Cortical resting motor threshold difference in asleep-awake craniotomy for motor eloquent gliomas: WHO grading influences motor pathway excitability.

Developing neurophysiological tools to predict WHO tumor grade can empower the treating teams for a better surgical decision-making process. A total of 38 patients with supratentorial diffuse gliomas underwent an asleep-awake-sedated craniotomies for tumor removal with intraoperative neuromonitoring. The resting motor threshold was calculated for different train stimulation paradigms during awake and asleep phases. Receiver operating characteristic analysis and Bayesian regression models were performed to analyze the prediction of tumor grading based on the resting motor threshold differences. Significant positive spearman correlations were observed between resting motor threshold excitability difference and WHO tumor grade for train stimulation paradigms of 5 (R = 0.54, P = 0.00063), 4 (R = 0.49, P = 0.002), 3 (R = 0.51, P = 0.001), and 2 pulses (R = 0.54, P = 0.0007). Kruskal-Wallis analysis of the median revealed a positive significant difference between the median of excitability difference and WHO tumor grade in all paradigms. Receiver operating characteristic analysis showed 3 mA difference as the best predictor of high-grade glioma across different patterns of motor pathway stimulation. Bayesian regression found that an excitability difference above 3 mA would indicate a 75.8% probability of a glioma being high grade. Our results suggest that cortical motor excitability difference between the asleep and awake phases in glioma surgery could correlate with tumor grade.

Ultra-early navigated transcranial magnetic stimulation for perioperative stroke: anatomo-functional report.

Navigated repetitive transmagnetic stimulation is a non-invasive and safe brain activity modulation technique. When combined with the classical rehabilitation process in stroke patients it has the potential to enhance the overall neurologic recovery. We present a case of a peri-operative stroke, treated with ultra-early low frequency navigated repetitive transmagnetic stimulation over the contralesional hemisphere. The patient received low frequency navigated repetitive transmagnetic stimulation within 12 hours of stroke onset for seven consecutive days and a significant improvement in his right sided weakness was noticed and he was discharge with normal power. This was accompanied by an increase in the number of positive responses evoked by navigated repetitive transmagnetic stimulation and a decrease of the resting motor thresholds at a cortical level. Subcortically, a decrease in the radial, axial, and mean diffusivity were recorded in the ipsilateral corticospinal tract and an increase in fractional anisotropy, axial diffusivity, and mean diffusivity was observed in the interhemispheric fibers of the corpus callosum responsible for the interhemispheric connectivity between motor areas. Our case demonstrates clearly that ultra-early low frequency navigated repetitive transmagnetic stimulation applied to the contralateral motor cortex can lead to significant clinical motor improvement in patients with subcortical stroke.

Yoga as an Add-on Therapy in Parkinson's Disease: A Single Group Open-label Trial.

OBJECTIVE: We aimed to evaluate the effect of yoga on motor and non-motor symptoms and cortical excitability in patients with Parkinson's disease (PD). METHODS: We prospectively evaluated 17 patients with PD at baseline, after one month of conventional care, and after one month of supervised yoga sessions. The motor and non-motor symptoms were evaluated using the Unified Parkinson's disease Rating Scale (motor part III), Hoehn and Yahr stage, Montreal Cognitive Assessment, Hamilton depression rating scale, Hamilton anxiety rating scale, non-motor symptoms questionnaire and World Health Organization quality of life questionnaire. Transcranial magnetic stimulation was used to record resting motor threshold, central motor conduction time, ipsilateral silent period (iSP), contralateral silent period (cSP), short interval intracortical inhibition (SICI), and intracortical facilitation. RESULTS: The mean age of the patients was 55.5 ± 10.8 years, with a mean duration of illness of 4.0 ± 2.5 years. The postural stability of the patients significantly improved following yoga (0.59 ± 0.5 to 0.18 ± 0.4, p = 0.039). There was a significant reduction in the cSP from baseline (138.07 ± 27.5 ms) to 4 weeks of yoga therapy (116.94 ± 18.2 ms, p = 0.004). In addition, a significant reduction in SICI was observed after four weeks of yoga therapy (0.22 ± 0.10) to (0.46 ± 0.23), p = 0.004). CONCLUSION: Yoga intervention can significantly improve postural stability in patients with PD. A significant reduction of cSP and SICI suggests a reduction in GABAergic neurotransmission following yoga therapy that may underlie the improvement observed in postural stability. CLINICALTRIALSGOV IDENTIFIER: CTRI/2019/02/017564.

