Alterations In Cortical Excitability Research Articles

Neurophysiological effects of repetitive transcranial magnetic stimulation (rTMS) in treatment resistant depression

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) is effective for treatment resistant depression (TRD), but little is known about rTMS’ effects on neurophysiological markers. We previously identified neurophysiological markers in depression (N45 and N100) of GABA receptor mediated inhibition. Here, we indexed TMS-electroencephalographic (TMS-EEG) effects of rTMS. MethodsTMS-EEG data was analyzed from a double blind 2:1 randomized active (10 Hz left/bilateral):sham rTMS TRD trial. Participants underwent TMS-EEG over left dorsolateral prefrontal cortex (DLPFC) before and after 6 weeks of rTMS. 30 had useable datasets. TMS-evoked potentials (TEP) and components (N45, N100, P60) were examined with global mean field analysis (GMFA) and locally in DLPFC regions of interest. ResultsThe N45 amplitude differed between active and sham groups over time, N100 amplitude did not. N45 (t = 2.975, p = 0.007) and N100 amplitudes (t = 2.177, p = 0.042) decreased after active rTMS, demonstrating alterations in cortical inhibition. TEP amplitudes decreased after active rTMS in left (t = 4.887, p < 0.001) and right DLPFC (t = 4.403, p < 0.001) not sham rTMS, demonstrating alterations in cortical excitability. ConclusionsOur results provide important new knowledge regarding rTMS effects on TMS-EEG measures in TRD, suggesting rTMS reduces neurophysiological markers of inhibition and excitability. SignificanceThese findings uncover potentially important neurophysiological mechanisms of rTMS action.

Contribution of the right temporoparietal junction and ventromedial prefrontal cortex to theory of mind in autism: A randomized, sham-controlled tDCS study.

Theory of mind (ToM) is the ability to attribute subjective mental states to oneself and others and is significantly impaired in autism spectrum disorder (ASD). A frontal-posterior network of regions including the ventromedial prefrontal cortex (vmPFC) and temporoparietal junction (TPJ) is involved in ToM. Previous studies show an underactivation of these regions in ASD. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation method for causally investigating brain-behavior relationships via induction of cortical excitability alterations. tDCS, mostly over the dorsolateral prefrontal cortex, has been increasingly applied for improving behavioral problems in ASD leaving other potentially interesting regions untouched. Here we investigated contribution of the vmPFC and right TPJ in ToM abilities of ASD children via tDCS in a pilot study. Sixteen children with ASD (mean age=10.7± 1.9) underwent three tDCS sessions (1mA, 20 min) in a randomized, sham-controlled design. Stimulation protocols included: (a) anodal vmPFC tDCS, (b) anodal r-TPJ tDCS, and (c) sham tDCS. ToM abilities were explored during tDCS using the theory of mind test (TOMT). Our results show that activation of the vmPFC with anodal tDCS significantly improved ToM in children with ASD compared with both, r-TPJ tDCS, and sham stimulation. Specifically, precursors of ToM (e.g., emotion recognition, perception, and imitation) and elementary ToM skills (e.g., first-order mental state reasoning) were significantly improved by anodal vmPFC tDCS. Based on these results, the vmPFC could be a potential target region for the reduction of ASD symptoms via noninvasive brain stimulation, which should be examined in larger detail in future studies. LAY SUMMARY: Theory of mind (ToM) is the ability to infer mental states of oneself and others, which is impaired in autism. Brain imaging studies have shown involvement of two brain regions in ToM (ventromedial prefrontal cortex, temporoparietal junction) which are underactivated in autism. We increased activation of these regions via noninvasive brain stimulation in this experiment to see how it would affect ToM abilities in autism. We found that increased activation of the ventromedial prefrontal cortex improved ToM abilities in children with autism.

