Jason L. Neva

A Review of Transcranial Magnetic Stimulation and Multimodal Neuroimaging to Characterize Post-Stroke Neuroplasticity

Following stroke, the brain undergoes various stages of recovery where the central nervous system can reorganize neural circuitry (neuroplasticity) both spontaneously and with the aid of behavioral rehabilitation and non-invasive brain stimulation. Multiple neuroimaging techniques can characterize common structural and functional stroke-related deficits, and importantly, help predict recovery of function. Diffusion tensor imaging (DTI) typically reveals increased overall diffusivity throughout the brain following stroke, and is capable of indexing the extent of white matter damage. Magnetic resonance spectroscopy (MRS) provides an index of metabolic changes in surviving neural tissue after stroke, serving as a marker of brain function. The neural correlates of altered brain activity after stroke have been demonstrated by abnormal activation of sensorimotor cortices during task performance, and at rest, using functional magnetic resonance imaging (fMRI). Electroencephalography (EEG) has been used to characterize motor dysfunction in terms of increased cortical amplitude in the sensorimotor regions when performing upper limb movement, indicating abnormally increased cognitive effort and planning in individuals with stroke. Transcranial magnetic stimulation (TMS) work reveals changes in ipsilesional and contralesional cortical excitability in the sensorimotor cortices. The severity of motor deficits indexed using TMS has been linked to the magnitude of activity imbalance between the sensorimotor cortices. In this paper, we will provide a narrative review of data from studies utilizing DTI, MRS, fMRI, EEG, and brain stimulation techniques focusing on TMS and its combination with uni- and multimodal neuroimaging methods to assess recovery after stroke. Approaches that delineate the best measures with which to predict or positively alter outcomes will be highlighted.

Evaluation of differences in brain neurophysiology and morphometry associated with hand function in individuals with chronic stroke.

PURPOSE Rehabilitation interventions need to be optimized to maximize therapeutic effects and minimize stroke-related disability. However, a comprehensive understanding of the neural substrates underlying recovery is lacking. The purpose of this study was to investigate relationships between brain anatomy, physiology and hand motor function in individuals with chronic stroke. METHODS Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) approaches were used to evaluate cortical excitability and brain structural morphometry in individuals with chronic stroke. Hemispheric differences and relationships between these measures and hand dexterity were evaluated. RESULTS Hemispheric differences were observed for TMS and MRI measures. Bilateral hand dexterity correlated with TMS resting motor threshold and precentral gyral thickness. Transcallosal inhibition across hemispheres was positively associated with midcallosal white matter volume. Regression modeling results demonstrated that combining TMS and MRI measures predicted unique amounts of variance in hand dexterity. CONCLUSIONS RESULTS confirm and extend findings showing differences in brain structure and function after stroke. RESULTS suggested a structure-function relationship underlying interhemispheric connectivity in chronic stroke. The utility of combined TMS and MRI measures to predict motor function can be used in future investigations to aid identifying optimal biomarkers of stroke recovery to predict response to rehabilitation to maximize treatment outcomes.

Multiple measures of corticospinal excitability are associated with clinical features of multiple sclerosis

In individuals with multiple sclerosis (MS), transcranial magnetic stimulation (TMS) may be employed to assess the integrity of corticospinal system and provides a potential surrogate biomarker of disability. The purpose of this study was to provide a comprehensive examination of the relationship between multiple measures corticospinal excitability and clinical disability in MS (expanded disability status scale (EDSS)). Bilateral corticospinal excitability was assessed using motor evoked potential (MEP) input-output (IO) curves, cortical silent period (CSP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and transcallosal inhibition (TCI) in 26 individuals with MS and 11 healthy controls. Measures of corticospinal excitability were compared between individuals with MS and controls. We evaluated the relationship(s) between age and clinical demographics such as age at MS onset (AO), disease duration (DD) and clinical disability (EDSS) with measures of corticospinal excitability. Corticospinal excitability thresholds were higher, MEP latency and CSP onset delayed and MEP durations prolonged in individuals with MS compared to controls. Age, DD and EDSS correlated with corticospinal excitability thresholds. Also, TCI duration and the linear slope of the MEP amplitude IO curve correlated with EDSS. Hierarchical regression modeling demonstrated that combining multiple TMS-based measures of corticospinal excitability accounted for unique variance in clinical disability (EDSS) beyond that of clinical demographics (AO, DD). Our results indicate that multiple TMS-based measures of corticospinal and interhemispheric excitability provide insights into the potential neural mechanisms associated with clinical disability in MS. These findings may aid in the clinical evaluation, disease monitoring and prediction of disability in MS.