Corticospinal and intracortical responses from both motor cortices following unilateral concentric versus eccentric contractions.

Cross-education is the phenomenon where training of one limb can cause neuromuscular adaptations in the opposite untrained limb. This effect has been reported to be greater after eccentric (ECC) than concentric (CON) strength training; however, the underpinning neurophysiological mechanisms remain unclear. Thus, we compared responses to transcranial magnetic stimulation (TMS) in both motor cortices following single sessions of unilateral ECC and CON exercise of the elbow flexors. Fourteen healthy adults performed three sets of 10 ECC and CON right elbow flexor contractions at 75% of respective maximum on separate days. Elbow flexor maximal voluntary isometric contraction (MVIC) torques were measured before and after exercise, and responses to single- and paired-pulse TMS were recorded from the non-exercised left and exercised right biceps brachii. Pre-exercise and post-exercise responses for ECC and CON were compared by repeated measures analyses of variance (ANOVAs). MVIC torque of the exercised arm decreased (p < 0.01) after CON (-30 ± 14%) and ECC (-39 ± 13%) similarly. For the non-exercised left biceps brachii, resting motor threshold (RMT) decreased after CON only (-4.2 ± 3.9% of maximum stimulator output [MSO], p < 0.01), and intracortical facilitation (ICF) decreased (-15.2 ± 20.0%, p = 0.038) after ECC only. For the exercised right biceps, RMT increased after ECC (8.6 ± 6.2% MSO, p = 0.014) but not after CON (6.4 ± 8.1% MSO, p = 0.066). Thus, unilateral ECC and CON elbow flexor exercise modulated excitability differently for the non-exercised hemisphere. These findings suggest that responses after a single bout of exercise may not reflect longer term adaptations.

The effects of transcutaneous auricular vagal nerve stimulation on cortical GABAergic and cholinergic circuits: A transcranial magnetic stimulation study.

Neurophysiological evidence that transcutaneous auricular vagal nerve stimulation (taVNS) affects neuronal signalling at the cortical level is sparse. We used transcranial magnetic stimulation to assess the effect of taVNS on the excitability of intracortical GABAergic and cholinergic circuits. In this within-subject, double-blind study on 30 healthy participants, we used TMS paradigms to assess the effect of a single session of taVNS at 100 Hz and sham earlobe VNS (sVNS) on short-interval intracortical inhibition (SICI) curve and short-latency afferent inhibition (SAI). Control experiment was performed on additional 15 participants using the same experimental settings, but delivering no stimulation (xVNS). Bayesian statistics were used to assess the differences, producing % values that reflect the certainty that the values of interest were decreased during or after stimulation compared with baseline. taVNS increased SICI (96.3%), whereas sVNS decreased SICI (1.2%). SAI was not affected by taVNS, although it was decreased during sVNS (1.34% and 9.1%, for interstimulus intervals 20 and 24 ms, respectively). The changes in TMS parameters detected during sVNS were present in the same direction in the control experiment with no stimulation. Our study provides evidence that taVNS increases the activity of cortical GABAAergic system, leaving cortical cholinergic circuits unaffected. Changes in intracortical cortical excitability during sVNS, which were also observed in the control experiment with no stimulation were likely the effect of expectation related to participation in an interventional study.

