On the Use of TMS to Investigate the Pathophysiology of Neurodegenerative Diseases

Neurodegenerative diseases are a collection of disorders that result in the progressive degeneration and death of neurons. They are clinically heterogenous and can present as deficits in movement, cognition, executive function, memory, visuospatial awareness and language. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool that allows for the assessment of cortical function in vivo. We review how TMS has been used for the investigation of three neurodegenerative diseases that differ in their neuroanatomical axes: (1) Motor cortex—corticospinal tract (motor neuron diseases), (2) Non-motor cortical areas (dementias), and (3) Subcortical structures (parkinsonisms). We also make four recommendations that we hope will benefit the use of TMS in neurodegenerative diseases. Firstly, TMS has traditionally been limited by the lack of an objective output and so has been confined to stimulation of the motor cortex; this limitation can be overcome by the use of concurrent neuroimaging methods such as EEG. Given that neurodegenerative diseases progress over time, TMS measures should aim to track longitudinal changes, especially when the aim of the study is to look at disease progression and symptomatology. The lack of gold-standard diagnostic confirmation undermines the validity of findings in clinical populations. Consequently, diagnostic certainty should be maximized through a variety of methods including multiple, independent clinical assessments, imaging and fluids biomarkers, and post-mortem pathological confirmation where possible. There is great interest in understanding the mechanisms by which symptoms arise in neurodegenerative disorders. However, TMS assessments in patients are usually carried out during resting conditions, when the brain network engaged during these symptoms is not expressed. Rather, a context-appropriate form of TMS would be more suitable in probing the physiology driving clinical symptoms. In all, we hope that the recommendations made here will help to further understand the pathophysiology of neurodegenerative diseases

The Role of Astrocytes in Remyelination.

Remyelination is the regeneration of myelin sheaths following demyelination. This regenerative process is critical for the re-establishment of axonal conduction velocity and metabolic support to the axons. Successful remyelination in the CNS generally depends on the activation, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs). However, other cell types play critical roles in establishing where a lesion is conducive for regeneration. In the last few years, several studies have described beneficial and detrimental roles played by astrocytes in remyelination. This review will discuss recent developments in the concept of astrocyte reactivity, what is known about the astrocytic contribution to remyelination, and highlight future avenues of investigation.The authors’ laboratory is supported by funding from the UK Multiple Sclerosis Society (MS50), The Adelson Medical Research Foundation, and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). KSR is supported by a postdoctoral fellowship from the Multiple Sclerosis Society of Canad

Variability and predictors of response to continuous theta burst stimulation: a TMS-EEG study

Continuous theta-burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation paradigm reported to decrease the excitability of the stimulated cortical area and which is thought to reflect a form of inhibitory synaptic plasticity. However, since its introduction, the effect of cTBS has shown a remarkable variability in its effects, which are often quantified by measuring the amplitude of motor evoked potentials (MEPs). Part of this inconsistency in experimental results might be due to an intrinsic variability of TMS effects caused by genetic or neurophysiologic factors. However, it is also possible that MEP only reflect the excitability of a sub-population of output neurons; resting EEG power and measures combining TMS and electroencephalography (TMS-EEG) might represent a more thorough reflection of cortical excitability. The aim of the present study was to verify the robustness of several predictors of cTBS response, such as I wave recruitment and baseline MEP amplitude, and to test cTBS after-effects on multiple neurophysiologic measurements such as MEP, resting EEG power, local mean field power (LMFP), TMS-related spectral perturbation (TRSP), and inter-trial phase clustering (ITPC). As a result, we were not able to confirm either the expected decrease of MEP amplitude after cTBS or the ability of I wave recruitment and MEP amplitude to predict the response to cTBS. Resting EEG power, LMFP, TRSP, and ITPC showed a more consistent trend toward a decrease after cTBS. Overall, our data suggest that the effect of cTBS on corticospinal excitability is variable and difficult to predict with common electrophysiologic markers, while its effect might be clearer when probed with combined TMS and EEG

tDCS changes in motor excitability are specific to orientation of current flow

BACKGROUND: Measurements and models of current flow in the brain during transcranial Direct Current Stimulation (tDCS) indicate stimulation of regions in-between electrodes. Moreover, the folded cortex results in local fluctuations in current flow intensity and direction, and animal studies suggest current flow direction relative to cortical columns determines response to tDCS. METHODS: Here we test this idea by using Transcranial Magnetic Stimulation Motor Evoked Potentials (TMS-MEP) to measure changes in corticospinal excitability following tDCS applied with electrodes aligned orthogonal (across) or parallel to M1 in the central sulcus. RESULTS: Current flow models predicted that the orthogonal electrode montage produces consistently oriented current across the hand region of M1 that flows along cortical columns, while the parallel electrode montage produces non-uniform current directions across the M1 cortical surface. We find that orthogonal, but not parallel, orientated tDCS modulates TMS-MEPs. We also show modulation is sensitive to the orientation of the TMS coil (PA or AP), which is thought to select different afferent pathways to M1. CONCLUSIONS: Our results are consistent with tDCS producing directionally specific neuromodulation in brain regions in-between electrodes, but shows nuanced changes in excitability that are presumably current direction relative to column and axon pathway specific. We suggest that the direction of current flow through cortical target regions should be considered for targeting and dose-control of tDCS