Inhibitory Effect of Apomorphine on Focal and Nonfocal Plasticity in the Human Motor Cortex

Dopamine is crucial for neuroplasticity, which is considered to be the neurophysiological foundation of learning and memory. The specific effect of dopamine on plasticity such as long-term potentiation (LTP) and long-term depression (LTD) is determined by receptor subtype specificity, concentration level, and the kind of plasticity induction technique. In healthy human subjects, the dopamine precursor levodopa (L-DOPA) exerts a dosage-dependent non-linear effect on motor cortex plasticity. Low and high dosage L-DOPA impaired or abolished plasticity, while medium-dose preserved and reversed plasticity in previous studies. Similar dosage-dependent effects were also observed for selective D1-like and D2-like receptor activation that favor excitatory and inhibitory plasticity, respectively. However, such a dosage-dependent effect has not been explored for a nonselective dopamine agonist such as apomorphine in humans. To this aim, nonfocal and focal motor cortex plasticity induction using paired associative stimulation (PAS) and transcranial direct current stimulation (tDCS) were performed respectively in healthy participants under 0.1, 0.2, 0.3 mg apomorphine or placebo drug. Transcranial magnetic stimulation-elicited motor-evoked potentials were used to monitor motor cortical excitability alterations. We hypothesized that, similar to L-DOPA, apomorphine will affect motor cortex plasticity. The results showed that apomorphine with the applied dosages has an inhibitory effect for focal and nonfocal LTP-like and LTD-like plasticity, which was either abolished, diminished or reversed. The detrimental effect on plasticity induction under all dosages of apomorphine suggests a predominantly presynaptic mechanism of action of these dosages.

Exploring and optimizing the neuroplastic effects of anodal transcranial direct current stimulation over the primary motor cortex of older humans

BackgroundtDCS modulates cortical plasticity and has shown potential to improve cognitive/motor functions in healthy young humans. However, age-related alterations of brain structure and functions might require an adaptation of tDCS-parameters to achieve a targeted plasticity effect in older humans and conclusions obtained from young adults might not be directly transferable to older adults. Thus, our study aimed to systematically explore the association between tDCS-parameters and induced aftereffects on motor cortical excitability to determine optimal stimulation protocols for older individuals, as well as to investigate age-related differences of motor cortex plasticity in two different age groups of older adults. Methods32 healthy, volunteers from two different age groups of Young-Old (50–65 years, n = 16) and Old-Old (66–80 years, n = 16) participated in this study. Anodal tDCS was applied over the primary motor cortex, with respective combinations of three intensities (1, 2, and 3 mA) and durations (15, 20, and 30 min), in a sham-controlled cross-over design. Cortical excitability alterations were monitored by single-pulse TMS-induced MEPs until the next day morning after stimulation. ResultsAll active stimulation conditions resulted in a significant enhancement of motor cortical excitability in both age groups. The facilitatory aftereffects of anodal tDCS did not significantly differ between age groups. We observed prolonged plasticity in the late-phase range for two protocols with the highest stimulation intensity (i.e., 3 mA-20 min, 3 mA-30 min). ConclusionsOur study highlights the role of stimulation dosage in tDCS-induced neuroplastic aftereffects in the motor cortex of healthy older adults and delivers crucial information about optimized tDCS protocols in the domain of the primary motor cortex. Our findings might set the grounds for the development of optimal stimulation protocols to reinstate neuroplasticity in different cortical areas and induce long-lasting, functionally relevant plasticity in normal aging and in pathological conditions, which would require however systematic tDCS titration studies over respective target areas.

