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

Polarity-dependent effect of low-frequency stimulation on amygdaloid kindling in rats - Uncorrected Proof

2012-05-17

Abstract: Background: Low-frequency stimulation (LFS, <5 Hz) has been proposed as an alternative option for the treatment of epilepsy. The stimulation pole, anode and cathode, may make different contributions to the anti-epileptic effect of LFS.Objective: To determine whether electrode polarity influences the anti-epileptic effect of LFS at the kindling focus in amygdaloid kindling rats.Methods: The effect of bipolar and monopolar (or unipolar) LFS at the amygdala in different polarity directions on amygdaloid kindling acquisition, kindled seizures and electroencephalogram (EEG) were tested.Results: Bipolar LFS in the same direction of polarity as the kindling stimulation but not in the reverse direction retarded kindling acquisition. Anodal rather than cathodal monopolar LFS attenuated kindling acquisition and kindled seizures. Bipolar LFS showed a stronger anti-epileptic effect than monopolar LFS. Furthermore, anodal LFS (both bipolar and monopolar) decreased, while cathodal LFS increased the power of the EEG from the amygdala; the main changes in power were in the delta (0.5–4 Hz) band, which was specifically increased during kindling acquisition.Conclusions: Our results provide the first evidence that the effect of LFS at the kindling focus on amygdaloid kindling in rats is polarity-dependent, and this may be due to the different effects of anodal and cathodal LFS on the activity in the amygdala, especially on the delta band activity. So, It is likely that the electrode polarity, especially that for anodal current, is a key factor affecting the clinical effects of LFS on epilepsy.

Differences between a single session and repeated sessions of 1 Hz TMS by double-cone coil prefrontal stimulation for the improvement of tinnitus - Uncorrected Proof

Sven Vanneste, Dirk De Ridder — 2012-05-16

Abstract: Tinnitus related distress is associated with increased activity in the anterior cingulate cortex (ACC). In a recent study, it was demonstrated that a single session of low frequency prefrontal TMS using a double-cone coil (DCC) modulating the ACC (AC/DC TMS, anterior cingulate cortex targeted modulation by Double-Cone coil) yields a transient improvement in subjects with chronic tinnitus. An increasing number of studies demonstrated that repeated sessions of low frequency TMS to the temporoparietal area can significantly improve tinnitus complaints. Our aim is to determine the extent to which repeated sessions of AC/DC TMS can modulate tinnitus in comparison to a single session. Seventy-three tinnitus patients received a single (N = 46) or repetitive (N = 27) session(s) of TMS using a DCC placed over the prefrontal cortex. Our results indicate that both single sessions as well as multiple sessions (i.e. 8 sessions) of AC/DC TMS suppress both tinnitus distress (respectively 7.60% vs. 26.19%) and tinnitus intensity (respectively 7.12% vs. 19.60%) transiently. It was further shown that multiple sessions of AC/DC TMS generate a higher suppression effect in comparison to a single session of AC/DC TMS and that more patients responded to repeated sessions of 1 Hz stimulation in comparison to a single session. Our findings give further support to the fact that non-auditory areas are involved in tinnitus intensity and tinnitus distress and that more patients respond to repeated sessions with a higher suppression effect in comparison to patients who received a single session, suggesting that the approach of daily TMS sessions is relevant.

High frequency stimulation can suppress globally seizures induced by 4-AP in the rat hippocampus: An acute in vivo study - Uncorrected Proof

Chia-Chu Chiang, Chou-Ching K. Lin, Ming-Shaung Ju, Dominique M. Durand — 2012-05-16

Abstract: Background: High frequency stimulation (HFS) on the hippocampus can locally suppress epileptiform activity in-vitro and decrease seizure frequency in vivo. In-vitro HFS on the ventral commissural tract, a novel target, was shown to block the axonal conduction and suppress activity in the CA1 and CA3 neuron.Objective: To study the spatial extent of seizure suppression by HFS applied on the tract and focus site in an in vivo experiment.Methods: Five adult Sprague–Dawley rats were recruited. Six electrodes were placed on the septal, middle, and temporal hippocampus bilaterally to simultaneously record seizure activity in the entire hippocampus. Seizure activity was induced by injecting 4-aminopyridine (4-AP) into the right middle part of the hippocampus. Following induction, HFS (100 Hz) was applied to the tract and the focus site at 100, 300 and 500 μA.Results: The induced seizure activity was dominated by two patterns, high frequency spiking and pseudo-periodic spikes. Either tract or focus site stimulation could generate suppression of only the pseudo-periodic spikes. The suppression rates were dependent on stimulation amplitude (P < 0.005, chi square test). However, HFS also caused conversion of the seizure pattern. The conversion rates increased with higher stimulation amplitudes and were higher with focus site stimulation (P < 0.01, Fisher's exact test).Conclusions: The results of this study have two practical implications , both tract and focus site stimulation can produce global suppression of hippocampus and the choice of stimulation parameters is critical in order to produce suppression, but not conversion, of seizure pattern.

Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: A pilot study - Uncorrected Proof

2012-05-14

Abstract: Background: We demonstrated that prolonged transcranial magnetic intermittent theta burst stimulation (iTBS, 1200 pulses/session = iTBS1200) produces longer-lasting facilitation in corticospinal excitability than ordinary form of iTBS in healthy subjects.Objective: Here we show the safety and small-scale efficacy of iTBS1200 over ipsilesional primary motor cortex (M1) in subacute stroke patients.Methods: Twelve patients with first-time, subacute ischemic stroke of the middle cerebral artery were randomized into 2 groups that received 10 daily sessions of either iTBS1200 or sham stimulation (n = 6/group) over ipsilesional M1 hand region in addition to medical and rehabilitation treatments. The primary outcome measures were safety and tolerability. The secondary outcome measures included the National Institute of Health Stroke Scale (NIHSS), Upper Extremity Fugl–Meyer Test (UE-FMT), Action Research Arm Test (ARAT), active motor thresholds (aMT)/motor-evoked potentials (MEPs) from the extensor carpi radialis (ECR), and magnetoencephalography on post-intervention day 1 and post-stroke day 60.Results: iTBS or sham stimulation was well tolerated by all patients without seizures or significant adverse effects. Compared with the matched controls, the iTBS group showed measurable improvements in the NIHSS and the proximal UE-FMT scores on post-intervention day 1 and post-stroke day 60. Nevertheless, the hand ARAT scores, aMT and MEPs from the paretic ECR were not different between groups. Post-movement beta synchronization increased over iTBS-conditioned M1 on post-intervention day 1 in testable patients.Conclusion: Repetitive sessions of iTBS1200 over ipsilesional M1 of subacute stroke patients are safe and the potential benefits encourage a larger trial to determine the efficacy in stroke patients. (ClinicalTrials.gov: NCT-01323881).

Cerebellar rTMS stimulation may induce prolonged clinical benefits in essential tremor, and subjacent changes in functional connectivity: An open label trial - Uncorrected Proof

2012-05-14

Abstract: Background: Cerebello-thalamo-cortical (CTC) pathways dysfunction is involved in pathological oscillations causing tremor in essential tremor (ET). Low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can effectively modulate the cerebellar output.Objective: As one session of rTMS can induce a brief improvement, we hypothesized that repeated sessions might have a cumulative and potentially long-term therapeutic effect on ET. We assessed, in an open label trial, the efficacy of one-week rTMS treatment on tremor and on the motor-CTC dysfunction in ET patients.Methods: Resting-state fMRI functional connectivity was used as an indicator of CTC network integrity in 11 ET patients and 11 healthy subjects. Resting-state fMRI connectivity was quantified at baseline in patients and control subjects between the cerebellum and the motor network, and between the cerebellum and the default brain network (DBN) taken as control. The fMRI study was repeated in patients after 5 days of bilateral 1 Hz rTMS applied to the posterior cerebellar cortex. Tremor was assessed clinically (Fahn–Tolosa–Marin scale) and quantified using electromyographic and accelerometric recordings at baseline (day 1, before the cerebellar stimulation) and after the end of the cerebellar stimulation period at day 5, day 12 and day 29.Results: Repeated rTMS over the cerebellum significantly improved total and specific (tremor, drawing, functional disability) scores, and reduced tremor amplitude (P 0.909), but not in the DBN. The effects persisted for 3 weeks after the last session.Conclusion: Cerebellar stimulation could be an effective treatment option for patients with severe essential tremor.