Promoting Motor Cortical Plasticity with Acute Aerobic Exercise: A Role for Cerebellar Circuits

Acute aerobic exercise facilitated long-term potentiation-like plasticity in the human primary motor cortex (M1). Here, we investigated the effect of acute aerobic exercise on cerebellar circuits, and their potential contribution to altered M1 plasticity in healthy individuals (age: 24.8 ± 4.1 years). In Experiment   1, acute aerobic exercise reduced cerebellar inhibition (CBI) (n = 10, p = 0.01), elicited by dual-coil paired-pulse transcranial magnetic stimulation. In Experiment   2, we evaluated the facilitatory effects of aerobic exercise on responses to paired associative stimulation, delivered with a 25 ms (PAS25) or 21 ms (PAS21) interstimulus interval (n = 16 per group). Increased M1 excitability evoked by PAS25, but not PAS21, relies on trans-cerebellar sensory pathways. The magnitude of the aerobic exercise effect on PAS response was not significantly different between PAS protocols (interaction effect: p = 0.30); however, planned comparisons indicated that, relative to a period of rest, acute aerobic exercise enhanced the excitatory response to PAS25 (p = 0.02), but not PAS21 (p = 0.30). Thus, the results of these planned comparisons indirectly provide modest evidence that modulation of cerebellar circuits may contribute to exercise-induced increases in M1 plasticity. The findings have implications for developing aerobic exercise strategies to “prime” M1 plasticity for enhanced motor skill learning in applied settings.

Selectivity of conventional electrodes for recording motor evoked potentials: an investigation with high-density surface electromyography.

The objective of this study was to determine whether motor evoked potentials (MEPs) elicited with transcranial magnetic stimulation and measured with conventional bipolar electromyography (EMG) are influenced by crosstalk from non‐target muscles.

An acute bout of exercise modulates both intracortical and interhemispheric excitability

Primary motor cortex (M1) excitability is modulated following a single session of cycling exercise. Specifically, short‐interval intracortical inhibition and intracortical facilitation are altered following a session of cycling, suggesting that exercise affects the excitability of varied cortical circuits. Yet we do not know whether a session of exercise also impacts the excitability of interhemispheric circuits between, and other intracortical circuits within, M1. Here we present two experiments designed to address this gap in knowledge. In experiment 1, single and paired pulse transcranial magnetic stimulation (TMS) were used to measure intracortical circuits including, short‐interval intracortical facilitation (SICF) tested at 1.1, 1.5, 2.7, 3.1 and 4.5 ms interstimulus intervals (ISIs), contralateral silent period (CSP) and interhemispheric interactions by measuring transcallosal inhibition (TCI) recorded from the abductor pollicus brevis muscles. All circuits were assessed bilaterally pre and two time points post (immediately, 30 min) moderate intensity lower limb cycling. SICF was enhanced in the left hemisphere after exercise at the 1.5 ms ISI. Also, CSP was shortened and TCI decreased bilaterally after exercise. In Experiment 2, corticospinal and spinal excitability were tested before and after exercise to investigate the locus of the effects found in Experiment 1. Exercise did not impact motor‐evoked potential recruitment curves, Hoffman reflex or V‐wave amplitudes. These results suggest that a session of exercise decreases intracortical and interhemispheric inhibition and increases facilitation in multiple circuits within M1, without concurrently altering spinal excitability. These findings have implications for developing exercise strategies designed to potentiate M1 plasticity and skill learning in healthy and clinical populations.