The Effect of Bilateral Anodal Transcranial Direct Current Stimulation versus Treadmill Training on Brain Activities, Gait Functions, Level of Participation and Enjoyment of Children with Cerebral Palsy: A Randomized Controlled Trial Protocol

ABSTRACT Background Cerebral palsy (CP) possesses bilateral sensory-motor cortical excitability alterations. In past studies, researchers have applied unilateral anodal transcranial direct stimulation (tDCS) with inconsistent findings. Objective Examining the effects of treadmill training with either unilateral or bilateral anodal tDCS stimulation on brain activities, gait, and body functions of children with CP. Design Randomized-clinical-trial. Participants Eighty children with CP will be allocated into: treadmill/bilateral-tDCS, treadmill/unilateral-tDCS, treadmill/sham-tDCS, and treadmill groups. Additional 20 neurotypical children will be recruited for comparison. Intervention Planned intervention will implement ten-sessions of treadmill training (50% of maximum-ground speed) either with unilateral-tDCS over left sensory-motor, or bilateral-tDCS over left/right sensory-motor areas. Brain activities, gait, body functions, and participation will be assessed at pre-intervention, post-intervention, and at one-month follow-up. Result and Discussion This study would contribute to extant findings on the use of tDCS stimulation in children with CP and to our understanding of the appropriateness of the planned outcome measures.

Evidence that corticofugal propagation of ALS pathology is not mediated by prion-like mechanism.

Amyotrophic lateral sclerosis (ALS) arises from the combined degeneration of motor neurons (MN) and corticospinal neurons (CSN). Recent clinical and pathological studies suggest that ALS might start in the motor cortex and spread along the corticofugal axonal projections (including the CSN), either via altered cortical excitability and activity or via prion-like propagation of misfolded proteins. Using mouse genetics, we recently provided the first experimental arguments in favour of the corticofugal hypothesis, but the mechanism of propagation remained an open question. To gain insight into this matter, we tested here the possibility that the toxicity of the corticofugal projection neurons (CFuPN) to their targets could be mediated by their cell autonomous-expression of an ALS causing transgene and possible diffusion of toxic misfolded proteins to their spinal targets. We generated a Crym-CreERT2 mouse line to ablate the SOD1G37R transgene selectively in CFuPN. This was sufficient to fully rescue the CSN and to limit spasticity, but had no effect on the burden of misfolded SOD1 protein in the spinal cord, MN survival, disease onset and progression. The data thus indicate that in ALS corticofugal propagation is likely not mediated by prion-like mechanisms, but could possibly rather rely on cortical hyperexcitability.

Neuronavigation based 10 sessions of repetitive transcranial magnetic stimulation therapy in chronic migraine: an exploratory study.

Chronic migraine is a disease of altered cortical excitability. Repetitive transcranial magnetic stimulation provides a novel non-invasive method to target the nociceptive circuits in the cortex. Motor cortex is one such potential target. In this study, we targeted the left motor cortex using fMRI-guided neuronavigation. Twenty right-handed patients were randomized into real and sham rTMS group. Baseline subjective pain assessments were done using visual analog scale (VAS) and questionnaires: State-Trait Anxiety Inventory, Becks Depression Inventory, and Migraine Disability Assessment (MIDAS) questionnaire. Objectively, pain was assessed by means of thermal pain thresholds using quantitative sensory testing. For corticomotor excitability parameters, resting motor thresholds and motor-evoked potentials were mapped. For rTMS total, 600 pulses in 10 trains at 10Hz with an intertrain interval of 60s were delivered in each session. Ten such sessions were given 5days per week over 2 consecutive weeks. The duration of each session was 10min. Real rTMS was administered at 70% of Resting MT. All the tests were repeated post-intervention and after 1month of follow-up. There are no studies reporting the use of fMRI-based TMS for targeting the motor cortex in CM patients. We observed a significant reduction in the mean VAS rating, headache frequency, and MIDAS questionnaire in real rTMS group which was maintained after 1month of follow-up. Ten sessions of fMRI-based rTMS over the left motor cortex may provide long-term pain relief in CM, but further studies are warranted to confirm our preliminary findings.

Induction of long-term potentiation-like plasticity in the primary motor cortex with repeated anodal transcranial direct current stimulation – Better effects with intensified protocols?