Anodal transcranial direct current stimulation (tDCS) over supplementary motor area (SMA) but not pre-SMA promotes short-term visuomotor learning - Uncorrected Proof

2012-05-09

Abstract: Background: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability and thereby influencing motor behaviour and learning.Hypothesis: While there is increasing knowledge about the importance of the primary motor cortex (M1) in short- and long-term motor skill learning, little is known about the role of secondary motor areas such as the supplementary and pre-supplementary motor area (SMA/pre-SMA) especially in short-term motor skill learning. Since SMA but not pre-SMA is directly connected to M1, we hypothesize that anodal tDCS over SMA but not pre-SMA will facilitate motor skill learning.Methods: We applied anodal tDCS (tDCSanodal) over left SMA, pre-SMA or M1 (n = 12 in each group) while subjects performed a sequential pinch force task (SPFT) with their right hand and compared SPFT performance relative to sham (tDCSsham).Results: For the first time, we could show that apart from tDCSanodal over left M1 also SMA but not pre-SMA stimulation promotes short-term motor skill learning relative to tDCSsham.Conclusions: Our findings provide novel evidence about the role of SMA in short-term motor skill learning. This knowledge might be beneficial in developing hypothesis-driven clinical studies in neurorehabilitation.

The effect of transcutaneous vagus nerve stimulation on pain perception – An experimental study - Uncorrected Proof

2012-05-09

Abstract: Background: Recent preclinical work strongly suggests that vagus nerve stimulation efficiently modulates nociception and pain processing in humans. Most recently, a medical device has offered a transcutaneous electrical stimulation of the auricular branch of the vagus nerve (t-VNS) without any surgery.Objective: Our study investigates whether t-VNS may have the potential to alter pain processing using a controlled design.Methods: Different submodalities of the somatosensory system were assessed with quantitative sensory testing (QST) including a tonic heat pain paradigm in 48 healthy volunteers. Each subject participated in two experimental sessions with active t-VNS (stimulation) or sham t-VNS (no stimulation) on different days in a randomized order (crossed-over). One session consisted of two QST measurements on the ipsi- and contralateral hand, each before and during 1 h of a continuous t-VNS on the left ear using rectangular pulses (250 μS, 25 Hz).Results: We found an increase of mechanical and pressure pain threshold and a reduction of mechanical pain sensitivity. Moreover, active t-VNS significantly reduced pain ratings during sustained application of painful heat for 5 min compared to sham condition. No relevant alterations of cardiac or breathing activity or clinical relevant side effects were observed during t-VNS.Conclusions: Our findings of a reduced sensitivity of mechanically evoked pain and an inhibition of temporal summation of noxious tonic heat in healthy volunteers may pave the way for future studies on patients with chronic pain addressing the potential analgesic effects of t-VNS under clinical conditions.

Differential effects of left parietal theta-burst stimulation on order and quantity processing - Corrected Proof

2012-04-30

Abstract: Numbers can be used to represent different meanings, including order information (‘Steve lives at house number 24’) and quantity (‘Steve is paid 24 pounds’). The few previous neuroimaging studies that investigated order and quantity processing reported conflicting evidence as to whether same or partially overlapping brain systems are engaged in these processes. Such inconsistencies may be related to the use of neuroimaging techniques which do not allow causal inference regarding brain-behaviour relationships. To overcome this problem, the present study employed continuous theta-burst stimulation (TBS) to investigate whether interference to either the left or right parietal regions affected order and quantity in similar or different ways. Results revealed that following TBS to the left intraparietal sulcus, quantity processing was impaired and order facilitated; TBS to the contralateral brain region led to no specific effects in either order or quantity processing. These findings suggest that there are at least partially different neuronal populations involved in order and quantity processing, and that the left parietal cortex is critical for both processes.

Double-blind randomized controlled study showing symptomatic and cognitive superiority of bifrontal over bitemporal electrode placement during electroconvulsive therapy for schizophrenia - Corrected Proof

2012-04-25

Abstract: Background: Several studies show that bifrontal electrode placement produces relatively fewer cognitive adverse effects than bitemporal placement during electroconvulsive therapy (ECT) in depression. There are no reports comparing these electrode placements in schizophrenia.Objectives: This study compared the clinical and cognitive effects of bifrontal and bitemporal electrode placements in schizophrenia patients referred for electroconvulsive therapy (ECT).Methods: 122 schizophrenia patients who were prescribed ECT were randomized to receive ECT with either bifrontal (BFECT; n = 62) or bitemporal (BTECT; n = 60) placement. Their concomitant anti-psychotic medications and the number of ECT sessions were not controlled. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS), Bush-Francis Catatonia Rating Scale (BFCRS), and the Nurse Observation Scale for Inpatient Evaluation (NOSIE). Cognitive functions were assessed 24-h after the final ECT using a battery of tests. Clinical improvement was compared using chi-square test, repeated measures ANOVA and analysis of covariance (ANCOVA). Cognitive adverse effects were compared using t-test.Results: At the end of 2 weeks (after 6 ECT sessions) 63% and 13.2% of BFECT and BTECT patients respectively had met the response criterion for BPRS (40% reduction in total score; OR = 20.8; 95% CI = 3.61–34.33). BFECT patients showed significantly faster clinical response on BPRS (Time × Group interaction effect: P = 0.001), BFCRS (P < 0.001) and the NOSIE total assets score (P = 0.003). ANCOVA using baseline scores as covariates and treatment-resistance status as between-subject factor showed that BFECT patients had significantly greater improvement in all measures. BFECT patients had significantly higher PGI-memory-scale total score than BTECT patients (t = 5.16; P < 0.001). They also showed superior performance in other cognitive measures.Conclusions: BFECT results in superior clinical and cognitive outcomes than BTECT in schizophrenia patients referred for ECT.

Commentary on: Deng et al., Electric field depth-focality tradeoff in transcranial magnetic stimulation: Simulation comparison of 50 coil designs - Corrected Proof

Yiftach Roth, Gaby S. Pell, Abraham Zangen — 2012-04-25

The review by Deng et al. in this edition modeling 50 theoretical and practical coils is a comprehensive and important article that compares the electric field depth-focality profile of various coils using a spherical head model. The use of a spherical model facilitates the definition of a simple and universal metric framework for a convenient comparison of the depth and focality characteristics of all TMS coils. Yet, the gain in generality and simplicity of this approach comes at the expense of losing some valuable features that must be acknowledged.

Accelerometers for ECT seizures? - Corrected Proof

Saxby Pridmore — 2012-04-25

ECT is bedeviled by lack of agreed objective seizure descriptors. A traditional descriptor is seizure length. However, the identification of seizure end-point remains problematic.

Nucleus of the solitary tract chemical stimulation induces extracellular norepinephrine release in the lateral and basolateral amygdala - Corrected Proof

Nadia Edith García-Medina, María Isabel Miranda — 2012-04-20

Abstract: The NTS catecholaminergic neurons, activated by a variety of afferent stimuli, are ideally situated to coordinate afferent signaling to multiple brain regions. In particular, there is evidence that systemic epinephrine injections induce a significant increase of norepinephrine (NE) in the amygdala during enhanced memory, which can be disrupted by NTS chemical blockade or interruption of vagal afferents. The present experiment was conducted to obtain information about the levels of NE release induced by activation of the whole NTS, which projects to the lateral and basolateral amygdala. Therefore, we compared NE levels before and after general stimulation of the NTS and the amygdala in anesthetized rats, without any behavioral or vagal stimulation, to find out the degree of noradrenergic activation modulated by the NTS through all its projections to the lateral and basolateral amygdala, as well as the degree of noradrenergic activation which may occur locally in the amygdala through rapid and general activation of this structure.

Introduction: Brain stimulation in cognitive neuroscience - Corrected Proof

Shirley Fecteau, Vincent Walsh — 2012-04-20

It is a privilege to have been invited to commission articles for this special issue of Brain Stimulation. Under the guidance of Mark George and the deputy editors, the Journal has rapidly become the publication of record for all aspects of electromagnetic brain stimulation. Part of the success lies in bringing together diverse approaches to brain stimulation that necessarily exposes cognitive neuroscientists to clinicians, experimenters to modellers and all the brain stimulation communities to new technical and methodological developments. One of the goals of this issue is to illustrate the connection and value of cognitive neuroscience to other branches of brain stimulation science. The quality of the papers we have attracted and accepted bears testimony to the range and maturity of brain stimulation work relevant to cognitive neuroscience and we are grateful to all the authors for their efforts.

Corticospinal excitability in patients with anoxic, traumatic, and non-traumatic diffuse brain injury - Corrected Proof

2012-04-19

Abstract: Background: Transcranial magnetic stimulation (TMS) have been frequently used to explore changes in motor cortex excitability in stroke and traumatic brain injury, while the extent of motor cortex reorganization in patients with diffuse non-traumatic brain injury remains largely unknown.Objective/hypothesis: It was hypothesized that the motor cortex excitability would be decreased and would correlate to the severity of brain injury and level of functioning in patients with anoxic, traumatic, and non-traumatic diffuse brain injury.Methods: TMS was applied to primary motor cortices of 19 patients with brain injury (5 traumatic and 14 non-traumatic causes; on average four months after insult), and 9 healthy controls. The test parameters included resting motor threshold (RMT), short intracortical inhibition (SICI), intracortical facilitation (ICF), and short latency afferent inhibition (SAI). Excitability parameters were correlated to the severity of brain injury measured with Glasgow Coma Scale and the level of functioning assessed using the Ranchos Los Amigos Levels of Cognitive Functioning Assessment Scale and Functional Independence Measure.Results: The patient group revealed a significantly decreased SICI and SAI compared to healthy controls with the amount of SICI correlated significantly to the severity of brain injury. Other electrophysiological parameters did not differ between the groups and did not exhibit any significant relationship with clinical functional scores.Conclusions: The present study demonstrated the impairment of the cortical inhibitory circuits in patients with brain injury of traumatic and non-traumatic aetiology. Moreover, the significant correlation was found between the amount of SICI and the severity of brain injury.

Subcortical substrates of TMS induced modulation of the cortico-cortical connectivity - Corrected Proof

2012-04-16

Abstract: Background: Transcranial magnetic stimulation (TMS) can modulate transiently the physiological brain oscillations, e.g. the alpha rhythm. It has been hypothesized that this effect is not limited to the stimulated region but involves subcortical and distant cortical areas.Methods: We applied single pulse TMS to the primary motor cortex (M1) of healthy subjects to interfere the cortical oscillatory activity recorded by simultaneous EEG and calculated the cortico-cortical coherence and power in the alpha and beta band. To study the structural substrate of the functional connectivity we performed diffusion tensor imaging and fractional anisotropy analysis (FA). To capture the pathways involved we applied probabilistic tractography to reconstruct the entire network.Results: Suprathreshold TMS of M1 induced a consistent enhancement of interhemispheric cortico-cortical alpha band coherence that lasted ca. 175 ms. after the pulse has been applied. The changes were confined to the interhemispheric central EEG electrodes (i.e. C3-C4). There were no consistent changes in the beta band. Power analysis revealed a longer lasting increase in the beta band after TMS pulses. A cluster in the contralateral thalamus showed a linear relationship between regional FA and TMS induced change in alpha band coherence. Probabilistic tractography presents the transcallosal and the contralateral thalamocortical pathways as essential for the observed oscillatory synchronisation.Conclusion: TMS induces an enhancement of oscillatory interaction between corresponding central regions of both hemispheres in the alpha band. The contralateral thalamus, transcallosal fibres and the contralateral thalamocortical pathways may constitute critical brain structures mediating the TMS induced change in oscillatory coupling.

Extremely low-frequency electromagnetic fields activate the antioxidant pathway Nrf2 in a Huntington's disease-like rat model - Corrected Proof

2012-04-16

Abstract: 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.

rTMS in the management of allodynia from brachial plexus injuries - Corrected Proof

Federica Bertolucci, Chiara Fanciullacci, Bruno Rossi, Carmelo Chisari — 2012-04-16

Here we describe the case of a 35-year-old woman suffering from allodynia due to a traumatic brachial plexus injury treated by means of high frequency rTMS. The patient had a car accident and afterwords she reported a polytrauma with head and cervical trauma with fractures of the laminae of C7 and T1, double fracture of the radio and complete paralysis of the right brachial plexus. CT and MRI documented hemorrhagic imbibition of the right supraclavicular soft tissues and post-traumatic swelling of the brachial plexus' roots from C6-C7 to D1-D2 and thickening of the other roots. Electromyography was suggesting for a multilevel suffering (from C4 to T1).

Parieto-motor functional connectivity is impaired in Parkinson's disease - Corrected Proof

2012-04-16

Abstract: Background: Bradykinesia in Parkinson's disease is associated with a difficulty in selecting and executing motor actions, likely due to alterations in the functional connectivity of cortico-cortical circuits.Objective/hypothesis: Our aims were to analyse the functional interplay between the posterior parietal cortex and the ipsilateral primary motor area in Parkinson's disease using bifocal transcranial magnetic stimulation, to evaluate its modulation by dopaminergic treatment and its relationship to a simple choice reaction task.Methods: We studied 12 Parkinson's disease patients with and without dopaminergic treatment and 12 healthy controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right posterior parietal cortex and the right primary motor area using different conditioning stimulus intensities and interstimulus intervals. Reaction and movement times were studied by a simple choice reaction task.Results: In controls, we observed a significant facilitation of motor evoked potential amplitudes at 4 ms interstimulus interval when conditioning stimulus intensity was set to 90% of resting motor threshold. This functional interaction was not observed in Parkinson's disease patients without dopaminergic treatment and was not restored with treatment. Moreover, correlation analyses revealed that Parkinson's disease patients with less impaired parieto-motor interaction were faster in executing reaching movements in a choice reaction time task, suggesting that the functional parieto-motor impairment described here could be related to bradykinesia observed in Parkinson's disease patients.Conclusions: Parieto-motor functional connectivity is impaired in Parkinson's disease. The reduced efficacy of this connection could be related to presence of bradykinesia previously observed in Parkinson's disease.

Task-specific facilitation of cognition by cathodal transcranial direct current stimulation of the cerebellum - Corrected Proof

Paul A. Pope, R. Chris Miall — 2012-04-05

Abstract: A role for the cerebellum in cognition is controversial, but it is a view that is becoming increasingly popular. The aim of the current study was to investigate this issue using transcranial Direct Current Stimulation (tDCS) during two cognitive tasks that require comparable motor skills, but different levels of working memory and attention. Three groups of twenty-two participants each performed the Paced Auditory Serial Addition Task (PASAT) and a novel variant of this task called the Paced Auditory Serial Subtraction Task (PASST), together with a verb generation task and its two controls, before and after the modulation of cortico-cerebellar connectivity using anodal or cathodal tDCS over the cerebellum. Participants’ performance in the difficult PASST task significantly improved after cathodal stimulation compared to sham or anodal stimulation. Improvement in the easier PASAT was equal across all three stimulation conditions. Improvement in verbal response latencies were also greatest during the PASST task after cathodal stimulation, compared to sham and anodal stimulation, and became less variable. Results for the verb generation task complimented those for the PASST, such that the rate and consistency of participants’ verbal responses were facilitated by cathodal stimulation, compared to sham and anodal stimulation. These findings suggest that DC stimulation over the right cerebellum affects working memory and attention differently depending on task difficulty. They support a role for the cerebellum in cognitive aspects of behaviour, whereby activity in the prefrontal cortex is likely dis-inhibited by cathodal tDCS stimulation over the right cerebellar cortex, which normally exerts an overall inhibitory tone on the cerebral cortex. We speculate that the cerebellum is capable of releasing cognitive resources by dis-inhibition of prefrontal regions of cerebral cortex, enhancing performance when tasks become demanding.

Effect of continuous theta burst stimulation of the right dorsolateral prefrontal cortex on cerebral blood flow changes during decision making - Corrected Proof

2012-04-05

Abstract: Decision making is a cognitive function relaying on a complex neural network. In particular, the right dorsolateral prefrontal cortex (DLPFC) plays a key role within this network. We used positron emission tomography (PET) combined with continuous theta burst transcranial magnetic stimulation (cTBS) to investigate neuronal and behavioral changes in normal volunteers while performing a delay discounting (DD) task. We aimed to test whether stimulation of right DLPFC would modify the activation pattern of the neural circuit underlying decision making during the DD task and influence discounting behavior.We found that cTBS of the right DLPFC influenced decision making by reducing impulsivity and inducing participants to favor large but delayed rewards instead of immediate but small rewards. Stimulation also affected activation in several prefrontal areas associated with DD. In particular, we observed a reduced regional cerebral blood flow (rCBF) in the ipsilateral DLPFC (BA 46) extending into the rostral part of the prefrontal cortex (BA 10) as well as a disrupted relationship between impulsivity (k-value) and rCBF in these and other prefrontal areas.These findings suggest that transcranial magnetic stimulation of the DLPFC influences the neural network underlying impulsive decision making behavior.

Progressive enhancement of alpha activity and visual function in patients with optic neuropathy: A two-week repeated session alternating current stimulation study - Corrected Proof

2012-04-05

Abstract: Introduction: Repetitive transorbital alternating current stimulation (rtACS) can improve visual deficits in patients with optic nerve damage. Recent retrospective results suggest that rtACS enhances oscillatory brain activity. The exact mechanisms of rtACS are unclear and little is known about possibly frequency-specific neural-plastic mechanisms. An association between bandwidth-confined neural-entrainment and vision recovery maximization could offer a novel therapeutic option for patients with optic neuropathy.Objectives: The goal of this prospective open-label study was to investigate if the enhancement of rhythmic brain activity over 10 days of consecutive rtACS stimulation is associated with visual field recovery. The secondary goal was to investigate neurophysiological mechanisms related to frequency dependent adaptive plasticity.Methods: 18 Patients with visual field impairments resulting from pre-chiasmatic partial optic nerve damage received rtACS on 10 consecutive days. Daily, subject-specific treatment parameters (<500 μA, 9–37 Hz, 25–40 min/day) were defined and EEG-spectra collected prior to and after rtACS. Visual field data was collected at day 1 and 10. The change of spectral-power in classic bandwidths were investigated and correlated with visual field deficit recovery.Results: After 10 days of rtACS alpha-power over bilateral occipital electrodes was significantly larger than at baseline (FTime x alpha-power p < 0.01). This effect was progressive over subsequent days of stimulation (cubic-fit, R2 0.70, RMSE 0.008). Perimetric results improved significantly, but they were not associated with changes in alpha-synchronization.Discussion: rtACS can induce cumulative bandwidth-confined changes in brain rhythms over multiple sessions. These findings are in line with the notion of brain-state dependent and bandwidth-confined entrainment as well as rtACS facilitated visual recovery .

Motor mapping of implied actions during perception of emotional body language - Corrected Proof

Sara Borgomaneri, Valeria Gazzola, Alessio Avenanti — 2012-04-05

Abstract: Background: Perceiving and understanding emotional cues is critical for survival. Using the International Affective Picture System (IAPS) previous TMS studies have found that watching humans in emotional pictures increases motor excitability relative to seeing landscapes or household objects, suggesting that emotional cues may prime the body for action.Objective/Hypothesis: Here we tested whether motor facilitation to emotional pictures may reflect the simulation of the human motor behavior implied in the pictures occurring independently of its emotional valence.Methods: Motor-evoked potentials (MEPs) to single-pulse TMS of the left motor cortex were recorded from hand muscles during observation and categorization of emotional and neutral pictures. In experiment 1 participants watched neutral, positive and negative IAPS stimuli, while in experiment 2, they watched pictures depicting human emotional (joyful, fearful), neutral body movements and neutral static postures.Results: Experiment 1 confirms the increase in excitability for emotional IAPS stimuli found in previous research and shows, however, that more implied motion is perceived in emotional relative to neutral scenes. Experiment 2 shows that motor excitability and implied motion scores for emotional and neutral body actions were comparable and greater than for static body postures.Conclusions: In keeping with embodied simulation theories, motor response to emotional pictures may reflect the simulation of the action implied in the emotional scenes. Action simulation may occur independently of whether the observed implied action carries emotional or neutral meanings. Our study suggests the need of controlling implied motion when exploring motor response to emotional pictures of humans.

Dance and emotion in posterior parietal cortex: A low-frequency rTMS study - Corrected Proof

Marie-Hélène Grosbras, Haodan Tan, Frank Pollick — 2012-04-05

Abstract: Background: The neural bases of emotion are most often studied using short non-natural stimuli and assessed using correlational methods. Here we use a brain perturbation approach to make causal inferences between brain activity and emotional reaction to a long segment of dance.Objective/hypothesis: We aimed to apply offline rTMS over the brain regions involved in subjective emotional ratings to explore whether this could change the appreciation of a dance performance.Methods: We first used functional magnetic resonance imaging (fMRI) to identify regions correlated with fluctuating emotional rating during a 4-min dance performance, looking at both positive and negative correlation. Identified regions were further characterized using meta-data interrogation. Low-frequency repetitive TMS was applied over the most important node in a different group of participants prior to them rating the same dance performance as in the fMRI session.Results: FMRI revealed a negative correlation between subjective emotional judgement and activity in the right posterior parietal cortex. This region is commonly involved in cognitive tasks and not in emotional task. Parietal rTMS had no effect on the general affective response, but it significantly (P<0.05 using exact t-statistics) enhanced the rating of the moments eliciting the highest positive judgements.Conclusion: These results establish a direct link between posterior parietal cortex activity and emotional reaction to dance. They can be interpreted in the framework of competition between resources allocated to emotion and resources allocated to cognitive functions. They highlight potential use of brain stimulation in neuro-æsthetic investigations.

Brain stimulation and inhibitory control - Corrected Proof

Chi-Hung Juan, Neil G. Muggleton — 2012-04-04

Abstract: Inhibitory control mechanisms are important in a range of behaviours to prevent execution of motor acts which, having been planned, are no longer necessary or appropriate. Examples of this can be seen in a range of sports, such as cricket and baseball, where the choice between execution and inhibition of a bat swing must be made in a very brief time window. Deficits in inhibitory control have been associated with problems in behavioural regulation in impulsive violence as well as a range of clinical disorders. The roles of various areas, including the frontal eye fields (FEF), the pre-supplementary motor area (pre-SMA) and the inferior frontal gyrus, in inhibitory control have been investigated using an inhibitory control task and both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Typically effects on response inhibition but no effects on response generation have been seen. The contributions of these areas to performance seem to differ with, for example, pre-SMA being involved when the task is relatively novel whereas this is not the case for FEF. The findings from brain stimulation studies offer both insight into which areas are necessary for effective inhibitory control and recent extension of findings for the role of the inferior frontal gyrus illustrate how the specific functions by which these areas contribute may be further clarified. Future work, including making use of the temporal specificity of TMS and combination of TMS/tDCS with other neuroimaging techniques, may further clarify the nature and functions played by the network of areas involved in inhibitory control.

Translational application of neuromodulation of decision-making - Corrected Proof

Jean Levasseur-Moreau, Shirley Fecteau — 2012-04-03

Abstract: Recent cognitive neuroscience studies indicate that noninvasive brain stimulation can modulate a wide spectrum of behaviors in healthy individuals. Such modulation of behaviors provides novel insights into the fundamentals and neurobiology of cognitive functions in the healthy brain, but also suggests promising prospects for translational applications into clinical populations. One type of behavior that can be modulated with noninvasive brain stimulation is decision-making. For instance, brain stimulation can induce more cautious or riskier behaviors. The capacity of influencing processes involved in decision-making is of particular interest because such processes are at the core of human social and emotional functioning (or dysfunctioning). We review cognitive neuroscience studies that have successfully modulated processes involved in decision-making with transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), including risk taking, reward seeking, impulsivity, and fairness consideration. We also discuss potential clinical relevance of these findings for patients who have still unmet therapeutic need and whose alterations in decision-making represent hallmarks of their clinical symptomatology, such as individuals with addictive disorders.

