism to dysfunctional LTD-like plasticity in schizophrenia.

Modulation of large-scale brain networks by transcranial direct current stimulation evidenced by resting-state functional MRI - Corrected Proof

2011-09-07

Background: Brain areas interact mutually to perform particular complex brain functions such as memory or language. Furthermore, under resting-state conditions several spatial patterns have been identified that resemble functional systems involved in cognitive functions. Among these, the default-mode network (DMN), which is consistently deactivated during task periods and is related to a variety of cognitive functions, has attracted most attention. In addition, in resting-state conditions some brain areas engaged in focused attention (such as the anticorrelated network, AN) show a strong negative correlation with DMN; as task demand increases, AN activity rises, and DMN activity falls.Objective: We combined transcranial direct current stimulation (tDCS) with functional magnetic resonance imaging (fMRI) to investigate these brain network dynamics.Methods: Ten healthy young volunteers underwent four blocks of resting-state fMRI (10-minutes), each of them immediately after 20 minutes of sham or active tDCS (2 mA), on two different days. On the first day the anodal electrode was placed over the left dorsolateral prefrontal cortex (DLPFC) (part of the AN) with the cathode over the contralateral supraorbital area, and on the second day, the electrode arrangement was reversed (anode right-DLPFC, cathode left-supraorbital).Results: After active stimulation, functional network connectivity revealed increased synchrony within the AN components and reduced synchrony in the DMN components.Conclusions: Our study reveals a reconfiguration of intrinsic brain activity networks after active tDCS. These effects may help to explain earlier reports of improvements in cognitive functions after anodal-tDCS, where increasing cortical excitability may have facilitated reconfiguration of functional brain networks to address upcoming cognitive demands.

I-wave origin and modulation - Corrected Proof

2011-09-01

The human motor cortex can be activated by transcranial magnetic stimulation (TMS) evoking a high-frequency repetitive discharge of corticospinal neurones. The exact physiologic mechanisms producing the corticospinal activity still remain unclear because of the complexity of the interactions between the currents induced in the brain and the circuits of cerebral cortex, composed of multiple excitatory and inhibitory neurons and axons of different size, location, orientation and function. The aim of current paper is to evaluate whether the main characteristics of the activity evoked by single- and paired-pulse and repetitive TMS, can be accounted by the interaction of the induced currents in the brain with the key anatomic features of a simple cortical circuit composed of the superficial population of excitatory pyramidal neurons of layers II and III, the large pyramidal neurons in layer V, and the inhibitory GABA cells. This circuit represents the minimum architecture necessary for capturing the most essential cortical input-output operations of neocortex. The interaction between the induced currents in the brain and this simple model of cortical circuitry might explain the characteristics and nature of the repetitive discharge evoked by TMS, including its regular and rhythmic nature and its dose-dependency and pharmacologic modulation. The integrative properties of the circuit also provide a good framework for the interpretation of the changes in the cortical output produced by paired and repetitive TMS.

Modulation of cortical activity after anodal transcranial direct current stimulation of the lower limb motor cortex: a functional MRI study - Corrected Proof

2011-08-29

Background and Objectives: Functional magnetic resonance imaging (fMRI) has shown that transcranial direct current stimulation (tDCS) of the hand motor cortex modulates cortical activity of the healthy human brain. However, few studies have assessed the effects of tDCS on the leg motor cortex. We therefore used fMRI to examine the modulating effects of tDCS on lower limb motor cortex responses.Methods: In this sham-controlled case-control study, 11 subjects were exposed to active anodal (n = 6) or sham (n = 5) stimulation, with the anode being positioned on the leg motor cortex of the right hemisphere. Each tDCS was delivered for 15 minutes at 2 mA, with each subject receiving a total of four stimulatory sessions on consecutive days. Cortical activity was measured before the first and after the fourth session by fMRI, and changes in cortical activity were calculated.Results: Anodal tDCS increased activation of the ipsilateral supplementary motor area and lowered the extent of activation of both anterior cingulate gyri, the right middle and superior temporal gyri, the middle and superior frontal gyri, and the primary and secondary somatosensory cortices.Conclusions: Anodal tDCS increased corticospinal excitability of the lower limb motor cortex in healthy subjects, suggesting that multiple brain cortical areas may be associated with leg motor performance via involvement of variable corticocortical connections.

Single-pulse TMS related syncopal spell in a healthy subject - Corrected Proof

Aviad A. Hadar, Stergios Makris, Kielan Yarrow — 2011-08-26

We report the following TMS-related seizure or spell. The subject was a 22-year-old healthy woman who had no risk factors and was not taking any medications. She was screened using a self-report questionnaire for contraindications for TMS, including past or present neurologic, cardiac, and psychiatric conditions, family history of epilepsy, sleep deprivation, medicinal or recreational drug use, and recent use of alcohol or high doses of caffeine. Written informed consent was then obtained.

Short duration transcranial direct current stimulation (tDCS) modulates verbal memory - Corrected Proof

Amir Homayoun Javadi, Paul Cheng, Vincent Walsh — 2011-08-26

Transcranial direct current stimulation (tDCS) is a noninvasive method of modulating cortical excitability. The aim of this study was to investigate the effects of short-duration tDCS (1.6 seconds per trial) on memory performance, and whether the effects were affected by stimulation administered early or late in a trial. Participants memorize words under anodal and cathodal tDCS to the left dorsolateral prefrontal cortex (DLPFC) in two separate sessions in no-stimulation, early stimulation, and late stimulation trials. Early stimulation occurred during word presentation, whereas late stimulation occurred after word presentation. Early anodal tDCS led to significantly better accuracy and speed in a subsequent recognition test compared to anodal late or no-stimulation conditions. Early cathodal tDCS, on the other hand, led to significantly worse accuracy and speed in a subsequent recognition test compared with cathodal late or no-stimulation conditions. The results of this study suggest that short-duration tDCS can modulate memory performance and highlight the importance of period of stimulation.