BackgroundA single session of anodal tDCS induces LTP-like plasticity which lasts for about 1 h, while repetition of stimulation within a time interval of 30 min results in late-phase effects lasting for at least 24 h with standard stimulation protocols. ObjectiveIn this pilot study, we explored if the after-effects of a recently developed intensified single session stimulation protocol are relevantly prolonged in the motor cortex by repetition of this intervention. Methods16 healthy right-handed subjects participated in this study. The effects of an intensified (3 mA-20min) and a standard anodal tDCS protocol (1 mA-15min) with short (20 min) and long (3 h) repetition intervals were compared with the effects of respective single session tDCS protocols (3 mA-20min, 1 mA-15min, and Sham). Cortical excitability alterations were monitored by single-pulse TMS-elicited MEPs. ResultsCompared to sham, both single session tDCS protocols (1 mA-15min, and 3 mA-20min) resulted in cortical excitability enhancements lasting for about 30 min after stimulation. The short repetition interval (20 min) resulted in a prolongation of after-effects for the standard protocol, which lasted for more than 24 h after stimulation. For the intensified protocol, the prolongation of after-effects was limited to 120 min after stimulation. The long repetition interval (3 h) resulted in no excitability-enhancing after-effects for the intensified, and only minor excitability enhancement within the first 30 min after the intervention for the standard protocol. ConclusionThese results suggest a non-linearity of late-phase LTP-like plasticity induction, which was dependent not only on the interval of intervention repetition, but also on other protocol characteristics, including intensity, and duration of tDCS. Further studies in larger samples are needed to confirm these results.

TDCS-Enhanced Consolidation of Writing Skills and Its Associations With Cortical Excitability in Parkinson Disease: A Pilot Study

Background. Learning processes of writing skills involve the re-engagement of previously established motor programs affected by Parkinson disease (PD). To counteract the known problems with consolidation in PD, transcranial direct current stimulation (tDCS) could be imperative to achieve a lasting regeneration of habitual motor skills. Objective. To examine tDCS-enhanced learning of writing and explore alterations in cortical excitability after stimulation in PD compared with healthy controls (HCs). Methods. Ten patients and 10 HCs received 2 training sessions combined with 20 minutes of 1-mA anodal tDCS or sham on the left primary motor cortex in a randomized crossover design. Writing skills on a tablet and paper were assessed at baseline, after training, and after 1 week of follow-up. Before and immediately after the intervention, cortical excitability and inhibition were measured during rest and activity. Results. Writing amplitude and velocity improved when practice was tDCS supplemented compared with sham in PD. Benefits were sustained at retention for trained and untrained tasks on the tablet as well as for writing on paper. No improvements were found for HCs. Reduced resting motor thresholds after tDCS indicated tDCS-enhanced cortical excitability. Additionally, increments in motor-evoked potential amplitudes correlated with improved writing in PD, whereas HCs showed the opposite pattern. Conclusion. Our results endorse the usefulness of tDCS-boosted learning in PD, at least when applied to improving writing capacity. Although further confirmatory studies are needed, these novel findings are striking because tDCS-mediated consolidation was found for learning a motor task directly affected by PD.

Changes of motor cortical excitability and response inhibition in patients with obsessive–compulsive disorder

Deficits in cortical inhibitory processes have been suggested as underlying pathophysiological mechanisms of obsessive–compulsive disorder (OCD). We examined whether patients with OCD have altered cortical excitability using paired-pulse transcranial magnetic stimulation (TMS). We also tested associations between TMS indices and OCD-related characteristics, including age of onset and response inhibition in the go/no-go paradigm, to examine whether altered cortical excitability contributes to symptom formation and behavioural inhibition deficit in patients with OCD. We assessed motor cortex excitability using paired-pulse TMS in 51 patients with OCD and 39 age-matched healthy controls. We also assessed clinical symptoms and response inhibition in the go/nogo task. All patients were undergoing treatment with serotonin reuptake inhibitors. We performed repeated-measures multivariate analysis of covariance to compare TMS indices between patients with OCD and controls. Compared to controls, patients with OCD showed a shorter cortical silent period and decreased intracortical facilitation. However, we found no significant difference between groups for resting motor threshold or short-interval intracortical inhibition. In the OCD group, the shortened cortical silent period was associated with a prompt reaction time in the go/no-go task and with early onset of OCD. We could not exclude the influence of medications on motor cortex excitability. These findings suggest abnormal cortical excitability in patients with OCD. The associations between cortical silent period and response inhibition and age of onset further indicate that altered cortical excitability may play an important role in the development of OCD.