Impaired automatic but intact volitional inhibition in primary tic disorders

The defining character of tics is that they can be transiently suppressed by volitional effort of will, and at a behavioural level this has led to the concept that tics result from a failure of inhibition. However, this logic conflates the mechanism responsible for the production of tics with that used in suppressing them. Volitional inhibition of motor output could be increased to prevent the tic from reaching the threshold for expression, although this has been extensively investigated with conflicting results. Alternatively, automatic inhibition could prevent the initial excitation of the striatal tic focus-a hypothesis we have previously introduced. To reconcile these competing hypotheses, we examined different types of motor inhibition in a group of 19 patients with primary tic disorders and 15 healthy volunteers. We probed proactive and reactive inhibition using the conditional stop-signal task, and applied transcranial magnetic stimulation to the motor cortex, to assess movement preparation and execution. We assessed automatic motor inhibition with the masked priming task. We found that volitional movement preparation, execution and inhibition (proactive and reactive) were not impaired in tic disorders. We speculate that these mechanisms are recruited during volitional tic suppression, and that they prevent expression of the tic by inhibiting the nascent excitation released by the tic generator. In contrast, automatic inhibition was abnormal/impaired in patients with tic disorders. In the masked priming task, positive and negative compatibility effects were found for healthy controls, whereas patients with tics exhibited strong positive compatibility effects, but no negative compatibility effect indicative of impaired automatic inhibition. Patients also made more errors on the masked priming task than healthy control subjects and the types of errors were consistent with impaired automatic inhibition. Errors associated with impaired automatic inhibition were positively correlated with tic severity. We conclude that voluntary movement preparation/generation and volitional inhibition are normal in tic disorders, whereas automatic inhibition is impaired-a deficit that correlated with tic severity and thus may constitute a potential mechanism by which tics are generated

Impaired automatic but intact volitional inhibition in primary tic disorders

The defining character of tics is that they can be transiently suppressed by volitional effort of will, and at a behavioural level this has led to the concept that tics result from a failure of inhibition. However, this logic conflates the mechanism responsible for the production of tics with that used in suppressing them. Volitional inhibition of motor output could be increased to prevent the tic from reaching the threshold for expression, although this has been extensively investigated with conflicting results. Alternatively, automatic inhibition could prevent the initial excitation of the striatal tic focus—a hypothesis we have previously introduced. To reconcile these competing hypotheses, we examined different types of motor inhibition in a group of 19 patients with primary tic disorders and 15 healthy volunteers. We probed proactive and reactive inhibition using the conditional stop-signal task, and applied transcranial magnetic stimulation to the motor cortex, to assess movement preparation and execution. We assessed automatic motor inhibition with the masked priming task. We found that volitional movement preparation, execution and inhibition (proactive and reactive) were not impaired in tic disorders. We speculate that these mechanisms are recruited during volitional tic suppression, and that they prevent expression of the tic by inhibiting the nascent excitation released by the tic generator. In contrast, automatic inhibition was abnormal/impaired in patients with tic disorders. In the masked priming task, positive and negative compatibility effects were found for healthy controls, whereas patients with tics exhibited strong positive compatibility effects, but no negative compatibility effect indicative of impaired automatic inhibition. Patients also made more errors on the masked priming task than healthy control subjects and the types of errors were consistent with impaired automatic inhibition. Errors associated with impaired automatic inhibition were positively correlated with tic severity. We conclude that voluntary movement preparation/generation and volitional inhibition are normal in tic disorders, whereas automatic inhibition is impaired—a deficit that correlated with tic severity and thus may constitute a potential mechanism by which tics are generated

Disentangling EEG responses to TMS due to cortical and peripheral activations

BACKGROUND: the use of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the functional evaluation of the cerebral cortex in health and disease is becoming increasingly common. However, there is still some ambiguity regarding the extent to which brain responses to auditory and somatosensory stimulation contribute to the TMS-evoked potential (TEP). OBJECTIVE/HYPOTHESIS: to measure separately the contribution of auditory and somatosensory stimulation caused by TMS, and to assess their contribution to the TEP waveform, when stimulating the motor cortex (M1). METHODS: 19 healthy volunteers underwent 7 blocks of EEG recording. To assess the impact of auditory stimulation on the TEP waveform, we used a standard figure of eight coil, with or without masking with a continuous noise reproducing the specific time-varying frequencies of the TMS click, stimulating at 90% of resting motor threshold. To further characterise auditory responses due to the TMS click, we used either a standard or a sham figure of eight coil placed on a pasteboard cylinder that rested on the scalp, with or without masking. Lastly, we used electrical stimulation of the scalp to investigate the possible contribution of somatosensory activation. RESULTS: auditory stimulation induced a known pattern of responses in electrodes located around the vertex, which could be suppressed by appropriate noise masking. Electrical stimulation of the scalp alone only induced similar, non-specific scalp responses in the in the central electrodes. TMS, coupled with appropriate masking of sensory input, resulted in specific, lateralized responses at the stimulation site, lasting around 300 ms. CONCLUSIONS: if careful control of confounding sources is applied, TMS over M1 can generate genuine, lateralized EEG activity. By contrast, sensory evoked responses, if present, are represented by non-specific, late (100-200 ms) components, located at the vertex, possibly due to saliency of the stimuli. Notably, the latter can confound the TEP if masking procedures are not properly used