Effect of Lumbar Drainage on Cortical Excitability in Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the clinical triad of gait disturbance, urinary incontinence, and memory impairment with normal cerebrospinal fluid (CSF) pressure. Transcranial magnetic stimulation (TMS) has been used to assess the corticospinal motor pathways in patients with iNPH with conflicting results. METHODS: Our study included 11 patients with iNPH and 13 healthy controls. All the subjects underwent TMS and resting motor threshold (RMT), central motor conduction time (CMCT), short-interval intracortical inhibition (SICI), intracortical facilitation, and silent period (SP) were recorded in the upper limb. Besides, RMT and CMCT in lower limb were also recorded. Cognitive assessments were done using mini-mental status examination, Montreal cognitive assessment (MoCA), and Addenbrooke's cognitive evaluation III (ACE III). Same parameters were recorded 24 h of CSF (lumbar puncture, LP) drainage. RESULTS: Mean age of the iNPH patients was 69.00 ± 6.71 years with age at onset being 66.64 ± 7.10 years. Duration of disease was 1.80 ± 1.25 years. A significant difference was noted in CMCT for the lower limb (CMCT-LL), SICI, and ipsilateral SP between pre-LP NPH and controls. Also, there was a significant difference in MoCA and ACE III between pre-LP NPH and controls. A significant reduction was observed in lower limb RMT between pre- and post-LP NPH patients. Post LP, there was a reduction in the lower limb CMCT and improvement in SICI. CONCLUSION: A significant prolongation of CMCT-LL was observed in NPH patients. Lumbar CSF drainage in them resulted in a significant reduction in lower limb RMT thereby suggesting an increase in cortical excitability.

Resting motor threshold in the course of hand motor recovery after stroke: a systematic review.

BACKGROUND: Resting motor threshold is an objective measure of cortical excitability. Numerous studies indicate that the success of motor recovery after stroke is significantly determined by the direction and extent of cortical excitability changes. A better understanding of this topic (particularly with regard to the level of motor impairment and the contribution of either cortical hemisphere) may contribute to the development of effective therapeutical strategies in this cohort. OBJECTIVES: This systematic review collects and analyses the available evidence on resting motor threshold and hand motor recovery in stroke patients. METHODS: PubMed was searched from its inception through to 31/10/2020 on studies investigating resting motor threshold of the affected and/or the non-affected hemisphere and motor function of the affected hand in stroke cohorts. RESULTS: Overall, 92 appropriate studies (including 1978 stroke patients and 377 healthy controls) were identified. The analysis of the data indicates that severe hand impairment is associated with suppressed cortical excitability within both hemispheres and with great between-hemispheric imbalance of cortical excitability. Favorable motor recovery is associated with an increase of ipsilesional motor cortex excitability and reduction of between-hemispheric imbalance. The direction of change of contralesional motor cortex excitability depends on the amount of hand motor impairment. Severely disabled patients show an increase of contralesional motor cortex excitability during motor recovery. In contrast, recovery of moderate to mild hand motor impairment is associated with a decrease of contralesional motor cortex excitability. CONCLUSIONS: This data encourages a differential use of rehabilitation strategies to modulate cortical excitability. Facilitation of the ipsilesional hemisphere may support recovery in general, whereas facilitation and inhibition of the contralesional hemisphere may enhance recovery in severe and less severely impaired patients, respectively.

Clinical Utility of Longitudinal Measurement of Motor Threshold in Wilson's Disease.

This study describes the longitudinal changes of resting motor threshold (RMT) and central motor conduction time (CMCT) in 18 patients with Wilson's disease (WD). The RMT, CMCT, and Global Assessment Scale for Wilson Disease (GAS-WD) were measured at baseline and at follow-up after 12.94 ± 7.23 months. There was a significant decrease in the RMT (72.11 ± 18.62 vs. 63.7 ± 15.52%; p-value = 0.002) and GAS-WD scores (14.38 ± 5.35 vs. 9.77 ± 6.47 ms; p-value = 0.04). CMCT did not improve despite chelation therapy. Hence, RMT may serve as a marker of chelation efficacy in WD.

When imaging meets neurophysiology: the value of navigated transcranial magnetic stimulation for preoperative neurophysiological mapping prior to brain tumor surgery.