GABA-ergic tone hypothesis in hepatic encephalopathy – Revisited

ObjectiveThe GABA hypothesis of hepatic encephalopathy (HE) proposes an increased cerebral GABA-ergic tone in HE but has not been investigated in vivo in HE-patients yet. Cortical GABA-ergic and glutamatergic neurotransmission in HE-patients were evaluated using transcranial magnetic stimulation. MethodsTwenty-one patients with HE grade 1 and 2 and age matched controls participated in the study. GABA-ergic (short- and long-interval intracortical inhibition (SICI and LICI)) and glutamatergic (intracortical and short-interval intracortical facilitation (ICF and SICF)) excitability of the primary motor cortex (M1) and global corticospinal excitability (motor threshold, motor evoked potential recruitment curve (MEP-RC) were compared between the groups. SICI and ICF were correlated to the critical flicker frequency (CFF) as measure for disease severity. ResultsIn HE-patients, the slope of MEP-RC was significantly shallower compared to healthy controls. SICI was significantly reduced in patients with HE grade 2 compared to healthy controls. In HE-patients, SICI and ICF was significantly correlated to CFF. ConclusionAlthough global corticospinal excitability was reduced in HE-patients, GABA-ergic inhibition was reduced in M1 depending on HE severity. Moreover CFF related alteration of GABAergic and glutamatergic neurotransmission in patients with HE could support the notion of a severity dependent alteration of cortical excitability. SignificanceThe decrease of cortical GABA-ergic tone challenges the classical GABA hypothesis in HE.

Physiology of Transcranial Direct Current Stimulation.

Direct current stimulation is a neuromodulatory noninvasive brain stimulation tool, which was first introduced in animal and human experiments in the 1950s, and added to the standard arsenal of methods to alter brain physiology as well as psychological, motor, and behavioral processes and clinical symptoms in neurological and psychiatric diseases about 20 years ago. In contrast to other noninvasive brain stimulation tools, such as transcranial magnetic stimulation, it does not directly induce cerebral activity, but rather alters spontaneous brain activity and excitability by subthreshold modulation of neuronal membranes. Beyond acute effects on brain functions, specific protocols are suited to induce long-lasting alterations of cortical excitability and activity, which share features with long-term potentiation and depression. These neuroplastic processes are important foundations for various cognitive functions such as learning and memory formation and are pathologically altered in numerous neurological and psychiatric diseases. This explains the increasing interest to investigate transcranial direct current stimulation (tDCS) as a therapeutic tool. However, for tDCS to be used effectively, it is crucial to be informed about physiological mechanisms of action. These have been increasingly elucidated during the last years. This review gives an overview of the current knowledge available regarding physiological mechanisms of tDCS, spanning from acute regional effects, over neuroplastic effects to its impact on cerebral networks. Although knowledge about the physiological effects of tDCS is still not complete, this might help to guide applications on a scientifically sound foundation.

The Perineuronal 'Safety' Net? Perineuronal Net Abnormalities in Neurological Disorders.