Perceptual improvement following repetitive sensory stimulation depends monotonically on stimulation intensity - Corrected Proof

Sandra Schlieper, Hubert R. Dinse — 2011-08-16

Background: Electrical repetitive sensory stimulation (rSS) is a direct and effective means of inducing plasticity processes in human beings, and is increasingly being used as a therapeutic intervention. Suprathreshold intensities induce beneficial effects on tactile perception and sensorimotor abilities. However, it is not known whether there is an optimal range of stimulus intensity.Methods: We investigated the effect of varied intensities (low, 1.19 ± 0.07 mA; intermediate, 3.33 ± 0.27 mA; and high, 4.42 ± 0.56 mA) on the outcome of a 30-minute electrical rSS applied to the index finger (intermittent high-frequency stimulation, 20 Hz and interburst interval, 5 seconds) in three groups (n = 10 each) of participants. As a marker of perceptual changes, we measured tactile spatial two-point discrimination on the stimulated finger and on the heel of the hand before and after the rSS.Results: rSS improved discrimination performance, with the gain being the highest in the high-intensity group and the lowest in the low-intensity group. Measurements on the heel of the hand revealed small improvements in the high-intensity group, indicative of recruitment processes.Conclusions: rSS of maximal intensity induced the strongest effects, indicative of a monotonic intensity-gain characteristic with no U-shaped dependency.

A computational model of direct brain excitation induced by electroconvulsive therapy: comparison among three conventional electrode placements - Corrected Proof

Siwei Bai, Colleen Loo, Amr Al Abed, Socrates Dokos — 2011-08-10

Background: Electroconvulsive therapy (ECT) is a highly effective treatment for severe depressive disorder. Efficacy and cognitive outcomes have been shown to depend on variations in electrode placement and other stimulus parameters, presumably because of differences in the pattern of neuronal activation. This latter effect, however, is poorly understood.Objective: In this study, we present an anatomically accurate human head computational model to stimulate neuronal excitation during ECT, to better understand the effects of varying electrode placement and stimulus parameters.Methods: Electric field and current density throughout the head, as well as direct neural activation within the brain, were computed using the finite element method. Regions representing passive volume conductors (skin, skull, cerebrospinal fluid) were extracellularly coupled to an excitable neural continuum region representing the brain. The skull was modeled with anistropic electrical conductivity.Results: Simulation results indicated that direct activation of the brain occurred immediately beneath the electrodes on the scalp, consistent with existing imaging studies. In addition, we found that the brainstem was also activated using a right unilateral electrode configuration. Simulation also demonstrated that a reduction in stimulus amplitude or pulse width led to a reduction in the spatial extent of brain activation.Conclusions: The novel model described in this study was able to simulate direct excitation of the brain during ECT, was useful in characterizing differences in neuronal activation as electrode placement, pulse width, and amplitude were altered, and is proposed as a tool for further exploring the effects of variations in ECT stimulation approaches. Results from the simulations assist in understanding recently described clinical phenomena, in particular, the reduction in cognitive side effects with ultrabrief pulse width stimulation, and greater effects of the ECT stimulus on cardiovascular function with unilateral electrode placement.

Does second-scale intertrial interval affect motor evoked potentials induced by single-pulse transcranial magnetic stimulation? - Corrected Proof

Petro Julkunen, Laura Säisänen, Taina Hukkanen, Nils Danner, Mervi Könönen — 2011-08-10

Objective: To determine whether a second-scale intertrial interval (ITI) of single-pulse transcranial magnetic stimulation (TMS) affects the measured amplitude of motor-evoked potentials (MEPs) representing individual corticospinal excitability. This was performed to challenge the common assumption of time invariance of such amplitudes.Methods: Navigated TMS was used to map the dominant hemisphere of nine healthy subjects for the cortical representation focus of the contralateral thenar muscle, and resting motor threshold (MT) was determined. Single-trial MEP amplitudes were analyzed from trains of 30 responses induced at an intensity of 120% of the MT, and constant ITIs were investigated at 1, 2, 3, 5, and 10 seconds as well as randomized at ranges of 1-3 seconds, 3-5 seconds, and 5-10 seconds. MEP responses were divided into three blocks of 10 consecutive responses within each stimulation train. Repeated samples ANOVA was used to assess whether the individual characteristic MEP amplitudes were time invariant, i.e., not affected by the different ITIs and stimulus blocks.Results: The individual single-trial MEP amplitudes were affected significantly (P < 0.05) by the ITI (8/8 subjects), block number (5/8 subjects), and ITI by block number interaction (6/8 subjects). One subject was excluded as the sphericity of the variances could not be confirmed. Consequently, the found time variant nature of the individual single-trial MEP amplitudes affected the estimates (means) of individual characteristic MEP amplitudes. This was also observed as a significant block number effect (P < 0.05) across all subjects.Conclusions: The individual characteristic MEP amplitudes are time variant, contrary to the common assumption. Hence, individual characteristic MEP amplitude estimates should be used cautiously, as erroneous conclusions could be made when assuming those as time invariant.