Maximal safe resection is the modern goal for surgery of intrinsic brain tumors located in or close to brain eloquent areas. Nowadays different neuroimaging techniques provide important anatomical and functional information regarding the brain functional organization that can be used to plan a customized surgical strategy to preserve functional networks, and to increase the extent of tumor resection. Among these techniques, navigated transcranial magnetic stimulation (nTMS) has recently gained great favor among the neurosurgical community for preoperative mapping and planning prior to brain tumor surgery. It represents an advanced neuroimaging technique based on the neurophysiological mapping of the functional cortical brain organization. Moreover, it can be combined with other neuroimaging techniques such as diffusion tensor imaging tractography, thus providing a reliable reconstruction of brain eloquent networks. Consequently, nTMS mapping may provide reliable noninvasive brain functional mapping, anticipating information that otherwise may be available to neurosurgeons only in the operating theater by using direct electrical stimulation. The authors describe the reliability and usefulness of the preoperative nTMS-based approach in neurosurgical practice, and briefly discuss their experience using nTMS as well as currently available evidence in the literature supporting its clinical use. In particular, special attention is reserved for the discussion of the role of nTMS as a novel tool for the preoperative neurophysiological mapping of motor and language networks prior to surgery of intrinsic brain tumors located in or close to eloquent networks, as well as for future and promising applications of nTMS in neurosurgical practice.

TMS motor mapping in brain tumor patients: more robust maps with an increased resting motor threshold.

OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) has found widespread usage across many clinical centers as part of their surgical planning routines. NTMS offers a non-invasive approach to delineation of the motor cortex, in which the region is outlined through electromagnetic stimulation and electromyographic recordings of target muscles. Several neurophysiological parameters such as the motor evoked potential (MEP) and its derivatives, the resting motor threshold (RMT) and motor latency, are collected. The present study investigates the clinical feasibility and reproducibility of increasing the MEP threshold in brain tumor patients, with the goal to improve the robustness of the procedure. MATERIALS AND METHODS: Twenty-three subjects with peri-motor cortex tumors underwent motor mapping with nTMS. RMT was calculated with both conventional 50-µV and experimental 500-µV MEP amplitude thresholds. Motor mapping was performed with 105% of both RMTs stimulator intensity using the FDI as the target muscle. RESULTS: Motor mapping was possible in 20 patients with both the conventional and experimental thresholds. No significant differences in area size were found between motor area maps generated with a conventional 50-µV threshold in comparison to those generated with the higher 500-µV threshold (50 µV 272.56 mm2 [170.47-434.31] vs. 500 µV 240.54 mm2 [169.77-362.84], P = 0.34). Latency time was significantly reduced in 500-µV recordings relative to 50-µV recordings (50 µV 23.38 ms [22.55-24.51] vs. 500 µV 22.57 ms [21.41-23.70], P < 0.001). Both electric field intensity (50 µV 63.81 V/m [54.26-76.11] vs. 500 µV 77.83 V/m [65.21-93.94], P < 0.001) and RMT (50 µV 33 MSO% [28-36] vs. 500 µV 39.5 MSO% [32-44], P < 0.001) were significantly greater with the higher 500-µV threshold. CONCLUSIONS: Our study demonstrates the feasibility of increasing the MEP detection threshold to 500 µV in brain tumor patients for RMT determination and motor area mapping with nTMS.

Estimation of the resting motor threshold (RMT) in transcranial magnetic stimulation using relative-frequency and threshold-hunting methods in brain tumor patients.

BACKGROUND: Application of transcranial magnetic stimulation is often based on the resting motor threshold. The aim of this study was to validate recent findings on the advantage of resting motor threshold estimation using adaptive threshold-hunting algorithms over the Rossini-Rothwell method in a clinical sample and healthy subjects. METHODS: Resting motor thresholds in 115 patients with a brain tumor and 10 healthy subjects were assessed using the Rossini-Rothwell method and compared to an adaptive threshold-hunting algorithm. In healthy subjects, this measurement was repeated twice to capture test-retest reliability of both methods. Efficiency of both methods was assessed by comparing the number of pulses needed for resting motor threshold estimation. RESULTS: There was no significant difference between the Rossini-Rothwell method and the adaptive threshold-hunting algorithm in patients and healthy controls with limits of agreement between ± 12 V/m. There was a strong intraclass correlation and both methods showed a good test-retest reliability. However, the adaptive threshold-hunting algorithm was significantly faster. CONCLUSIONS: The adaptive threshold-hunting algorithm was more efficient in assessing the resting motor threshold, while reaching comparable results as the Rossini-Rothwell method. Thus, our results support the advantage of adaptive threshold-hunting algorithms to determine the resting motor threshold also in a clinical sample.