Perineuronal nets (PNN) are extracellular matrix (ECM) assemblies that preferentially ensheath parvalbumin (PV) expressing interneurons. Converging evidence indicates that PV cells and PNN are impaired in a variety of neurological disorders. PNN development and maintenance is necessary for a number of processes within the CNS, including regulation of GABAergic cell function, protection of neurons from oxidative stress, and closure of developmental critical period plasticity windows. Understanding PNN functions may be essential for characterizing the mechanisms of altered cortical excitability observed in neurodegenerative and neurodevelopmental disorders. Indeed, PNN abnormalities have been observed in post-mortem brain tissues of patients with schizophrenia and Alzheimer’s disease. There is impaired development of PNNs and enhanced activity of its key regulator matrix metalloproteinase-9 (MMP-9) in Fragile X Syndrome, a common genetic cause of autism. MMP-9, a protease that cleaves ECM, is differentially regulated in a number of these disorders. Despite this, few studies have addressed the interactions between PNN expression, MMP-9 activity and neuronal excitability. In this review, we highlight the current evidence for PNN abnormalities in CNS disorders associated with altered network function and MMP-9 levels, emphasizing the need for future work targeting PNNs in pathophysiology and therapeutic treatment of neurological disorders.

Remote Changes in Cortical Excitability after Experimental Traumatic Brain Injury and Functional Reorganization.

Although cognitive and behavioral deficits are well known to occur following traumatic brain injury (TBI), motor deficits that occur even after mild trauma are far less known, yet are equally persistent. This study was aimed at making progress toward determining how the brain reorganizes in response to TBI. We used the adult rat controlled cortical impact injury model to study the ipsilesional forelimb map evoked by electrical stimulation of the affected limb, as well as the contralesional forelimb map evoked by stimulation of the unaffected limb, both before injury and at 1, 2, 3, and 4 weeks after using functional magnetic resonance imaging (fMRI). End-point c-FOS immunohistochemistry data following 1 h of constant stimulation of the unaffected limb were acquired in the same rats to avoid any potential confounds due to altered cerebrovascular coupling. Single and paired-pulse sensory evoked potential (SEP) data were recorded from skull electrodes over the contralesional cortex in a parallel series of rats before injury, at 3 days, and at 1, 2, 3, and 4 weeks after injury in order to determine whether alterations in cortical excitability accompanied reorganization of the cortical map. The results show a transient trans-hemispheric shift in the ipsilesional cortical map as indicated by fMRI, remote contralesional increases in cortical excitability that occur in spatially similar regions to altered fMRI activity and greater c-FOS activation, and reduced or absent ipsilesional cortical activity chronically. The contralesional changes also were indicated by reduced SEP latency within 3 days after injury, but not by blood oxygenation level-dependent fMRI until much later. Detailed interrogation of cortical excitability using paired-pulse electrophysiology showed that the contralesional cortex undergoes both an early and a late post-injury period of hyper-excitability in response to injury, interspersed by a period of relatively normal activity. From these data, we postulate a cross-hemispheric mechanism by which remote cortex excitability inhibits ipsilesional activation by rebalanced cortical excitation-inhibition.

Effects of Cathode Location and the Size of Anode on Anodal Transcranial Direct Current Stimulation Over the Leg Motor Area in Healthy Humans.

Objective: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) involves passing low currents through the brain and is a promising tool for the modulation of cortical excitability. In this study, we investigated the effects of cathode location and the size of anode for anodal tDCS of the right-leg area of the motor cortex, which is challenging due to its depth and orientation in the inter-hemispheric fissure.Methods: We first computationally investigated the effects of cathode location and the size of the anode to find the best montage for specificity of stimulation effects for the targeted leg motor area using finite element analysis (FEA). We then compared the best electrode montage found from FEA with the conventional montage (contralateral supraorbital cathode) via neurophysiological testing of both, the targeted as well as the contralateral leg motor area.Results: The conventional anodal tDCS electrode montage for leg motor cortex stimulation using a large-anode (5 cm × 7 cm, current strength 2 mA) affected the contralateral side more strongly in both the FEA and the neurophysiological testing when compared to other electrode montages. A small-anode (3.5 cm × 1 cm at 0.2 mA) with the same current density at the electrode surface and identical contralateral supraorbital cathode placement improved specificity. The best cathode location for the small-anode in terms of specificity for anodal tDCS of the right-leg motor area was T7 (10–10 EEG system).Conclusion: A small-anode (3.5 cm × 1 cm) with the same current density at the electrode surface as a large-anode (5 cm × 7 cm) resulted in similar cortical excitability alterations of the targeted leg motor cortex respresentation. In relation to the other stimulation conditions, the small-anode montage with the cathode positioned at T7 resulted in the best specificity.