Transcranial brain stimulation studies of episodic memory in young adults, elderly adults and individuals with memory dysfunction: A review - Corrected Proof

Rosa Manenti, Maria Cotelli, Ian H. Robertson, Carlo Miniussi — 2012-03-29

Abstract: Transcranial magnetic and electric stimulation studies examining episodic memory in young participants have established the role of the left prefrontal cortex during encoding and the right prefrontal cortex during episodic retrieval. Furthermore, these techniques have been used to verify the reduction in functional asymmetry in the prefrontal cortex that occurs with ageing, at least during encoding, suggesting the existence of compensatory adjustments for the structural and neurotransmitter loss that occurs with physiological ageing. Nevertheless, it has been shown that several factors can modulate performance based on the type of material or strategy used. It is important to note that although numerous studies have addressed the role of the prefrontal cortex in episodic memory, a number of studies have also demonstrated the involvement of a more distributed neural network sustaining this function involving the temporal lobes and parietal cortices. Finally, it is evident that the use of transcranial stimulation techniques might represent a powerful tool not only for investigating the involvement of cerebral areas in a specific cognitive task but also for designing interventional therapies for individuals with memory impairment.

Enhancing cognitive control components of insight problems solving by anodal tDCS of the left dorsolateral prefrontal cortex - Corrected Proof

Nili Metuki, Tal Sela, Michal Lavidor — 2012-03-27

Abstract: Background: Executive functions play a vital role in semantic processing. Recently, transcranial direct current stimulation (tDCS) over frontal regions associated with cognitive control has been found to enhance verbal insight problem solving. The aim of the current study was to extend our understanding of the cognitive control processes modulating verbal insight problem solving.Hypotheses: Anodal stimulation over the left Dorsolateral Prefrontal Cortex (DLPFC) was predicted to improve performance in solving insight problems. Particularly, it was expected that this effect would be focused on solution recognition, which is hypothesized to be directly related to control processes, and would be more pronounced for difficult problems, hypothesized to require more cognitive demand. Moreover, we predicted that this effect would be modulated by approach motivation tendencies, due to cognition and motivation interactions in the DLPFC.Methods: 21 participants performed a verbal insight problem task twice, once under active anodal tDCS over the left DLPFC and once under sham stimulation, with a one week interval between sessions. Participants had 7 s to generate a solution for each problem, and then were requested to indicate whether a target word was the correct solution or not.Results: Stimulation significantly enhanced solution recognition for difficult problems. This effect was modulated by trait motivation, i.e., was larger for participants with lower approach motivation. No effects were found for easy problems, or solution generation.Conclusions: Left DLPFC executive control modulates semantic processing of verbal insight problems. The observed synergy between language, cognition and motivation carries theoretical implication as well as practical consideration for future stimulation research.

Brain activity underlying visual perception and attention as inferred from TMS–EEG: A review - Corrected Proof

Paul Christopher John Taylor, Gregor Thut — 2012-03-27

Abstract: Probing brain functions by brain stimulation while simultaneously recording brain activity allows addressing major issues in cognitive neuroscience. We review recent studies where electroencephalography (EEG) has been combined with transcranial magnetic stimulation (TMS) in order to investigate possible neuronal substrates of visual perception and attention. TMS–EEG has been used to study both pre-stimulus brain activity patterns that affect upcoming perception, and also the stimulus-evoked and task-related inter-regional interactions within the extended visual-attentional network from which attention and perception emerge. Local processes in visual areas have been probed by directly stimulating occipital cortex while monitoring EEG activity and perception. Interactions within the attention network have been probed by concurrently stimulating frontal or parietal areas. The use of tasks manipulating implicit and explicit memory has revealed in addition a role for attentional processes in memory. Taken together, these studies helped to reveal that visual selection relies on spontaneous intrinsic activity in visual cortex prior to the incoming stimulus, their control by attention, and post-stimulus processes incorporating a re-entrant bias from frontal and parietal areas that depends on the task.

Stimulating the brain to study social interactions and empathy - Corrected Proof

Sébastien Hétu, Vincent Taschereau-Dumouchel, Philip L. Jackson — 2012-03-27

Abstract: Empathy is a multi-dimensional concept allowing humans to understand the emotions of others and respond adaptively from a social perspective. This mental process, essential to social interactions, has attracted the attention of many scholars from different fields of study but the blooming interest for empathy in cognitive neurosciences has rekindled this interest. This paper reviews the growing literature stemming from studies using brain stimulation techniques that have investigated directly or indirectly the different components of empathy, including resonance, self-other discrimination, and mentalizing. Some studies have also ventured toward the modulation of this complex process and toward the investigation of different components in populations that show reduced empathic skills. We argue that brain stimulation techniques have the potential to make a unique contribution to the field of empathy research with their exclusive capacity, compared to other brain imaging techniques, to modulate the neural systems involved in the distinct components of this process. Provided the development of innovative ecological paradigms that will put people in actual social interactions as well as comprehensive and adaptive models that can integrate research from different domains, the ultimate goal of this research domain is to devise protocols that can modulate empathy in people with developmental, neurological and psychiatric disorders.

Electric field depth–focality tradeoff in transcranial magnetic stimulation: Simulation comparison of 50 coil designs - Corrected Proof

Zhi-De Deng, Sarah H. Lisanby, Angel V. Peterchev — 2012-03-22

Abstract: Background: Various transcranial magnetic stimulation (TMS) coil designs are available or have been proposed. However, key coil characteristics such as electric field focality and attenuation in depth have not been adequately compared. Knowledge of the coil focality and depth characteristics can help TMS researchers and clinicians with coil selection and interpretation of TMS studies.Objective: To quantify the electric field focality and depth of penetration of various TMS coils.Methods: The electric field distributions induced by 50 TMS coils were simulated in a spherical human head model using the finite element method. For each coil design, we quantified the electric field penetration by the half-value depth, d1/2, and focality by the tangential spread, S1/2, defined as the half-value volume (V1/2) divided by the half-value depth, S1/2 = V1/2/d1/2.Results: The 50 TMS coils exhibit a wide range of electric field focality and depth, but all followed a depth–focality tradeoff: coils with larger half-value depth cannot be as focal as more superficial coils. The ranges of achievable d1/2 are similar between coils producing circular and figure-8 electric field patterns, ranging 1.0–3.5 cm and 0.9–3.4 cm, respectively. However, figure-8 field coils are more focal, having S1/2 as low as 5 cm2 compared to 34 cm2 for circular field coils.Conclusions: For any coil design, the ability to directly stimulate deeper brain structures is obtained at the expense of inducing wider electrical field spread. Novel coil designs should be benchmarked against comparison coils with consistent metrics such as d1/2 and S1/2.

Frontal and parietal theta burst TMS impairs working memory for visual-spatial conjunctions - Corrected Proof

2012-03-21

Abstract: In tasks that selectively probe visual or spatial working memory (WM) frontal and posterior cortical areas show a segregation, with dorsal areas preferentially involved in spatial (e.g. location) WM and ventral areas in visual (e.g. object identity) WM. In a previous fMRI study , we showed that right parietal cortex (PC) was more active during WM for orientation, whereas left inferior frontal gyrus (IFG) was more active during colour WM. During WM for colour-orientation conjunctions, activity in these areas was intermediate to the level of activity for the single task preferred and non-preferred information. To examine whether these specialised areas play a critical role in coordinating visual and spatial WM to perform a conjunction task, we used theta burst transcranial magnetic stimulation (TMS) to induce a functional deficit. Compared to sham stimulation, TMS to right PC or left IFG selectively impaired WM for conjunctions but not single features. This is consistent with findings from visual search paradigms, in which frontal and parietal TMS selectively affects search for conjunctions compared to single features, and with combined TMS and functional imaging work suggesting that parietal and frontal regions are functionally coupled in tasks requiring integration of visual and spatial information. Our results thus elucidate mechanisms by which the brain coordinates spatially segregated processing streams and have implications beyond the field of working memory.