Comparison of Rossini-Rothwell and adaptive threshold-hunting methods on the stability of TMS induced motor evoked potentials amplitudes.

Several methods can be used to determine the resting motor threshold (RMT) and by that recording transcranial magnetic stimulation (TMS) induced motor evoked potentials (MEPs). However, no research has compared the test retest reliability of these methods. Thus, the aim of this study was to determine intra- and inter-session reliability of Rossini-Rothwell (R-R) and parameter estimation by sequential testing (PEST) methods on TMS-induced MEPs and comparison of these two methods on RMT. Twelve healthy individuals participated in this study three times (T1, T2 and T3) over two days. TMS was applied using both R-R and PEST to estimate RMT and average of 25 MEPs were acquired at each of the three time points. The intra-class correlation coefficient indicated high intra-session reliability in the MEP amplitudes for both methods (0.79 and 0.88, R-R and PEST respectively). The RMT and MEP amplitudes had higher inter-session reliability in both methods (0.99 and 0.998, R-R and PEST respectively; 0.84 and 0.76, R-R and PEST respectively). There was no significant difference between methods for RMT at both T1 (maximum stimulator output of R-R vs. PEST, 33.7% ± 7.7% vs. 33.8% ± 7.6%, p = 0.75) and T3 (maximum stimulator output of R-R vs. PEST, 33.5% ± 7.3% vs. 33.7% ± 7.3%, p = 0.19). There was a significant positive correlation between the methods' estimates of RMT, with PEST requiring significantly fewer stimuli. This study shows that the R-R and PEST methods have high intra-and inter-session reliability and the same precision, with PEST having the advantage over R-R in speed of estimation of RMT.

Setup presentation and clinical outcome analysis of treating highly language-eloquent gliomas via preoperative navigated transcranial magnetic stimulation and tractography.

OBJECTIVE Awake surgery combined with intraoperative direct electrical stimulation (DES) and intraoperative neuromonitoring (IONM) is considered the gold standard for the resection of highly language-eloquent brain tumors. Different modalities, such as functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG), are commonly added as adjuncts for preoperative language mapping but have been shown to have relevant limitations. Thus, this study presents a novel multimodal setup consisting of preoperative navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging fiber tracking (DTI FT) as an adjunct to awake surgery. METHODS Sixty consecutive patients (63.3% men, mean age 47.6 ± 13.3 years) suffering from highly language-eloquent left-hemispheric low- or high-grade glioma underwent preoperative nTMS language mapping and nTMS-based DTI FT, followed by awake surgery for tumor resection. Both nTMS language mapping and DTI FT data were available for resection planning and intraoperative guidance. Clinical outcome parameters, including craniotomy size, extent of resection (EOR), language deficits at different time points, Karnofsky Performance Scale (KPS) score, duration of surgery, and inpatient stay, were assessed. RESULTS According to postoperative evaluation, 28.3% of patients showed tumor residuals, whereas new surgery-related permanent language deficits occurred in 8.3% of patients. KPS scores remained unchanged (median preoperative score 90, median follow-up score 90). CONCLUSIONS This is the first study to present a clinical outcome analysis of this very modern approach, which is increasingly applied in neurooncological centers worldwide. Although human language function is a highly complex and dynamic cortico-subcortical network, the presented approach offers excellent functional and oncological outcomes in patients undergoing surgery of lesions affecting this network.

Preservation of motor maps with increased motor evoked potential amplitude threshold in RMT determination.