T46. Correlates of motor disability and fatigue with alterations of cortical excitability and quantitative MRI parameters in relapsing remitting multiple sclerosis and neuromyelitis optica

Introduction Relapsing Remitting Multiple sclerosis(RRMS) and Neuromyelitis optica(NMO) are primary demyelinating disorders with almost similar clinical symptoms but have varied etiology and response to treatment. Methods To study and compare clinical (fatigue depression and disability scores), electrophysiological and imaging characteristics of RRMS and NMO including correlation of (Transcranial magnetic stimulation) TMS parameters with clinical scores and imaging;and improvement in TMS parameters pre and post steroids.23 RRMS and 14 NMO patients were recruited over a period of 5 years and all parameters were done pre and post steroid therapy. Results Mean age at presentation-RRMS-31.1 ± 12.2 years;NMO-34.8 ± 10.9 years. Mean duration of illness- RRMS-50.9 ± 58.1 months; NMO-42.9 ± 48.6 months. Age at onset of illness -RRMS-26.9 ± 10.7 years; NMO-31.9 ± 9.2 years. Frequency of episodes were high in NMO (predominantly myelopathy) as opposed to RRMS (Brainstem syndrome). Disability, fatigue scores and Cerebrospinal fluid pleocytosis were significantly high in NMO than RRMS. Somatosensory Evoked Potentials (EPs) showed significant prolongation in RRMS while Visual EPs showed no difference between both entities. Duration of illness correlated positively with total T1, T2 lesion load and disability scores with T1 lesion load in RRMS. No correlation was found in any clinical scores and lesion load in NMO. As compared to NMO right uncus, insula and anterior cingulate gyrus were relatively preserved in RRMS with atrophy of left pre cuneus,cuneus,occipital gyrus,cerebellum and bilateral pulvinar as identified by voxel based morphometric analysis. Both RRMS and NMO showed significant prolongation of Central motor conduction time (CMCT) whereas reduction in Motor Evoked Potential (MEP) amplitudes and prolongation of contralateral silent periods was significant only in RRMS. In paired stimulation studies, none of the patients in RRMS and NMO group had intracortical facilitation (ICF) and Short interval intracortical inhibition (SICI) was found to be elevated in both group of patients, with more inhibition compared to controls. Trend towards improvement was noted in both the groups post steroids, in Resting Motor Threshold, MEP amplitude and ICF. Disability was found to have negative correlation with SICI in RRMS patients. Conclusion Patients of NMO were of later age at onset with more disability and fatigue compared to RRMS. Duration of illness correlated with total MRI lesion load and disability with T1 lesion load in RRMS.TMS parameters were found to be significantly abnormal in RRMS than NMO with significant CMCT prolongation in both the groups which improved post steroid therapy.Lack of cortical excitability was noted in both the groups with increased cortical inhibition.Negative correlation of disability with SICI was also noted only in RRMS and not NMO with no correlation of TMS parameters with fatigue and depression.TMS thereby helps in evaluation and assessment of response to therapy in both RRMS and NMO.

Alteration of cortical excitability and its modulation by Miglustat in Niemann-Pick disease type C

Niemann-Pick type C (NP-C) is a rare, neurodegenerative, lysosomal storage disease. Cortical excitability using different transcranial magnetic stimulation (TMS) protocols together with clinical and neuropsychological testing was longitudinally assessed in a patient with NP-C. Cerebellar inhibition, a measure for the integrity of the cerebello-thalamo-cortical network, was impaired. Short-latency afferent inhibition, a measure for cholinergic transmission, and cognitive functions were also impaired and improved under Miglustat treatment. Short interval intracortical facilitation, a marker for glutamatergic neurotransmission, was absent initially but increased after treatment with Miglustat. Our results provide new insights into pathophysiological mechanisms of NP-C and the response to Miglustat treatment.