Bifrontal and bioccipital transcranial direct current stimulation (tDCS) does not induce mood changes in healthy volunteers: a placebo controlled study - Corrected Proof

Mark Plazier, Kathleen Joos, Sven Vanneste, Jan Ost, Dirk De Ridder — 2011-08-08

Transcranial direct current stimulation (tDCS) is the application of a weak electrical direct current (1.5 mA), which has the ability to modulate spontaneous firing rates of the cortical neurons by depolarizing or hyperpolarizing the neural resting membrane potential. tDCS in patients with depressive disorders has been proven to be an interesting therapeutic method potentially influencing pathologic mood states. Except one study, no alterations in mood could be confirmed applying tDCS in healthy participants. In this study, bifrontal or bioccipital stimulation was applied in 17 healthy subjects during 20 minutes with 1.5 mA in a placebo-controlled manner. Bifrontal stimulation consisted of both anodal and cathodal placement on right and left dorsolateral prefrontal cortex (DLPFC) in two separate sessions. Using a set of self-reported moodscales (SUDS, POMS-32, PANAS, BISBAS) no significant mood changes could be observed, neither with bifrontal nor bioccipital tDCS. As already demonstrated by previous studies, we confirmed the minimal side effects and the safety of this neuromodulation technique.

Transient effects of 80 Hz stimulation on gait in STN DBS treated PD patients: a 15 months follow-up study - Corrected Proof

2011-08-02

Background: 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.Objective: 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.Methods: 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.Results: 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.Conclusions: 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.

Prolonged visual memory enhancement after direct current stimulation in Alzheimer’s disease - Corrected Proof

2011-07-28

Background: Immediately after patients with Alzheimer’s disease (AD) receive a single anodal transcranial direct current stimulation (tDCS) session their memory performance improves. Whether multiple tDCS sessions improve memory performance in the longer term remains unclear.Objective: In this study we aimed to assess memory changes after five consecutive sessions of anodal tDCS applied over the temporal cortex in patients with AD.Methods: A total of 15 patients were enrolled in two centers. Cognitive functions were evaluated before and after therapeutic tDCS. tDCS was delivered bilaterally through two scalp anodal electrodes placed over the temporal regions and a reference electrode over the right deltoid muscle. The stimulating current was set at 2 mA intensity and was delivered for 30 minutes per day for 5 consecutive days.Results: After patients received tDCS, their performance in a visual recognition memory test significantly improved. We found a main effect of tDCS on memory performance, i.e., anodal stimulation improved it by 8.99% from baseline, whereas sham stimulation decreased it by 2.62%. tDCS failed to influence differentially general cognitive performance measures or a visual attention measure.Conclusions: Our findings show that after patients with AD receive anodal tDCS over the temporal cerebral cortex in five consecutive daily sessions their visual recognition memory improves and the improvement persists for at least 4 weeks after therapy. These encouraging results provide additional support for continuing to investigate anodal tDCS as an adjuvant treatment for patients with AD.

Repetitive transcranial magnetic stimulation: hearing safety considerations - Corrected Proof

Stéphane Tringali, Xavier Perrot, Lionel Collet, Annie Moulin — 2011-07-27

Background: The guidelines for use of repetitive transcranial magnetic stimulation (rTMS) advise frequent updating of rTMS safety guidelines and recommendations. Although rTMS can produce sound of more than 120 dB C, which is sufficient to induce hearing loss, the effect of rTMS noise on the hearing of both patients and rTMS practitioners is understudied.Objective: This study investigated the effects of rTMS noise on subjects’ hearing using otoacoustic emissions evoked by clicks (transiently evoked otoacoustic emissions, TEOAEs), which is an objective and sensitive method of cochlear exploration.Methods: Hearing thresholds and TEOAEs were recorded in 24 normal-hearing healthy subjects before and after a real or sham rTMS session (a single 20-minute session applied to the superior temporal gyrus with 1200 pulses at 100% of the individual motor threshold).Results: No significant difference in hearing thresholds was observed between subjects exposed to real or sham rTMS. However, the difference in TEOAE amplitude between pre- and post-rTMS sessions increased significantly with rTMS noise for those subjects the least protected by earplugs, showing a post-rTMS slight decrease of TEOAE amplitude for high rTMS intensities and hence minor hearing function alteration. However, this correlation was no longer found 1 hour after the rTMS session.Conclusions: These findings suggest that, even when rTMS is used within normal safety limits and with good hearing protection, rTMS noise can transiently disturb hearing mechanisms in normal-hearing healthy subjects. This transient effect of rTMS on hearing may be an important consideration for Institutional Review Boards when rTMS is used at higher stimulation intensities.

Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex modulates declarative memory - Corrected Proof

Amir Homayoun Javadi, Vincent Walsh — 2011-07-27

Background: Previous studies have claimed that weak transcranial direct current stimulation (tDCS) induces persisting activity changes in the human motor cortex and working memory, but to date no studies have evaluated the effects of tDCS on declarative memory.Objective: Our aim was to determine whether anodal and cathodal transcranial direct current stimulation would differentially modify performance in a word memorization task during encoding or recognition when administered over the left dorsolateral prefrontal cortex (DLPFC).Methods: In two experiments, 32 participants underwent a series of word memorization tasks. This task was performed during sham, anodal, and cathodal stimulation applied over the left DLPFC. Moreover, participants in the first experiment performed the same task with anodal tDCS of the primary motor cortex (M1).Results: During encoding, anodal stimulation of the left DLPFC improved memory, whereas cathodal stimulation of the same area impaired memory performance in later recognition. Anodal stimulation of M1 had no effect on later recognition. During recognition cathodal stimulation of the left DLPFC impaired recognition compared with sham stimulation of the same area and anodal stimulation had a trend toward improving the recognition.Conclusions: The results indicated that active stimulation of the left DLPFC leads to an enhancement or impairment of verbal memorization depending on the polarity of the stimulation. Furthermore, this effect was specific to the site of stimulation.