OBJECTIVE: Non-invasive pre-surgical mapping of eloquent brain areas with navigated transcranial magnetic stimulation (nTMS) is a useful technique linked to the improvement of surgical planning and patient outcomes. The stimulator output intensity and subsequent resting motor threshold determination (rMT) are based on the motor-evoked potential (MEP) elicited in the target muscle with an amplitude above a predetermined threshold of 50 µV. However, a subset of patients is unable to achieve complete relaxation in the target muscles, resulting in false positives that jeopardize mapping validity with conventional MEP determination protocols. Our aim is to explore the feasibility and reproducibility of a novel mapping approach that investigates how an increase of the MEP amplitude threshold to 300 and 500 µV affects subsequent motor maps. MATERIALS AND METHODS: Seven healthy subjects underwent motor mapping with nTMS. RMT was calculated with the conventional methodology in conjunction with experimental 300- and 500-µV MEP amplitude thresholds. Motor mapping was performed with 105% of rMT stimulator intensity using the FDI as the target muscle. RESULTS: Motor mapping was possible in all patients with both the conventional and experimental setups. Motor area maps with a conventional 50-µV threshold showed poor correlation with 300-µV (α = 0.446, p < 0.001) maps, but showed excellent consistency with 500-µV motor area maps (α = 0.974, p < 0.001). MEP latencies were significantly less variable (23 ms for 50 µV vs. 23.7 ms for 300 µV vs. 23.7 ms for 500 µV, p < 0.001). A slight but significant increase of the electric field (EF) value was found (EF: 60.8 V/m vs. 64.8 V/m vs. 66 V/m p < 0.001). CONCLUSION: Our study demonstrates the feasibility of increasing the MEP detection threshold to 500 µV in rMT determination and motor area mapping with nTMS without losing precision.

Clinical Factors Underlying the Inter-individual Variability of the Resting Motor Threshold in Navigated Transcranial Magnetic Stimulation Motor Mapping.

Correctly determining individual's resting motor threshold (rMT) is crucial for accurate and reliable mapping by navigated transcranial magnetic stimulation (nTMS), which is especially true for preoperative motor mapping in brain tumor patients. However, systematic data analysis on clinical factors underlying inter-individual rMT variability in neurosurgical motor mapping is sparse. The present study examined 14 preselected clinical factors that may underlie inter-individual rMT variability by performing multiple regression analysis (backward, followed by forward model comparisons) on the nTMS motor mapping data of 100 brain tumor patients. Data were collected from preoperative motor mapping of abductor pollicis brevis (APB), abductor digiti minimi (ADM), and flexor carpi radialis (FCR) muscle representations among these patients. While edema and age at exam in the ADM model only jointly reduced the unexplained variance significantly, the other factors kept in the ADM model (gender, antiepileptic drug intake, and motor deficit) and each of the factors kept in the APB and FCR models independently significantly reduced the unexplained variance. Hence, several clinical parameters contribute to inter-individual rMT variability and should be taken into account during initial and follow-up motor mappings. Thus, the present study adds basic evidence on inter-individual rMT variability, whereby some of the parameters are specific to brain tumor patients.

A common SCN1A splice-site polymorphism modifies the effect of carbamazepine on cortical excitability--a pharmacogenetic transcranial magnetic stimulation study.

OBJECTIVE: SCN1A encodes the alpha subunit of the voltage-gated sodium channel and plays a crucial role in several epilepsy syndromes. The common SCN1A splice-site polymorphism rs3812718 (IVS5N+5 G>A) might contribute to the pathophysiology underlying genetic generalized epilepsies and is associated with electrophysiologic properties of the channel and the effect of sodium-channel blocking antiepileptic drugs. We assessed the effects of the rs3812718 genotype on cortical excitability at baseline and after administration of carbamazepine in order to investigate the mechanism of this association. METHODS: Paired-pulse transcranial magnetic stimulation (TMS) was applied in 92 healthy volunteers with the homozygous genotypes AA or GG of rs3812718 at baseline and after application of 400 mg of carbamazepine or placebo in a double-blind, randomized, crossover design. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP) were determined. RESULTS: At baseline there was no significant difference in any TMS parameter. Genotype GG was associated with a higher carbamazepine-induced increase in CSP duration as compared to AA (multivariate analysis of covariance [MANCOVA], p = 0.013). An expected significant increase in RMT was genotype independent. SIGNIFICANCE: We found that the rs3812718 genotype modifies the effect of carbamazepine on CSP duration (mainly reflecting modulation of γ-aminobutyric acid (GABA)ergic inhibition), but not on RMT (mainly reflecting modulation of voltage-gated sodium channels). This provides evidence that rs3812718 affects the pharmacoresponse to carbamazepine via an effect on GABAergic cortical interneurons. Our results also confirm that TMS is useful to investigate the effect of genetic variants on cortical excitability and pharmacoresponse.