Disentangling EEG responses to TMS due to cortical and peripheral activations

Background: the use of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the functional evaluation of the cerebral cortex in health and disease is becoming increasingly common. However, there is still some ambiguity regarding the extent to which brain responses to auditory and somatosensory stimulation contribute to the TMS-evoked potential (TEP). Objective/Hypothesis: to measure separately the contribution of auditory and somatosensory stimulation caused by TMS, and to assess their contribution to the TEP waveform, when stimulating the motor cortex (M1). Methods: 19 healthy volunteers underwent 7 blocks of EEG recording. To assess the impact of auditory stimulation on the TEP waveform, we used a standard figure of eight coil, with or without masking with a continuous noise reproducing the specific time-varying frequencies of the TMS click, stimulating at 90% of resting motor threshold. To further characterise auditory responses due to the TMS click, we used either a standard or a sham figure of eight coil placed on a pasteboard cylinder that rested on the scalp, with or without masking. Lastly, we used electrical stimulation of the scalp to investigate the possible contribution of somatosensory activation. Results: auditory stimulation induced a known pattern of responses in electrodes located around the vertex, which could be suppressed by appropriate noise masking. Electrical stimulation of the scalp alone only induced similar, non-specific scalp responses in the in the central electrodes. TMS, coupled with appropriate masking of sensory input, resulted in specific, lateralized responses at the stimulation site, lasting around 300 ms. Conclusions: if careful control of confounding sources is applied, TMS over M1 can generate genuine, lateralized EEG activity. By contrast, sensory evoked responses, if present, are represented by non-specific, late (100–200 ms) components, located at the vertex, possibly due to saliency of the stimuli. Notably, the latter can confound the TEP if masking procedures are not properly used

Transcranial evoked potentials can be reliably recorded with active electrodes

Electroencephalographic (EEG) signals evoked by transcranial magnetic stimulation (TMS) are usually recorded with passive electrodes (PE). Active electrode (AE) systems have recently become widely available; compared to PE, they allow for easier electrode preparation and a higher-quality signal, due to the preamplification at the electrode stage, which reduces electrical line noise. The performance between the AE and PE can differ, especially with fast EEG voltage changes, which can easily occur with TMS-EEG; however, a systematic comparison in the TMS-EEG setting has not been made. Therefore, we recorded TMS-evoked EEG potentials (TEPs) in a group of healthy subjects in two sessions, one using PE and the other using AE. We stimulated the left primary motor cortex and right medial prefrontal cortex and used two different approaches to remove early TMS artefacts, Independent Component Analysis and Signal Space Projection—Source Informed Recovery. We assessed statistical differences in amplitude and topography of TEPs, and their similarity, by means of the concordance correlation coefficient (CCC). We also tested the capability of each system to approximate the final TEP waveform with a reduced number of trials. The results showed that TEPs recorded with AE and PE do not differ in amplitude and topography, and only few electrodes showed a lower-than-expected CCC between the two methods of amplification. We conclude that AE are a viable solution for TMS-EEG recording

Variability and Predictors of Response to Continuous Theta Burst Stimulation: A TMS-EEG Study

Continuous theta-burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation paradigm reported to decrease the excitability of the stimulated cortical area and which is thought to reflect a form of inhibitory synaptic plasticity. However, since its introduction, the effect of cTBS has shown a remarkable variability in its effects, which are often quantified by measuring the amplitude of motor evoked potentials (MEPs). Part of this inconsistency in experimental results might be due to an intrinsic variability of TMS effects caused by genetic or neurophysiologic factors. However, it is also possible that MEP only reflect the excitability of a sub-population of output neurons; resting EEG power and measures combining TMS and electroencephalography (TMS-EEG) might represent a more thorough reflection of cortical excitability. The aim of the present study was to verify the robustness of several predictors of cTBS response, such as I wave recruitment and baseline MEP amplitude, and to test cTBS after-effects on multiple neurophysiologic measurements such as MEP, resting EEG power, local mean field power (LMFP), TMS-related spectral perturbation (TRSP), and inter-trial phase clustering (ITPC). As a result, we were not able to confirm either the expected decrease of MEP amplitude after cTBS or the ability of I wave recruitment and MEP amplitude to predict the response to cTBS. Resting EEG power, LMFP, TRSP, and ITPC showed a more consistent trend toward a decrease after cTBS. Overall, our data suggest that the effect of cTBS on corticospinal excitability is variable and difficult to predict with common electrophysiologic markers, while its effect might be clearer when probed with combined TMS and EEG