The effect of propofol-remifentanil anesthesia on selected seizure quality indices in electroconvulsive therapy - Corrected Proof

Stephen H. Dinwiddie, David B. Glick, Morris B. Goldman — 2011-07-27

Background: Use of a short-acting opiate to potentiate anesthetic induction agents has been shown to increase seizure duration in electroconvulsive therapy (ECT), but little is known of the effect of this combination on indices of seizure quality.Objective: To determine whether anesthetic modality affects commonly provided indices of seizure quality.Methods: Twenty-five subjects were given propofol 2 mg/kg body weight for their first ECT session, at which time seizure threshold was titrated. Subjects thereafter alternated between that anesthetic regimen or propofol 0.5 mg/kg plus remifentanil 1 mcg/kg. Linear mixed models with random subject effect, adjusting for electrode placement, electrical charge, and number of treatments, were fit to estimate effect of anesthesia on seizure duration and several standard seizure quality indices (average seizure energy, time to peak electroencephalography (EEG) power, maximum sustained power, interhemispheric coherence, early and midictal EEG amplitude, and maximum sustained interhemispheric EEG coherence).Results: Propofol-remifentanil anesthesia significantly lengthened seizure duration and was associated with longer time to reach maximal EEG power and coherence as well as maximal degree of interhemispheric EEG coherence. No effect was seen on early ictal amplitude or average seizure energy index.Conclusions: Propofol-remifentanil anesthesia prolongs seizure duration and has a significant effect on some, but not all, measures of seizure quality. This effect may be of some benefit in cases where adequate seizures are otherwise difficult to elicit. Varying anesthetic technique may allow more precise investigation of the relationships between and relative impacts of commonly used seizure quality indices on clinical outcomes and ECT-related cognitive side effects.

Decoding emotional prosody: resolving differences in functional neuroanatomy from fMRI and lesion studies using TMS - Corrected Proof

L. Alba-Ferrara, A. Ellison, R.L.C. Mitchell — 2011-07-18

Background: Prosody conveys information about the emotional state and intention of others. Lesion studies have shown that damage to the right posterior temporal region is associated with prosody decoding deficits. Dissimilarly to findings from lesion studies, neuroimaging data show substantial bilateral peri-Sylvian activation.Objective: This study aimed to investigate the involvement of the left and right superior temporal gyrus (STG) in prosodic and semantic processing using transcranial magnetic stimulation (TMS). These two regions of interest were chosen for their correspondence to Wernicke’s area in the left hemisphere and its analog in the right.Methods: Offline TMS with a stimulation frequency of 1 Hz and intensity of 60% of stimulator output (approximately 1.1 Tesla) with one pulse applied per second for 10 minutes (600 pulses) was performed. Directly after TMS on the right STG, the left STG or sham-stimulation, participants completed a prosody decoding or a semantic judgment task (whether the tone/meaning was happy or sad).Results: Reaction times (RT) for the prosodic task were significantly slower when TMS was applied in the right STG in comparison to left STG and sham conditions. TMS over both right and left STG delayed RT in the semantic task, significantly when the tone of voice was incongruent with the meaning.Conclusions: Our data strongly suggests that left temporal regions are not crucial to the basic task of prosody decoding per se; however, the analogous region on the right is. Hence, involvement of the left STG in prosodic decoding revealed in previous imaging data is incidental.

Intraoperative microelectrode recording for the delineation of subthalamic nucleus topography in Parkinson’s disease - Corrected Proof

2011-07-11

Background: The subthalamic nucleus (STN) as an effective target for deep brain stimulation (DBS) in advanced Parkinson’s disease is functionally divided into the dorsolateral sensorimotor and the ventromedial limbic and associative parts. To implant electrodes for DBS close to the sensorimotor region is considered crucial for optimal motor benefit and for avoidance of potential cognitive and behavioral side effects.Objective: The aim of this study was to determine whether the functional segregation of the STN is associated with distinct and region-specific neuronal activity patterns and action potential properties obtained by intraoperative microelectrode recordings.Methods: In 12 Parkinson's disease patients, stepwise intraoperative microelectrode recordings were performed using five concentrically configured electrodes starting 10 mm above the calculated target point until the dorsal border of the substantia nigra.Results: Based on autocorrelogram analysis of a total of 329 single units, we found a higher occurrence of oscillatory (P < 0.01) and bursty (P = 0.058) spike pattern in the dorsal versus the ventral STN. In contrast the ventral region was characterized by irregular firing neurons (P < 0.01). There were no significant differences in firing frequency, coefficient of variance, asymmetry index as well as spike form, duration, and amplitude.Conclusions: Among all parameters analyzed in the study, spike pattern is the only convenient electrophysiologic parameter for the differentiation of STN subregions in patients with Parkinson’s disease. The autocorrelogram-based analysis of spike activity seems to be of certain value for the delineation of the dorsolateral STN and might therefore facilitate the precise electrode implantation for DBS.

A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia - Corrected Proof

2011-07-11

Background: Repetitive transcranial magnetic stimulation (rTMS) has been investigated for its treatment efficacy for the negative symptoms of schizophrenia. Previous studies have targeted the dorsolateral prefrontal cortex (DLPFC), which is associated with the pathophysiology of this disorder. Several rTMS parameters have been explored in the treatment of negative symptoms and include stimulating the left and bilateral DLPFC at several different frequencies and number of sessions. Results of such studies have been inconsistent, while high-frequency rTMS has shown greatest promise.Objective/Hypothesis: The objective of this study was to evaluate the efficacy of bilateral high-frequency rTMS in the treatment of negative symptoms in schizophrenia. It was hypothesized rTMS would alleviate negative symptoms in schizophrenia.Methods: Twenty-five patients were enrolled in this double-blind placebo-controlled randomized trial. Bilateral 20 Hz rTMS was MRI-targeted to the DLPFC at 90% RMT administered daily for 4 weeks for a total of 20 treatments. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative symptom scale (PANSS), and controlling for depression as measured with the Calgary Depression Scale (CDS) at baseline, 1, 2, 3, 4, and 2 weeks after the treatment course.Results: No significant group or time differences were found on negative symptoms or depressive symptoms after rTMS. Bilateral high-frequency rTMS did not alleviate negative symptoms in patients with schizophrenia.Conclusions: These findings indicate that such symptoms are unresponsive to rTMS treatment or that more optimized parameters are needed to achieve improved therapeutic efficacy.

Guidelines for precise and accurate computational models of tDCS - Corrected Proof

Marom Bikson, Abhishek Datta — 2011-07-04

During transcranial electrical stimulation, including transcranial direct current stimulation (tDCS), current is induced in the brain. Because different electrode montages result in distinct brain current flow, researchers and clinicians can adjust montage to target or avoid specific brain regions in an application specific manner. Though tDCS montage design often follow basic rules-of-thumb (e.g., increased/decreased excitability “under” the anode/cathode), computational models of brain current flow during tDCS (also called “forward” models) provide more accurate insight into detailed current flow patterns, and in some cases challenge simplified electrode-placement assumptions. With the increased recognition of the value of computational forward models in informing tDCS montage design and interpretation of results, there have been recent advances in modeling tools and a proliferation of publications. In considering new electrode montages, and especially in potentially vulnerable populations, forward models are the main tool to relate the externally controllable dose parameters (electrode number, position, size, shape, current) with resulting brain current flow–the use and adequacy of these models is considered here.

Detection of the facial expression of emotion and self-report measures in empathic situations are influenced by sensorimotor circuit inhibition by low-frequency rTMS - Corrected Proof

Michela Balconi, Adriana Bortolotti — 2011-06-20

Background: Empathic responses to facial cues are a main social competency. Both appraisal processes (facial emotion detection) and self-perceived empathy (empathic responsiveness) in response to emotional faces are thought to be related to empathic behavior, although no systematic analysis has been performed to assess their relationship.Objectives: The current research explored the contribution of the frontal sensorimotor system to facial detection and self-reported empathic measures by using repetitive transcranial magnetic stimulation (rTMS) to produce a temporary disruption of this specific cortical site.Methods: Eighteen subjects were asked to detect facial expression of emotions (anger, fear, happiness, and neutrality) and to evaluate their empathic responsiveness to these facial cues. A 5-second rTMS (1 Hz, inhibition paradigm) pulse was delivered before the stimulus onset.Results: Error rates and response times (RTs) increased when brain activity was disrupted, specifically in response to anger and fear. Self-reported measures showed a concomitant decreased empathic response when the frontal sensorimotor system was deactivated.Conclusions: The ability to monitor emotional cues and the behavioral empathic responsiveness to emotional situations was shown to be partially compromised in the case of frontal activity disruption, highlighting the main role of the sensorimotor system for empathic social skills.

Safety and tolerability of repetitive transcranial magnetic stimulation in patients with pathologic positive sensory phenomena: a review of literature - Uncorrected Proof

Paul A. Muller, Alvaro Pascual-Leone, Alexander Rotenberg — 2011-06-16

Background: Repetitive transcranial magnetic stimulation (rTMS) is emerging as a valuable therapeutic and diagnostic tool. rTMS appears particularly promising for disorders characterized by positive sensory phenomena that are attributable to alterations in sensory cortical excitability. Among these are tinnitus, auditory and visual hallucinations, and pain syndromes.Objective: Despite studies addressing rTMS efficacy in suppression of positive sensory symptoms, the safety of stimulation of potentially hyperexcitable cortex has not been fully addressed. We performed a systematic literature review and metaanalysis to describe the rTMS safety profile in these disorders.Methods: Using the PubMed database, we performed an English-language literature search from January 1985 to April 2011 to review all pertinent publications. Per study, we noted and listed pertinent details. From these data we also calculated a crude per-subject risk for each adverse event.Results: One hundred six publications (n = 1815) were identified with patients undergoing rTMS for pathologic positive sensory phenomena. Adverse events associated with rTMS were generally mild and occurred in 16.7% of subjects. Seizure was the most serious adverse event, and occurred in three patients with a 0.16% crude per-subject risk. The second most severe adverse event involved aggravation of sensory phenomena, occurring in 1.54%.Conclusions: The published data suggest rTMS for the treatment or diagnosis of pathologic positive sensory phenomena appears to be a relatively safe and well-tolerated procedure. However, published data are lacking in systematic reporting of adverse events, and safety risks of rTMS in these patient populations will have to be addressed in future prospective trials.

Current steering to activate targeted neural pathways during deep brain stimulation of the subthalamic region - Corrected Proof

Ashutosh Chaturvedi, Thomas J. Foutz, Cameron C. McIntyre — 2011-06-03

Deep brain stimulation (DBS) has steadily evolved into an established surgical therapy for numerous neurological disorders, most notably Parkinson's disease (PD). Traditional DBS technology relies on voltage-controlled stimulation with a single source; however, recent engineering advances are providing current-controlled devices with multiple independent sources. These new stimulators deliver constant current to the brain tissue, irrespective of impedance changes that occur around the electrode, and enable more specific steering of current towards targeted regions of interest. In this study, we examined the impact of current steering between multiple electrode contacts to directly activate three distinct neural populations in the subthalamic region commonly stimulated for the treatment of PD: projection neurons of the subthalamic nucleus (STN), globus pallidus internus (GPi) fibers of the lenticular fasiculus, and internal capsule (IC) fibers of passage. We used three-dimensional finite element electric field models, along with detailed multicompartment cable models of the three neural populations to determine their activations using a wide range of stimulation parameter settings. Our results indicate that selective activation of neural populations largely depends on the location of the active electrode(s). Greater activation of the GPi and STN populations (without activating any side effect related IC fibers) was achieved by current steering with multiple independent sources, compared to a single current source. Despite this potential advantage, it remains to be seen if these theoretical predictions result in a measurable clinical effect that outweighs the added complexity of the expanded stimulation parameter search space generated by the more flexible technology.

Effects of simultaneous bilateral tDCS of the human motor cortex - Corrected Proof

2011-06-02

Background: Transcranial direct current stimulation (tDCS) is a noninvasive technique that has been investigated as a therapeutic tool for different neurologic disorders. Neuronal excitability can be modified by application of DC in a polarity-specific manner: anodal tDCS increases excitability, while cathodal tDCS decreases excitability. Previous research has shown that simultaneous bilateral tDCS of the human motor cortex facilitates motor performance in the anodal stimulated hemisphere much more than when the same hemisphere is stimulated using unilateral anodal motor cortex tDCS.Objective: The main purpose of this study was to determine whether simultaneous bilateral tDCS is able to increase cortical excitability in one hemisphere whereas decreasing cortical excitability in the contralateral hemisphere. To test our hypothesis, cortical excitability before and after bilateral motor cortex tDCS was evaluated. Moreover, the effects of bilateral tDCS were compared with those of unilateral motor cortex tDCS.Methods: We evaluated cortical excitability in healthy volunteers before and after unilateral or bilateral tDCS using transcranial magnetic stimulation.Results: We demonstrated that simultaneous application of anodal tDCS over the motor cortex and cathodal tDCS over the contralateral motor cortex induces an increase in cortical excitability on the anodal-stimulated side and a decrease in the cathodal stimulated side. We also used the electrode montage (motor cortex-contralateral orbit) method to compare the bilateral tDCS montage with unilateral tDCS montage. The simultaneous bilateral tDCS induced similar effects to the unilateral montage on the cathode-stimulated side. On the anodal tDCS side, the simultaneous bilateral tDCS seems to be a slightly less robust electrode arrangement compared with the placement of electrodes in the motor cortex-contralateral orbit montage. We also found that intersubject variability of the excitability changes that were induced by the anodal motor cortex tDCS using the bilateral montage was lower than that with the unilateral montage.Conclusions: This is the first study in which cortical excitability before and after bilateral motor cortex tDCS was extensively evaluated, and the effects of bilateral tDCS were compared with unilateral motor cortex tDCS. Simultaneous bilateral tDCS seems to be a useful tool to obtain increases in cortical excitability of one hemisphere whereas causing decreases of cortical excitability in the contralateral hemisphere (e.g.,to treat stroke).

Daily transcranial direct current stimulation (tDCS) leads to greater increases in cortical excitability than second daily transcranial direct current stimulation - Corrected Proof

Angelo Alonzo, Joseph Brassil, Janet L. Taylor, Donel Martin, Colleen K. Loo — 2011-05-25

Background: Evidence from recent clinical trials suggests that transcranial direct current stimulation (tDCS) may have potential in treating neuropsychiatric disorders. However, the optimal frequency at which tDCS sessions should be administered is unknown.Objective/Hypothesis: This study investigated the effects of daily or second daily tDCS sessions on motor cortical excitability, over a 5-day period.Methods: Twelve healthy volunteers received daily or second daily sessions of tDCS to the left primary motor cortex over the study period, in a randomized, intraindividual crossover design. Motor cortical excitability was assessed before and after tDCS at each session through responses to transcranial magnetic stimulation.Results: Over a fixed 5-day period, tDCS induced greater increases in MEP amplitude when given daily rather than second daily. Analyses showed that this difference reflected greater cumulative effects between sessions rather than a greater response to each individual tDCS session.Conclusions: These results demonstrate that in the motor cortex of healthy volunteers, tDCS alters cortical excitability more effectively when given daily rather than second daily over a 5-day period.

Novel attempts to optimize vagus nerve stimulation parameters on serotonin neuronal firing activity in the rat brain - Corrected Proof

Stella Manta, Mostafa El Mansari, Pierre Blier — 2011-05-12

Background: Vagus nerve stimulation (VNS) is indicated for treatment-resistant epilepsy and depression. Electrophysiologic recordings in the rat brain have shown that VNS promptly increases the firing rate of NE neurons and subsequently that of 5-HT neurons. Thus far, it appears that the standard stimulation parameters currently used in depressed patients produce an optimal activation of 5-HT neurons.Objective/Hypothesis: This study was therefore aimed at investigating additional alterations of stimulation parameters to optimize VNS efficacy to further increase 5-HT neuronal activity.Methods: Rats were implanted with a VNS device and stimulated for 14 days using standard (0.25 mA/20 Hz/500 microseconds/30 seconds ON-5 minutes OFF, continuously) or various stimulation parameters: extension of the OFF period (30 seconds ON every 10 to 30 minutes), the OFF and ON periods, discontinuous stimulation (12 hours per day using standard parameters), and burst stimulation modes. Rat dorsal raphe 5-HT neurons were recorded under chloral hydrate anesthesia.Results: Both 12-hour stimulation periods for 14 days, and the 30-second stimulation every 10 or 15 minutes significantly increased the firing activity of 5-HT neurons to the same extent as standard parameters while the 30-minute intervals were ineffective. Stimulations in a burst mode and the pseudo-one-pulse stimulations also significantly increased 5-HT neuronal activity.Conclusions: These results indicate that less stimulation is sufficient to achieve the same VNS efficacy on 5-HT neuronal firing. These data may be relevant for patients using VNS because these new parameters could minimize or prevent side effects and increase battery life of the stimulator.