The therapeutic use of non-invasive brain stimulation in multiple sclerosis – a review

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and a leading cause of disability in young adults. Many disabling symptoms in MS, such as spasticity, pain, depression and cognitive deficits are not fully controlled by drug treatment. Non-invasive brain stimulation (NIBS) techniques can be used as tools for modulating altered cortical excitability and plasticity MS patients, providing an improvement in disabling symptoms affecting such patients. This review reported and summarized some of the most interesting and promising recent achievements regarding the therapeutic use of NIBS in MS patients. We reviewed the clinical application of transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), emphasizing their effect on clinical symptoms and signs that are commonly involved in MS patients. In addition, we shortly described new NIBS protocols, such as transcranial alternating current stimulation and transcranial focused ultrasound stimulation as potential and innovative therapeutic options to be applied in future studies in MS patients. We reviewed twenty-one studies covering six main clinical domains. Most of such studies focused on fatigues (33.3%), motor performance (19%) and spasticity (19%), sparse results were about pain (9.5%), cognitive abilities (9.5%), sensory deficit (4.8%) and bladder function (4.8%). The most promising results have been published for the improvement of motor (i.e. hand dexterity) and cognitive performances (i.e. attention and working memory) by applying rTMS or tDCS alone or in association with motor/cognitive training, for pain's treatment by using tDCS. There are still no official recommendations for the therapeutic use of tDCS or rTMS in MS. The huge inter-individual variability of NIBS efficacy is still a big challenge which needs to be solved. However, well-designed studies, deeper knowledge about pathomechanisms underlying MS, and the combination of such techniques with motor and cognitive rehabilitation might results in higher effectiveness of NIBS.

Toward a more personalized motor function rehabilitation in Myotonic dystrophy type 1: The role of neuroplasticity.

Myotonic dystrophy type 1 (DM1) is the most prevalent adult muscular dystrophy, often accompanied by impairments in attention, memory, visuospatial and executive functions. Given that DM1 is a multi-system disorder, it requires a multi-disciplinary approach, including effective rehabilitation programs, focusing on the central nervous system neuroplasticity, in order to develop patient-tailored rehabilitative procedures for motor function recovery. Herein, we performed a transcranial magnetic stimulation (TMS) study aimed at investigating central motor conduction time, sensory-motor plasticity, and cortical excitability in 7 genetically defined DM1 patients. As compared to healthy individuals, DM1 patients showed a delayed central motor conduction time and an abnormal sensory-motor plasticity, with no alteration of cortical excitability. These findings may be useful to define patient-tailored motor rehabilitative programs.

P067 Stage dependent alteration of cortical excitability in patients with hepatic encephalopathy

Altered cortical excitability is supposed to play a relevant role in the pathophysiology of hepatic encephalopathy (HE). However, most data is based on animal studies and only limited data of patients with HE is available. We therefore investigated cortical excitability in HE-patients at different disease stages using transcranial magnetic stimulation. In eleven patients with HE stage 1, ten patients with HE stage 2 and ten age matched healthy control subjects several measures for cortical excitability of the primary motor cortex, i. e. motor threshold, motor evoked potential recruitment curve (MEP-RC), short interval intracortical inhibition (SICI), long interval intracortical inhibition, intracortical facilitation and short interval intracortical facilitation were compared. The critical flicker frequency (CFF) was also measured as one marker of disease severity. In HE-patients the slope of the MEP-RC was shallower compared to healthy controls. Moreover SICI was significantly reduced in HE stage 2 patients compared to healthy controls and a relevant correlation between SICI and CFF was found. No differences were found in the other measures. Our results suggest a disease stage dependent alteration of motor cortical and corticospinal excitability in patients with HE.