Abnormal cortical excitability in patients with spinocerebellar ataxia type 12.

BACKGROUND: Spinocerebellar ataxia type 12 (SCA-12) is an uncommon autosomal dominant cerebellar ataxia characterized by action tremors in the upper limbs, dysarthria, head tremor, and gait ataxia. We aimed to evaluate the motor cortical excitability in patients with SCA-12 using transcranial magnetic stimulation (TMS). METHODS: The study was done in the department of Neurology at the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore. Nine patients with SCA-12 (2 females) and 10 healthy controls (2 females) were included in the study. TMS was performed in all the subjects and various parameters such as resting motor threshold (RMT), central motor conduction time (CMCT) and contralateral silent period (cSP) were recorded. The left motor cortex was stimulated and the recording was done from right first dorsal interossei muscle. The severity of ataxia was assessed using the scale for assessment and rating in ataxia (SARA). RESULTS: The mean age of the patients was 58.11 ± 7.56 years mean age at onset: 51.67 ± 4.18 years. The mean duration of illness was 9.44 ± 4.88 years. The mean SARA score was 13.83 ± 3.60. Patients with SCA-12 had significantly increased RMT (88.80 ± 12.78 %) compared to HC (44.90 ± 9.40 %, p < 0.05). A significantly prolonged CMCT was observed in patients (13.70 ± 2.52 msec) compared to HC (7.31 ± 1.21 msec, p < 0.05). In addition, cSP was significantly increased in SCA-12 patients (144.43 ± 25.79 msec) compared to HC (82.14 ± 28.90 msec, p < 0.05). CONCLUSIONS: Patients with SCA-12 demonstrate a reduced cortical excitability and increased cortical inhibition suggesting an increase in the GABAergic neurotransmission.

Relationship between excitability, plasticity and thickness of the motor cortex in older adults.

The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64 years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimer's Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies.

Systematic Evaluation of the Effects of Voluntary Activation on Lower Extremity Motor Thresholds.

The purpose of this investigation was to elucidate the relationship between the resting motor threshold (rMT) and active motor threshold (aMT). A cross-sectional comparison of MTs measured at four states of lower extremity muscle activation was conducted: resting, 5% maximal voluntary contraction (MVC), 10%MVC, and standing. MTs were measured at the tibialis anterior in the ipsilesional and contralesional limbs in participants in the chronic phase (>6 months) of stroke (n = 11) and in the dominant limb of healthy controls (n = 11). To compare across activation levels, the responses were standardized using averaged peak-to-peak background electromyography (EMG) activity measured at 10%MVC + 2SD for each participant, in addition to the traditional 0.05 mV criterion for rMT (rMT50). In all participants, as muscle activation increased, the least square mean estimates of MTs decreased (contralesional: p = 0.008; ipsilesional: p = 0.0015, healthy dominant: p < 0.0001). In healthy controls, rMT50 was significantly different from all other MTs (p < 0.0344), while in stroke, there were no differences in either limb (p > 0.10). This investigation highlights the relationship between rMT and aMTs, which is important as many stroke survivors do not present with an rMT, necessitating the use of an aMT. Future works may consider the use of the standardized criterion that accounted for background EMG activity across activation levels.

Increasing striatal dopamine release through repeated bouts of theta burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. A 18F-desmethoxyfallypride positron emission tomography study.

Introduction: Transcranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) - a Dopamine receptor-antagonist - the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured. Methods: 23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen). Results: Verum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session. Conclusion: Results suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression.