Changes in Cortical Activation by Transcranial Magnetic Stimulation Due to Coil Rotation Are Not Attributable to Cranial Muscle Activation

Transcranial magnetic stimulation coupled with electroencephalography (TMS-EEG) allows for the study of brain dynamics in health and disease. Cranial muscle activation can decrease the interpretability of TMS-EEG signals by masking genuine EEG responses and increasing the reliance on preprocessing methods but can be at least partly prevented by coil rotation coupled with the online monitoring of signals; however, the extent to which changing coil rotation may affect TMS-EEG signals is not fully understood. Our objective was to compare TMS-EEG data obtained with an optimal coil rotation to induce motor evoked potentials (M1standard) while rotating the coil to minimize cranial muscle activation (M1emg). TMS-evoked potentials (TEPs), TMS-related spectral perturbation (TRSP), and intertrial phase clustering (ITPC) were calculated in both conditions using two different preprocessing pipelines based on independent component analysis (ICA) or signal-space projection with source-informed reconstruction (SSP-SIR). Comparisons were performed with cluster-based correction. The concordance correlation coefficient was computed to measure the similarity between M1standard and M1emg TMS-EEG signals. TEPs, TRSP, and ITPC were significantly larger in M1standard than in M1emg conditions; a lower CCC than expected was also found. These results were similar across the preprocessing pipelines. While rotating the coil may be advantageous to reduce cranial muscle activation, it may result in changes in TMS-EEG signals; therefore, this solution should be tailored to the specific experimental context

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics

Диагностические возможности транскраниальной магнитной стимуляции для прогнозирования двигательного восстановления после инсульта

Transcranial magnetic stimulation is a method of focal non-invasive brain stimulation, characterized by high spatial and temporal resolution. To date, diagnostic transcranial magnetic stimulation has been used in clinical practice primarily to assess an involvement of the upper motor neurons and to measure the velocity of the neuronal impulse propagation. However, in the last 10 years, a possible range of transcranial magnetic stimulation diagnostic applications has significantly expanded. Many transcranial magnetic stimulation approaches are coming from scientific laboratories to clinical practice due to an increased availability of transcranial magnetic stimulation equipment, in particular, magnetic resonance imaging navigation for transcranial magnetic stimulation and a combination of the transcranial magnetic stimulation with electroencephalography and also due to an increased awareness of the clinicians. The diagnostic potential of transcranial magnetic stimulation in relation to motor recovery after a stroke can be classified into 4 directions:1) assessment of the vertical tracts integrity (primarily, the cortico-spinal tract); 2) an assessment of the cortical excitation-inhibition balance;3) probing of the functional and effective connectivity among brain regions (primarily, cortical convexity and cerebellum);4) motor mapping to evaluate cortical reorganization.In this article we will present these 4 directions of the transcranial magnetic stimulation application to study motor system pathophysiology and to predict motor outcome in stroke, including both existing and developing approaches.Транскраниальная магнитная стимуляция – метод фокальной неинвазивной стимуляции мозга, характеризующийся высоким пространственным и временным разрешением. До настоящего времени в рутинной клинической практике диагностическая транс- краниальная магнитная стимуляция использовалась в первую очередь для оценки вовлеченности центральных мотонейронов и измерения скорости проведения по различным участкам нервной системы. Однако в последние 10 лет возможный спектр диагностического применения этого метода существенно расширился. Многие подходы транскраниальной магнитной стимуляции переходят из научных лабораторий в клиническую практику благодаря повышению доступности оборудования, в особенности транскраниальной магнитной стимуляции с навигацией по данным магнитно-резонансной томографии и комбинации транскраниальной магнитной стимуляции c электроэнцефалографией, а также благодаря повышению информированности специалистов. Диагностический потенциал транскраниальной магнитной стимуляции в отношении двигательных нарушений после инсульта можно условно разделить на 4 направления: 1) оценка сохранности вертикальных трактов, в первую очередь кортико-спинального тракта из конкретной зоны коры; 2) оценка баланса возбуждения–торможения в коре; 3) оценка функциональной и эффективной связности между доступными для транскраниальной магнитной стимуляции регионами мозга (прежде всего конвекситальные зоны коры и мозжечок); 4) картирование двигательных областей коры для оценки пластических перестроек. В настоящей статье рассмотрены эти 4 направления, включая как существующие, так и разрабатываемые диагностические подходы транскраниальной магнитной стимуляции для исследования патофизиологии двигательной системы в целом и для пред- сказания двигательного восстановления после инсульта в частности

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics

Dynamic reorganization of TMS-evoked activity in subcortical stroke patients

Since early days after stroke, the brain undergoes a complex reorganization to allow compensatory mechanisms that promote functional recovery. However, these mechanisms are still poorly understood and there is urgent need to identify neurophysiological markers of functional recovery after stroke. Here we aimed to track longitudinally the time-course of cortical reorganization by measuring for the first time EEG cortical activity evoked by TMS pulses in patients with subcortical stroke. Thirteen patients in the sub-acute phase of ischemic subcortical stroke with motor symptoms completed the longitudinal study, being evaluated within 20 days and after 40, 60 and 180 days after stroke onset. For each time-point, EEG cortical activity evoked by single TMS pulses was assessed over the motor and parietal cortex of the affected and unaffected hemisphere. We evaluated global TMS-evoked activity and TMS-evoked oscillations in different frequency bands. These measurements were paralleled with clinical and behavioral assessment. We found that motor cortical activity measured by TMS-EEG varied across time in the affected hemisphere. An increase of TMS-evoked activity was evident at 40 days after stroke onset. Moreover, stroke patients showed a significant increase in TMS-evoked alpha oscillations, as highlighted performing analysis in the time-frequency domain. Notably, these changes indicated that crucial mechanisms of cortical reorganization occur in this short-time window. These changes coincided with the clinical improvement. TMS-evoked alpha oscillatory activity recorded at baseline was associated to better functional recovery at 40 and 60 days' follow-up evaluations, suggesting that the power of the alpha rhythm can be considered a good predictor of motor recovery. This study demonstrates that cortical activity increases dynamically in the early phases of recovery after stroke in the affected hemisphere. These findings point to TMS-evoked alpha oscillatory activity as a potential neurophysiological markers of stroke recovery and could be helpful to determine the temporal window in which neuromodulation should be potentially able to drive neuroplasticity in an effective functional direction

Dynamic reorganization of TMS-evoked activity in subcortical stroke patients

Since early days after stroke, the brain undergoes a complex reorganization to allow compensatory mechanisms that promote functional recovery. However, these mechanisms are still poorly understood and there is urgent need to identify neurophysiological markers of functional recovery after stroke. Here we aimed to track longitudinally the time-course of cortical reorganization by measuring for the first time EEG cortical activity evoked by TMS pulses in patients with subcortical stroke. Thirteen patients in the sub-acute phase of ischemic subcortical stroke with motor symptoms completed the longitudinal study, being evaluated within 20 days and after 40, 60 and 180 days after stroke onset. For each time-point, EEG cortical activity evoked by single TMS pulses was assessed over the motor and parietal cortex of the affected and unaffected hemisphere. We evaluated global TMS-evoked activity and TMS-evoked oscillations in different frequency bands. These measurements were paralleled with clinical and behavioral assessment. We found that motor cortical activity measured by TMS-EEG varied across time in the affected hemisphere. An increase of TMS-evoked activity was evident at 40 days after stroke onset. Moreover, stroke patients showed a significant increase in TMS-evoked alpha oscillations, as highlighted performing analysis in the time-frequency domain. Notably, these changes indicated that crucial mechanisms of cortical reorganization occur in this short-time window. These changes coincided with the clinical improvement. TMS-evoked alpha oscillatory activity recorded at baseline was associated to better functional recovery at 40 and 60 days' follow-up evaluations, suggesting that the power of the alpha rhythm can be considered a good predictor of motor recovery. This study demonstrates that cortical activity increases dynamically in the early phases of recovery after stroke in the affected hemisphere. These findings point to TMS-evoked alpha oscillatory activity as a potential neurophysiological markers of stroke recovery and could be helpful to determine the temporal window in which neuromodulation should be potentially able to drive neuroplasticity in an effective functional direction