Epidural electrical stimulation to improve chronic poststroke aphasia: A 5-year follow-up - Corrected Proof

Anne Balossier, Olivier Etard, Chloé Descat, Denis Vivien, Evelyne Emery — 2011-05-11

Background: Aphasia is an incapacitating deficit experienced by almost 25% of patients after a left hemispheric ischemic stroke. Spontaneous recovery is considered to be limited to a period of 3 to 6 months. Although speech therapy performed during the first weeks may speed up this process and enhance its outcome, beyond this period it fails to change the global prognosis.Objective: We report a case of an unusual recovery of nonfluent chronic poststroke aphasia subsequent to extradural cortical stimulation.Methods: A right-handed woman experienced aphasia and drug-resistant central poststroke facial pain after a left superficial Sylvian ischemic stroke at the age of 58 years old. Four years after the stroke, the patient was included in a clinical trial to establish the efficiency of epidural electric stimulation on neuropathic pain. As an improvement in her language performance was noted, a speech evaluation was added to the initial protocol to quantify the benefit. Twelve months after the surgical implantation, pain and language performance were assessed in a double-blind manner during two consecutive 1-month periods when the stimulator was randomly enabled or disabled. The same evaluation was performed after 5 years of stimulation.Results: Eventually, epidural electric stimulation significantly and sustainably improved her lexical access and speech fluency.Conclusions: Cortical stimulation may offer a new approach for the treatment of late chronic poststroke aphasia.

Effects of repeated electroconvulsive shock on methamphetamine-induced behavioral abnormalities in mice - Corrected Proof

Yu-Lin Chao, Hwei-Hsien Chen, Chia-Hsiang Chen — 2011-05-11

Background: Methamphetamine abuse and addiction can lead to impaired cognition and psychosis, and there is no effective treatment for methamphetamine-induced mental illnesses.Objective: 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.Methods: 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.Results: 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.Conclusions: 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.

Left lateralizing transcranial direct current stimulation improves reading efficiency - Uncorrected Proof

2011-05-09

Background: Poor reading efficiency is the most persistent problem for adults with developmental dyslexia. Previous research has demonstrated a relationship between left posterior temporal cortex (pTC) function and reading ability, regardless of dyslexia status.Objective/Hypothesis: In this study, we tested whether enhancing left lateralization of pTC using transcranial direct current stimulation (tDCS) improves reading efficiency in adults without dyslexia.Method: Twenty-five right-handed adults with no history of learning disorder participated. Real and sham “Left lateralizing” tDCS were applied to the pTC in separate sessions. Standardized word and nonword reading tests were given immediately after stimulation.Results: Modeling of the induced electrical field confirmed that tDCS was likely to increase left pTC excitability and reduce right pTC excitability as intended. Relative to sham, real tDCS induced improvements in word reading efficiency in below average readers.Conclusions: Enhancing left lateralization of the pTC using tDCS improves word reading efficiency in below-average readers. This demonstrates that left lateralization of the pTC plays a role in reading ability, and provides stimulation parameters that could be used for a trial of tDCS in adults with developmental dyslexia. Such short-term gains could amplify the effect of appropriate reading interventions when performed in conjunction with them.

Altered neurophysiologic response to intermittent theta burst stimulation in Tourette syndrome - Corrected Proof

Steve W. Wu, Donald L. Gilbert — 2011-05-03

Background: The motor system in Tourette syndrome has been found to be abnormal in previous fine-motor and neurophysiologic studies.Objective: This novel pilot study uses repetitive transcranial magnetic stimulation as a method to characterize the neurophysiology of the motor system in Tourette syndrome.Method: We investigated the modulation of cortical excitability in adult Tourette syndrome patients by measuring motor-evoked potential amplitudes before and after applying intermittent theta burst transcranial magnetic stimulation.Results: Motor-evoked potential amplitude changes over 1 and 10 minutes after intermittent theta burst transcranial magnetic stimulation were greater in 11 healthy controls than 10 adult patients with Tourette syndrome (P = 0.004).Conclusions: This altered neurophysiologic response to intermittent theta burst stimulation may contribute to the understanding of motor cortical mechanisms in Tourette syndrome.

Lack of clinically detectable acute changes on autonomic or thermoregulatory functions in healthy subjects after transcranial direct current stimulation (tDCS) - Corrected Proof

Ronney Jorge S. Raimundo, Carlos E. Uribe, Joaquim P. Brasil-Neto — 2011-04-27

Background: 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.Objective/Hypothesis: 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.Methods: 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.Results: A repeated-measures, mixed-design ANOVA showed significant changes in hand skin temperature (p=0.005) and cortisol levels (p < 0.001) after both real and sham stimulation. There were no statistically significant changes in any of the other measurements.Conclusions: 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.

Tremor-specific neuronal oscillation pattern in dorsal subthalamic nucleus of parkinsonian patients - Corrected Proof

2011-04-27

Background: Subthalamic nucleus (STN) deep brain stimulation effectively improves parkinsonian symptoms. It is hypothesized that distinct functional territories with different neurophysiologic activity within the STN relate to different symptoms.Objective: The aim of the study was to identify distinctive characteristics of STN neuronal activity related to tremor by directly comparing tremor sides with no-tremor sides. In addition, we studied the spatial pattern of frequency distributions within the STN in more detail.Methods: We analyzed intraoperative STN single/multiunit recordings from 33 tremor sides and 23 no-tremor sides. STN tracks were normalized to a length of 1 and subdivided into eight successive layers. The power spectral density was split into six frequency bands: theta (3-8 Hz), alpha (9-12 Hz), lower beta (13-20 Hz), upper beta (21-30 Hz), lower gamma (31-59 Hz), and upper gamma (60-100 Hz).Results: Tremor sides presented predominant theta frequency oscillations in the most dorsal layers of the STN, whereas in no-tremor sides beta frequencies predominated. Oscillatory activity was stronger in the dorsal STN than in the ventral, and this pattern was specific for frequencies in the theta, alpha, and beta bands, but not in the gamma bands.Conclusions: Our study supports the hypothesis that the presence of tremor is associated with a distinctive neuronal oscillations pattern. In particular, we demonstrate the specificity of the association of theta frequencies in the dorsal STN with tremor. Identification of symptom-specific characteristics of intraoperative microrecordings in the STN may lead to refinement of targeting for each patient, tailored to the specific clinical presentation.