Prefrontal rTMS for treating depression: Location and intensity results from the OPT-TMS multi-site clinical trial - Corrected Proof

2012-03-15

Abstract: Background: Motor cortex localization and motor threshold determination often guide Transcranial Magnetic Stimulation (TMS) placement and intensity settings for non-motor brain stimulation. However, anatomic variability results in variability of placement and effective intensity.Objective: Post-study analysis of the OPT-TMS Study reviewed both the final positioning and the effective intensity of stimulation (accounting for relative prefrontal scalp-cortex distances).Methods: We acquired MRI scans of 185 patients in a multi-site trial of left prefrontal TMS for depression. Scans had marked motor sites (localized with TMS) and marked prefrontal sites (5 cm anterior of motor cortex by the “5 cm rule”). Based on a visual determination made before the first treatment, TMS therapy occurred either at the 5 cm location or was adjusted 1 cm forward. Stimulation intensity was 120% of resting motor threshold.Results: The “5 cm rule” would have placed stimulation in premotor cortex for 9% of patients, which was reduced to 4% with adjustments. We did not find a statistically significant effect of positioning on remission, but no patients with premotor stimulation achieved remission (0/7). Effective stimulation ranged from 93 to 156% of motor threshold, and no seizures were induced across this range. Patients experienced remission with effective stimulation intensity ranging from 93 to 146% of motor threshold, and we did not find a significant effect of effective intensity on remission.Conclusions: Our data indicates that individualized positioning methods are useful to reduce variability in placement. Stimulation at 120% of motor threshold, unadjusted for scalp-cortex distances, appears safe for a broad range of patients.

How far can TMS coils be optimized? A partial resolution - Corrected Proof

Charles M. Epstein — 2012-03-14

A long-standing goal of TMS researchers has been to preserve focality of stimulation while allowing penetration to deep brain regions, and a remarkable variety of innovative coil designs has been directed towards that end. Unfortunately, as economists are fond of telling us, “there's no free lunch.” Deng et al. show that, overall, coils inducing Fig. 8 electric field patterns produce more focality relative to depth than coils inducing a circular electric field pattern. But the fundamental tradeoff is inflexible: the ability to directly stimulate deeper brain structures is obtained at the expense of inducing wider electrical field spread, and all coil designs tend to converge at depths of more than a few centimetres. Issues of relative efficiency and safety remain unsettled. But when it comes time to select TMS coils for specific applications, Peterchev and his colleagues have provided a much clearer pathway.

Phosphene thresholds correlate with paired-pulse suppression of visually evoked potentials - Corrected Proof

2012-03-14

Abstract: Background: Phosphene thresholds (PT) induced by transcranial magnetic stimulation (TMS) as well as paired-pulse suppression (PPS) of visually evoked potentials (VEP) are used to characterize visual cortex excitability, however, their relation remains unknown.Methods: We measured PT after single TMS over the occipital lobe, and recorded VEPs after paired-pulse stimulation at short stimulus-onset-asynchronies in the same subject. PPS was expressed by the ratio second to first response.Results: We found a negative correlation between PT and PPS (r = −0.36, P = 0.039) indicating that higher PT were associated with smaller ratios indicative of low excitability, and vice versa. There was no difference in PPS between subjects who perceived phosphenes and those who did not.Conclusions: Although both approaches target different mechanisms, PT and PPS seem to reflect common characteristics of visual cortex excitability. The lack of differences in PPS in subjects not perceiving phosphenes suggests that they might not have higher excitability levels.

Plasticity of motor threshold and motor-evoked potential amplitude – A model of intrinsic and synaptic plasticity in human motor cortex? - Corrected Proof

Igor Delvendahl, Nikolai H. Jung, Nicola G. Kuhnke, Ulf Ziemann, Volker Mall — 2012-02-29

Abstract: Background: Neuronal plasticity is the physiological correlate of learning and memory. In animal experiments, synaptic (i.e. long-term potentiation (LTP) and depression (LTD)) and intrinsic plasticity are distinguished. In human motor cortex, cortical plasticity can be demonstrated using transcranial magnetic stimulation (TMS). Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity.Objective/hypothesis: We investigated the role of changes of motor threshold and their relation to changes of MEP amplitudes.Methods: We induced plasticity by paired associative stimulation (PAS) with 25 ms or 10 ms inter-stimulus interval or by motor practice (MP) in 64 healthy subjects aged 18–31 years (median 24.0).Results: We observed changes of MEP amplitudes and motor threshold after PAS[25], PAS[10] and MP. In all three protocols, long-term individual changes in MEP amplitude were inversely correlated to changes in motor threshold (PAS[25]: P = .003, n = 36; PAS[10]: P = .038, n = 19; MP: P = .041, n = 19).Conclusion: We conclude that changes of MEP amplitudes and MT represent two indices of motor cortex plasticity. Whereas increases and decreases in MEP amplitude are assumed to represent LTP-like or LTD-like synaptic plasticity of motor cortex output neurons, changes of MT may be considered as a correlate of intrinsic plasticity.

Effects of transcranial Direct Current Stimulation (tDCS) on cortical activity: A computational modeling study - Corrected Proof

2012-02-29

Abstract: Although it is well-admitted that transcranial Direct Current Stimulation (tDCS) allows for interacting with brain endogenous rhythms, the exact mechanisms by which externally-applied fields modulate the activity of neurons remain elusive. In this study a novel computational model (a neural mass model including subpopulations of pyramidal cells and inhibitory interneurons mediating synaptic currents with either slow or fast kinetics) of the cerebral cortex was elaborated to investigate the local effects of tDCS on neuronal populations based on an in-vivo experimental study. Model parameters were adjusted to reproduce evoked potentials (EPs) recorded from the somatosensory cortex of the rabbit in response to air-puffs applied on the whiskers. EPs were simulated under control condition (no tDCS) as well as under anodal and cathodal tDCS fields. Results first revealed that a feed-forward inhibition mechanism must be included in the model for accurate simulation of actual EPs (peaks and latencies). Interestingly, results revealed that externally-applied fields are also likely to affect interneurons. Indeed, when interneurons get polarized then the characteristics of simulated EPs become closer to those of real EPs. In particular, under anodal tDCS condition, more realistic EPs could be obtained when pyramidal cells were depolarized and, simultaneously, slow (resp. fast) interneurons became de- (resp. hyper-) polarized. Geometrical characteristics of interneurons might provide some explanations for this effect.

Vagus nerve stimulation ameliorated deficits in one-way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats - Corrected Proof

2012-02-27

Abstract: Background: Vagus nerve stimulation (VNS) has been introduced as a therapeutic option for treatment-resistant depression. The neural and chemical mechanisms responsible for the effects of VNS are largely unclear.Methods: Bilateral removal of the olfactory bulbs (OBX) is a validated animal model in depression research. We studied the effects of vagus nerve stimulation (VNS) on disturbed one-way active avoidance learning and neurogenesis in the hippocampal dentate gyrus of rats.Results: After a stimulation period of 3 weeks, OBX rats acquired the learning task as controls. In addition, the OBX-related decrease of neuronal differentiated BrdU positive cells in the dentate gyrus was prevented by VNS.Conclusions: This suggests that chronic VNS and changes in hippocampal neurogenesis induced by VNS may also account for the amelioration of behavioral deficits in OBX rats. To the best of our knowledge, this is the first report on the restorative effects of VNS on behavioral function in an animal model of depression that can be compared with the effects of antidepressants.

Impairment of sensory-motor plasticity in mild Alzheimer’s disease - Corrected Proof

2012-02-27

Abstract: Background: Primary motor cortex (M1) is relatively spared in the early stages of Alzheimer’s disease (AD).Objective: Aim of the present study was to investigate whether abnormal M1 synaptic plasticity is present at an early stage of AD. We employed an electrophysiological protocol, named rapid paired associative stimulation (rPAS), involving repetitive transcranial magnetic stimulation (rTMS) paired with electrical stimulation of the contralateral median nerve, that modifies corticospinal excitability and short latency afferent inhibition (SAI).Methods: We studied 10 patients with a diagnosis of probable mild AD according to the Mini Mental State Examination score (minimum 21) and 14 age-matched control subjects. Motor evoked potentials (MEP) amplitudes and short-afferent inhibition (SAI) were measured at baseline before and for up to 60 min after 5Hz-rPAS in abductor pollicis brevis (APB). rPAS consisted of 600 pairs of transcranial magnetic stimuli, at a rate of 5 Hz for 2 min, coupled with electrical median nerve stimulation preceding TMS over the contralateral M1 at an inter-stimulus interval of 25 ms.Results: Baseline SAI was significantly reduced in AD patients. In the control subjects rPAS induced a significant increase in MEP amplitudes and a decrease of SAI in the APB muscle persistently for up to 1 h. Conversely 5Hz-rPAS did not induce any significant changes in MEP amplitudes and SAI in mild AD patients.Conclusions: Sensory-motor plasticity is impaired in the motor cortex of AD at an early stage of the disease.

Short interval intracortical facilitation correlates with the degree of disability in multiple sclerosis - Corrected Proof

2012-02-27

Abstract: Background: The Expanded Disability Status Scale (EDSS) is the most widely used measure of disability in MS, however because of its limitations surrogate markers of clinical disability progression are of high interest. Transcranial magnetic stimulation (TMS) measures of demyelination and cortical excitability correlate with disability levels in MS.Objective: Aim of this study was testing whether paired pulse (pp) TMS represents a reliable surrogate marker to measure clinical disability in MS.Methods: ppTMS measures of intracortical synaptic transmission such as short interval intracortical inhibition (SICI), long interval intracortical inhibition (LICI), short interval intracortical facilitation (SICF) and intracortical facilitation (ICF) were collected from 74 patients affected by MS. Correlation of EDSS scores with ppTMS measures was analyzed.Results: EDSS scores correlated with patient’s age, disease duration, Motor Evoked Potentials latency and thresholds and SICF measures but not with age of onset, SICI, ICF and LICI.Conclusions: These findings support a possible use of SICF and MEP latency as surrogate markers of disability in MS. Further research is warranted to determine the role of SICF in the follow up of disease progression and to validate its use as an endpoint in multiple sclerosis clinical trials.

Quadri-pulse stimulation induces stimulation frequency dependent cortical hemoglobin concentration changes within the ipsilateral motor cortical network - Corrected Proof

2012-02-24

Abstract: Background: Imaging studies investigating repetitive transcranial magnetic stimulation (rTMS) mediated hemodynamic consequences revealed inconsistent results, mainly due to differences in rTMS parameters and technical difficulties with simultaneous recordings during rTMS.Objective: /Hypothesis: Quadri-pulse rTMS (QPS) induces bidirectional long-term plasticity of the human primary motor cortex (M1). To evaluate its on-line effects, near infrared spectroscopy (NIRS) recordings were performed during QPS. We hypothesized that on-line effects during QPS are different from long-term aftereffects.Methods: Using a novel TMS - on-line multi-channel NIRS setup we recorded hemoglobin concentration [Hb] changes at the stimulated M1 and adjacent sensory-motor areas during QPS protocols inducing oppositely directed aftereffects (QPS-5: interstimulus interval (ISI) 5 ms, potentiation; QPS-50: ISI 50 ms, depression). In two experiments we studied NIRS changes during either single or repeated QPS bursts.Results: The repetitive QPS-5 bursts significantly decreased oxyhemoglobin concentration ([oxy-Hb]) in the ipsilateral M1. A single QPS-5 burst decreased [oxy-Hb] in the M1 and premotor cortex. QPS-50 induced no significant NIRS changes at any sites.Conclusions: QPS can significantly alter cortical hemodynamics depending on the stimulation frequency. While bidirectional long-term aftereffects of QPS reflect synaptic efficacy changes, unidirectional on-line effects during QPS may represent pure electrophysiological property changes within the cell membrane or synapse. Since neuronal postexcitatory inhibitory postsynaptic potentials typically peak within the first 10–20 ms, only pulses delivered at higher frequencies may lead to summation of the inhibitory effects, resulting in [oxy-Hb] decrease only after QPS-5. Our new TMS-NIRS setup may be valuable to investigate TMS induced neurovascular coupling mechanisms in humans.

Deep brain stimulation of the forniceal area enhances memory functions in experimental dementia: The role of stimulation parameters - Corrected Proof

2012-02-24

Abstract: Deep brain stimulation (DBS) is currently being evaluated as a potential therapy in improving memory functions in Alzheimer’s disease. The target for DBS and the stimulation parameters to be used are unknown. Here, we implanted bilateral electrodes in the vicinity of the fornix, a key element of the memory circuitry, and applied DBS with different stimulation frequencies and amplitudes in an experimental model of dementia. Rats received scopolamine, a muscarinic acetylcholine receptor antagonist, to mimic memory impairment. Rats were then tested in the object location task with the following conditions: (i) with attachment of stimulation cable (off stimulation), and (ii) with DBS at various amplitudes (50 μA, 100 μA and 200 μA), 100 μs pulse width and 100 Hz or 10 Hz stimulation frequency. DBS reversed the memory impairing effects of scopolamine when compared to sham rats. We found that the fornix is not sensitive to the frequency of stimulation, but rather to current levels. With the most optimal stimulation parameter, we found no side-effects on anxiety levels and general motor activity. These findings identify the fornix as a key region in controlling spatial memory functions. DBS of this region, using tailored stimulation parameters, has the potential to improve memory functions in conditions characterised by memory impairment.

Repetitive transcranial magnetic stimulation (rTMS) noise: A relevance for tinnitus treatment? - Corrected Proof

Stéphane Tringali, Xavier Perrot, Lionel Collet, Annie Moulin — 2012-02-23

Within the framework of rTMS safety, we took great interest in Muller‘s recent and thorough review about rTMS tolerability for patients with pathologic positive sensory phenomena, especially with tinnitus patients. The meta-analysis revealed 2.17% cases of tinnitus worsening, and the most prevalent explanation given for this worsening lies within the intricacies of magnetic stimulation of cortical networks. However, a more peripheral explanation could be proposed. Indeed, rTMS related noise seems particularly relevant when treating tinnitus patients, for several reasons:

Direct stereotactic targeting of the ventrointermediate nucleus of the thalamus based on anatomic 1.5-T MRI mapping with a white matter attenuated inversion recovery (WAIR) sequence - Corrected Proof

2012-02-23

Abstract: Background: The ventrointermediate nucleus (Vim) of the thalamus is still considered “invisible” on current magnetic resonance imaging (MRI), requiring indirect methods based on stereotactic atlases for estimation of its location. Direct visualization of Vim is desirable to improve targeting.Objective: To evaluate the ability of Inversion-Recovery 1.5-T MR images to produce high-resolution, anatomical depiction of the thalamus suitable for direct Vim targeting.Methods: Twenty patients with essential tremor or tremor associated with Parkinson’s disease received Vim deep brain stimulation (DBS). Fahn-Tolosa-Marin and Unified Parkinson’s Disease Rating Scale (UPDRS) tremor scores were assessed pre- and postoperatively. Preoperative stereotactic 1.5-T MR images of the thalamus were acquired using a White Matter Attenuated Inversion Recovery (WAIR) sequence. Thalamic nuclei were manually contoured on the basis of spontaneous MRI contrasts; labeling relied on 3D identification from stereotactic books and in-house ex vivo 4.7-T microscopic MRI atlas. Vim was then directly probed for electrophysiological confirmation and determination of the optimal site for electrode placement.Results: The shape, spatial orientation, and signal contrast of Vim as depicted on our WAIR images were similar to those observed on the Schaltenbrand and Bailey atlas, as well as in our high-field MRI atlas. These images were successfully used for pure direct Vim targeting: at the last follow-up (median = 46.3 months), the average tremor score improved from 3.80 preoperatively to 0.50 postoperatively (on stimulation; P < 0.01).Conclusion: 1.5-T MRI with WAIR sequence provides high-quality images of Vim suitable in DBS surgery, for accurate preoperative planning, direct targeting and anatomic analysis.

Hypothalamic stimulation enhances hippocampal BDNF plasticity in proportion to metabolic rate - Corrected Proof

Zhe Ying, Alejandro Covalin, Jack Judy, Fernando Gomez-Pinilla — 2012-02-23

Abstract: Background: Energy metabolism is emerging as a driving force for cellular events underlying cognitive processing. The hypothalamus integrates metabolic signals with the function of centers related to cognitive processing such as the hippocampus.Objective/hypothesis: Hypothalamic activity can influence molecular systems important for processing synaptic plasticity underlying cognition in the hippocampus. The neurotrophin BDNF may act as a mediator for the effects of energy metabolism on synaptic plasticity and cognitive function.Methods: The hypothalamus of rats confined to a respiratory chamber was electrically stimulated, and energy expenditure (EE) was assessed via indirect calorimetry. MRNA levels for BDNF and molecules related to synaptic plasticity and control of cellular energy metabolism were assessed in the hippocampus.Results: Electrical stimulation of the rat hypothalamus elevates mRNA levels of hippocampal BDNF. BDNF mRNA levels increased according to the metabolic rate of the animals, and in proportion to the mRNA of molecules involved in control of cellular energy metabolism such as ubiquitous mitochondrial creatine kinase (uMtCK).Conclusions: Results show a potential mechanism by which cellular energy metabolism impacts the substrates of cognitive processing, and may provide molecular basis for therapeutic treatments based on stimulation of deep brain structures.

Changes in psychological functioning signaling antidepressant response onset to transcranial magnetic stimulation - Corrected Proof

Dennis J.L.G. Schutter, Frank Koerselman — 2012-02-23

The cognitive neuropsychological model of antidepressant action proposes that the onset of therapeutic effects following treatment has been suggested to be preceded by improvement in psychological functioning . The subtle systematic changes in cognitive and emotive functioning are often not readily noted by the patient themselves or the people in the direct environment, but nevertheless indicate the onset of antidepressant action. However, the notion that there exists onset delay between therapeutic action and medicinal treatment has been challenged . According to the authors, approximately half of the patients who will respond to a six-week treatment will show signs of antidepressant action within two week following treatment onset. A reasonable explanation for the differences in onset latency may be that the commonly used clinical assessment tools lack the sensitivity to detect subtle improvements in psychological functioning and behavior. Furthermore, psychological tests which are designed to measure particular cognitive and emotive processes, such as visuospatial memory and attention for emotional facial expressions, usually involves a mental challenge as patients are faced with task instructions and the presentation of series of stimuli which requires mental effort. In other words, the sensitivity of detecting antidepressant action may actually be higher under physiologically active conditions.

H215O PET responses to deep brain stimulation - Corrected Proof

Erwin B. Montgomery — 2012-02-23

While not taking issue with the observational data reported by Bradberry et al. the inferences drawn are inconsistent with their own observations as well as a great many other observations previously reported but not reviewed in their article. First and most fundamental, the authors report deactivation of the supplementary motor area (SMA) and motor cortex (MC) with subthalamic nucleus (STN) deep brain stimulation (DBS). Yet, there have been several reports of electroencephalographic evoked potentials recorded in humans over those areas in response to STN DBS including using cadaver controls . Indeed, studies demonstrated aspects of the evoked potential consistent with antidromic activation of MC in humans and another demonstrating antidromic as well as oligosynaptic activation of MC neurons with STN DBS in non-human primates . Several studies have demonstrated increased MC excitability with STN DBS .

Close to threshold transcranial electrical stimulation preferentially activates inhibitory networks before switching to excitation with higher intensities - Corrected Proof

Vera Moliadze, Deniz Atalay, Andrea Antal, Walter Paulus — 2012-02-23

Abstract: Background: Recently we have shown that transcranial random noise (tRNS) and 140 Hz transcranial alternating current stimulations (tACS), applied over the primary motor cortex (M1) and using 10 min stimulation duration and 1 mA intensity, significantly increases cortical excitability as measured by motor evoked potentials at rest before and after stimulation.Objective/hypothesis: Here, by decreasing the stimulation intensity in 0.2 mA steps from 1.0 mA, we investigate to what extent intensity depends on the induced after-effects.Methods: All twenty-five subjects participated in two different experimental sessions each. They received tACS using 140 Hz frequency and full spectrum tRNS at five different intensities on separate days. Sham stimulation was used as a control.Results: Instead of receiving a simple threshold, unexpectedly, in these two independent data sets at threshold intensities of 0.4 mA we found a switch of the already known excitation achieved with an intensity of 1 mA to inhibition. The intermediate intensity ranges of 0.6 and 0.8 mA had no effect at all. Interestingly, the inhibition produced by 140 Hz tACS was stronger than that induced by tRNS.Conclusions: In summary, we have shown here the possibility of selectively controlling the enhancement or reduction of M1 excitability by applying different intensities of high frequency transcranial electrical stimulation.

Cortical magnetoencephalography of deep brain stimulation for the treatment of postural tremor - Corrected Proof

Allison T. Connolly, Jawad A. Bajwa, Matthew D. Johnson — 2012-02-23

Abstract: The effects of deep brain stimulation (DBS) on motor cortex circuitry in Essential tremor (ET) and Parkinson’s disease (PD) patients are not well understood, in part, because most imaging modalities have difficulty capturing and localizing motor cortex dynamics on the same temporal scale as motor symptom expression. Here, we report on the use of magnetoencephalography (MEG) to characterize sources of postural tremor activity within the brain of an ET/PD patient and the effects of bilateral subthalamic nucleus DBS on these sources. Recordings were performed during unilateral and bilateral DBS at stimulation amplitudes of 0 V, 1 V, and 3 V corresponding to no therapy, subtherapeutic, and therapeutic configurations, respectively. Dipole source localization in reference to the postural tremor frequency recorded with electromyography (EMG) showed prominent sources in both right and left motor cortices when no therapy was provided. These sources dissipated as the amplitude of stimulation increased to a therapeutic level (P = 0.0062). Coherence peaks between the EMG and MEG recordings were seen at both 4 Hz, postural tremor frequency, and at 8 Hz, twice the tremor frequency, with no therapy. Both peaks were reduced with therapeutic DBS. These results demonstrate the capabilities of MEG to record cortical dynamics of tremor during deep brain stimulation and suggest that MEG could be used to examine DBS in the context of motor symptoms of PD and of ET.

The fade-in – Short stimulation – Fade out approach to sham tDCS – Reliable at 1 mA for naïve and experienced subjects, but not investigators - Corrected Proof

2012-02-23

Abstract: Objective: Slowly ramping down initial current intensity after a minimal interval of stimulation is the de facto standard for sham stimulation in transcranial electrical stimulation research. The aim of this study is to further investigate the effectiveness of this method of blinding.Methods: We have investigated the time course of the cutaneous perception during 10 min of anodal, cathodal, and sham transcranial direct current stimulation, probing the perceived strength and site of the perceived sensation. We have also utilized post-stimulation assessment and measurements of sleepiness prior to and after the intervention. Previous exposure to tDCS has also been taken into account: the experiment has been repeated in naïve and experienced subject groups, and a group consisting of investigators who use tDCS as a research tool.Results: Although we have observed a general reduction in the perceived strength of the stimulation with time, we have not found the complete disappearance of the cutaneous perception during either the verum or the sham conditions. Experienced subjects were more likely to be able to differentiate between trials with stimulation and non-stimulation trials and to correctly identify sham and verum stimulation conditions.Conclusion: When taking only naïve and experienced subjects into account, there was no significant difference between the strength of the perceived stimulation in the verum and sham conditions. The fade-in – short stimulation – fade-out sham stimulation can be indistinguishable from verum stimulation, but not because it mimics the disappearance of the cutaneous sensations associated with the verum stimulation, but because these sensations persist also in the sham stimulation. The significance of this finding with potential confounding factors and limitations are discussed.

MRI-targeted repetitive transcranial magnetic stimulation of Heschl’s gyrus for refractory auditory hallucinations - Corrected Proof

2012-02-23

Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) has shown promise as a treatment for refractory auditory hallucinations (AH) in Schizophrenia. Most previous studies have examined the effect of low frequency, left-sided stimulation (LFL) (1 Hz) to the temporoparietal cortex (TPC). Priming stimulation (6 Hz) prior to LFL stimulation (hereby simply referred to as priming) has been shown to enhance the neurophysiological effects of LFL rTMS alone and, as such, may lead to greater attenuation of AH.Objective: Therefore, this study evaluated the efficacy of priming rTMS and LFL rTMS compared to sham rTMS using MRI targeting of Heschl’s gyrus (HG) within the TPC of subjects with SCZ experiencing refractory auditory hallucinations (AH).Methods: Subjects between the ages of 18 and 65 were recruited from a tertiary care university hospital. Fifty-four subjects with medication resistant AH were randomized to receive LFL, priming, or sham rTMS for 20 treatments. The primary outcome was reduction of hallucinatory symptoms as indexed by response rates on the Psychotic Symptoms Rating Scale (PSYRATS).Results: The response rates did not differ among the three treatment groups using an intention to treat analysis. The response rates did not differ in any of the secondary outcome measures. The treatment was well tolerated with minimal adverse effects including no changes in cognition during the study.Conclusion: These findings suggest that neither priming nor LFL rTMS of Heschl’s gyrus are effective at ameliorating refractory AH in schizophrenia.ClinicalTrials.gov Identifier: NCT01386918