Optimising the Application of Transcranial Direct Current Stimulation

The ability of transcranial direct current stimulation (tDCS) to modulate brain activity has vast scientific and therapeutic potential, however, its effects are often variable which limit its utility. Both current flow direction and variance in electric field intensities reaching a cortical target may be vital sources of the variable tDCS effects on neuroplastic change. Controlling for these and exploring the subsequent effects on corticospinal excitability is the aim of this thesis. I here attempted to optimise the delivery of tDCS application by investigating the controlled application of current flow direction and whether through the use of current flow models, we can deliver comparable electric fields with reduced variability across differential montages. To assess whether current flow models are useful, I further investigated if dose-control translates to more consistent physiological outcomes. I demonstrate, firstly, that different current flow directions did not differentially affect the two banks of the central sulcus. Secondly, with the use of dose-control, high-definition tDCS (HD-tDCS) remains focally more advantageous, even with the delivery of comparable electric field intensity and variability as posterior-anterior tDCS (PA-tDCS) to a cortical region. Thirdly, dose-controlled tDCS does not translate to reduced physiological variability. Together, the work presented here suggests that current flow models are useful for informing dose-controlled protocols and montage comparisons for improved tDCS delivery, however, controlling for anatomical differences in the delivery of electric fields to a target is not sufficient to reduce the variability of tDCS effects in physiology. Thus, the methodology for optimised tDCS delivery remains a subject for further improvement and investigation. Advancements in this field may lead to a trusted methodology assisting stroke survivors with a more effective and efficient motor recovery journey

EEG and TMS-EEG Studies on the Cortical Excitability and Plasticity associated with Human Motor Control and Learning

More than half of the activities of daily living rely on upper limb functions (Ingram et al., 2008). Humans perform upper limb movements with great ease and flexibility but even simple tasks require complex computations in the brain and can be affected following stroke leaving survivors with debilitating movement impairments. Hemispheric asymmetries related to motor dominance, imbalances between contralateral and ipsilateral primary motor cortices (M1) activity and the ability to adapt movements to novel environments play a key role in upper limb motor control and can affect recovery. Motor learning and control are critical in neurorehabilitation, however to effectively integrate these concepts into upper limb recovery treatments, a deeper understanding of the basic mechanisms of unimanual control is needed. This thesis aimed to investigate hemispheric asymmetries related to motor dominance, to evaluate the relative contribution of the contralateral and ipsilateral M1 during unilateral reaching preparation and finally to identify the neural correlates underlying the formation of a predictive internal model enabling to adapt movements to new environments. To this end electroencephalography (EEG), transcranial magnetic stimulation (TMS), simultaneous TMS-EEG were employed during a simple motor and a highly standardised robot-mediated task. The first study used TMS-EEG to examine differences in cortical excitability related to motor dominance by applying TMS over the dominant and non-dominant M1 at rest and during contraction. No hemispheric asymmetries related to hand dominance were found. The second study assessed the temporal dynamics of bi-hemispheric motor cortical excitability during right arm reaching preparation. TMS was applied either to the ipsilateral or contralateral M1 during different times of movement preparation. Significant bilateral M1 activation during unilateral reaching preparation was observed, with no significant differences between the contralateral and ipsilateral M1. Unimanual reaching preparation was associated with significant interactions of excitatory and inhibitory processes in both motor cortices. The third study investigated the neural correlates of motor adaptation. EEG was recorded during a robot-mediated adaptation task involving right arm reaching movements and cortical excitability was assessed by applying TMS over the contralateral M1 and simultaneously recording TMS responses with EEG before and after motor adaptation. It was found that an error-related negativity (ERN) over fronto-central regions correlated with performance improvements during adaptation, suggesting that this neural activity reflects the formation of a predictive internal model. Motor adaptation underlay significant modulations in cortical excitability (i.e. neuroplasticity) in sensorimotor regions. Finally, it was shown that native cortical excitability was linked to motor learning improvements during motor adaptation and explained the variability in motor learning across individuals. These experiments demonstrated that even unimanual motor control relies on interactions between excitatory and inhibitory mechanisms not only in the contralateral M1 but in a wider range of brain regions, shown by a bi-hemispheric activity during movement preparation, the formation of a predictive model in fronto-central regions during motor adaptation and neuroplastic changes in sensorimotor regions underlying motor adaptation during unimanual reaching