Efficacy and safety of bifocal tDCS as an interventional treatment for refractory schizophrenia - Corrected Proof

2011-04-25

To the Editor: Despite advances in pharmacotherapy, some disabling symptoms remain refractory in 30% of patients with schizophrenia such as auditory hallucinations (AH) and negative symptoms. In this context, peripheral neurostimulation techniques have been proposed to curtail these symptoms by modulating the abnormal cortical activity reported in neuroimaging studies. Thus: (1) “activating” high-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (l-DLPFC) could improve refractory negative symptoms; (2) “inhibitory” rTMS to the left temporoparietal cortex (l-TPC) could produces sustained reductions in resistant AH. However, these effects were transitory and nonspecific.

The relationship between TMS measures of functional properties and DTI measures of microstructure of the corticospinal tract - Corrected Proof

Annemarie Hübers, Johannes C. Klein, Jun-Suk Kang, Rüdiger Hilker, Ulf Ziemann — 2011-04-21

Background: Recently, a link between resting motor threshold (RMT) and local tissue microstructure, as indexed by fractional anisotropy (FA), was demonstrated in large parts of white matter. However, regions showing such correlations were generally found outside of the corticospinal tract (CST). Therefore, the question arises whether other electrophysiologic measurements could be more locally related to microstructural properties of the CST. In this study, we explored the relationship between such measurements and regional FA in a group of healthy volunteers.Objective/Hypothesis: We hypothesized that RMT might be more related to an overall susceptibility of white matter to TMS, whereas other electrophysiologic markers might be more specifically related to properties of the CST only.Methods: Thirty-seven subjects were included. We studied RMT, active motor threshold (AMT), intensity to evoke a motor-evoked potential (MEP) of 1 mV (S1mV), MEP input-output curve (IO-curve), and central motor conduction time (CMCT) using transcranial magnetic stimulation, and FA of the corticospinal tract using diffusion tensor magnetic resonance imaging. We performed voxel-wise and TBSS correlation analysis between these electrophysiologic measurements and FA. In addition, we tested for significant correlation between these parameters and mean diffusivity (MD).Results: On voxel-wise analysis, we did not detect significant correlations between any electrophysiologic parameter (RMT, AMT, S1mV, IO curve slope, CMCT) and FA. With TBSS, we detected correlations between FA and bilateral AMT, as well as left-hemispheric S1mV, but these correlations were found in locations unlikely to contribute to motor pathways.Conclusions: Although a relationship between structure and function has been shown in many other regions of the brain, it seems to be much more challenging to demonstrate such a relationship in the CST of healthy subjects.

The number of full-sine cycles per pulse influences the efficacy of multicycle transcranial magnetic stimulation - Corrected Proof

2011-04-20

Background: Previous studies have shown that the efficacy of transcranial magnetic stimulation (TMS) to excite corticospinal neurons depends on pulse waveform.Objective/Hypotheses: In this study, we examined whether the effectiveness of polyphasic TMS can be increased by using a pulse profile that consists of multiple sine cycles.Methods: In eight subjects, single-pulse TMS was applied to the left primary motor hand area through a round coil attached to a stimulator device that generated polyphasic pulses consisting of one to six full-sine cycles with a cycle length of 86 μs. In different blocks, we varied the number of sine cycles per pulse and recorded the motor-evoked potential (MEP) from the right first dorsal interosseus muscle. For each stimulus type, we determined resting motor threshold (RMT), stimulus-response curve (SRC), and mean MEP amplitude evoked at maximal stimulator output to assess the efficacy of stimulation.Results: Multicycle pulses were more effective than a single full-sine cycle in exciting corticospinal neurons. TMS with multicycle pulses resulted in lower RMT, larger MEP amplitudes at maximal stimulator output and a steeper slope of the SRC relative to a TMS pulse consisting of a single-sine cycle. The increase in efficacy was already evident when two full-sine cycles were used and did not increase further by adding more cycles to the TMS pulse.Conclusions: Increasing the number of full-sine cycles per pulse can improve the efficacy of TMS to excite corticospinal neurons, but there is no simple linear relationship between the number of cycles and TMS efficacy.

A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression - Corrected Proof

Paul B. Fitzgerald, Zafiris J. Daskalakis — 2011-04-19

Background: Repetitive transcranial magnetic stimulation (rTMS) is currently emerging as a new treatment for patients with mood disorders. Research into the use of rTMS for the treatment of patients with depression has been conducted now for a period of greater than 15 years and a considerable body of knowledge has accumulated informing its use.Objective: The aim of this paper was to review the use of various rTMS techniques for the treatment of depression and to provide practical suggestions to address the common issues encountered in the prescribing and administration of rTMS treatment.Methods: These suggestions have been informed both by a review of the relevant literature and the experience of the authors in the treatment of many patients with depression with rTMS over a period of 10 years.Results and Conclusions: High-frequency rTMS applied to the left dorsolateral prefrontal cortex, using a set of parameters very similar to those originally described in the mid-1990s, is an effective treatment for patients with major depressive disorder. Other forms of stimulation, such as low-frequency stimulation applied to the right prefrontal cortex and bilateral approaches, may prove valuable but require evaluation in larger trials. Significant benefit appears likely to accumulate through the use of methods that involve a more reliable targeting of prefrontal brain regions. Suggestions are also made around the use of rTMS treatment as a maintenance therapy and in specific illness subgroups.

Improved receptive and expressive language abilities in nonfluent aphasic stroke patients after application of rTMS: an open protocol case series - Corrected Proof

2011-04-14

Background: 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.Objective/Hypothesis: 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.Results: 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.Conclusions: 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.