Behavioral and Neural Evidence of the Rewarding Value of Exercise Behaviors: A Systematic Review

BackgroundIn a time of physical inactivity pandemic, attempts to better understand the factors underlying the regulation of exercise behavior are important. The dominant neurobiological approach to exercise behavior considers physical activity to be a reward; however, negative affective responses during exercise challenge this idea.ObjectiveOur objective was to systematically review studies testing the automatic reactions triggered by stimuli associated with different types of exercise behavior (e.g. physical activity, sedentary behaviors) and energetic cost variations (e.g. decreased energetic cost, irrespective of the level of physical activity). We also examined evidence supporting the hypothesis that behaviors minimizing energetic cost (BMEC) are rewarding.MethodsTwo authors systematically searched, screened, extracted, and analyzed data from articles in the MEDLINE database.ResultsWe included 26 studies. Three outcomes of automatic processes were tested: affective reactions, attentional capture, and approach tendencies. Behavioral results show that physical activity can become attention-grabbing, automatically trigger positive affect, and elicit approach behaviors. These automatic reactions explain and predict exercise behaviors; however, the use of a wide variety of measures prevents drawing solid conclusions about the specific effects of automatic processes. Brain imaging results are scarce but show that stimuli associated with physical activity and, to a lesser extent, sedentary behaviors activate regions involved in reward processes. Studies investigating the rewarding value of behaviors driving energetic cost variations such as BMEC are lacking.ConclusionReward is an important factor in exercise behavior. The literature based on the investigation of automatic behaviors seems in line with the suggestion that physical activity is rewarding, at least for physically active individuals. Results suggest that sedentary behaviors could also be rewarding, although this evidence remains weak due to a lack of investigations. Finally, from an evolutionary perspective, BMEC are likely to be rewarding; however, no study has investigated this hypothesis. In sum, additional studies are required to establish a strong and complete framework of the reward processes underlying automatic exercise behavior.

Predicting Motor Sequence Learning in Individuals With Chronic Stroke

Background. Conventionally, change in motor performance is quantified with discrete measures of behavior taken pre- and postpractice. As a high degree of movement variability exists in motor performance after stroke, pre- and posttesting of motor skill may lack sensitivity to predict potential for motor recovery. Objective. Evaluate the use of predictive models of motor learning based on individual performance curves and clinical characteristics of motor function in individuals with stroke. Methods. Ten healthy and fourteen individuals with chronic stroke performed a continuous joystick-based tracking task over 6 days, and at a 24-hour delayed retention test, to assess implicit motor sequence learning. Results. Individuals with chronic stroke demonstrated significantly slower rates of improvements in implicit sequence-specific motor performance compared with a healthy control (HC) group when root mean squared error performance data were fit to an exponential function. The HC group showed a positive relationship between a faster rate of change in implicit sequence-specific motor performance during practice and superior performance at the delayed retention test. The same relationship was shown for individuals with stroke only after accounting for overall motor function by including Wolf Motor Function Test rate in our model. Conclusion. Nonlinear information extracted from multiple time points across practice, specifically the rate of motor skill acquisition during practice, relates strongly with changes in motor behavior at the retention test following practice and could be used to predict optimal doses of practice on an individual basis.

Interhemispheric Pathways Are Important for Motor Outcome in Individuals with Chronic and Severe Upper Limb Impairment Post Stroke

Background Severity of arm impairment alone does not explain motor outcomes in people with severe impairment post stroke. Objective Define the contribution of brain biomarkers to upper limb motor outcomes in people with severe arm impairment post stroke. Methods Paretic arm impairment (Fugl-Meyer upper limb, FM-UL) and function (Wolf Motor Function Test rate, WMFT-rate) were measured in 15 individuals with severe (FM-UL ≤ 30/66) and 14 with mild–moderate (FM-UL > 40/66) impairment. Transcranial magnetic stimulation and diffusion weight imaging indexed structure and function of the corticospinal tract and corpus callosum. Separate models of the relationship between possible biomarkers and motor outcomes at a single chronic (≥6 months) time point post stroke were performed. Results Age (ΔR20.365, p = 0.017) and ipsilesional-transcallosal inhibition (ΔR20.182, p = 0.048) explained a 54.7% (p = 0.009) variance in paretic WMFT-rate. Prefrontal corpus callous fractional anisotropy (PF-CC FA) alone explained 49.3% (p = 0.007) variance in FM-UL outcome. The same models did not explain significant variance in mild–moderate stroke. In the severe group, k-means cluster analysis of PF-CC FA distinguished two subgroups, separated by a clinically meaningful and significant difference in motor impairment (p = 0.049) and function (p = 0.006) outcomes. Conclusion Corpus callosum function and structure were identified as possible biomarkers of motor outcome in people with chronic and severe arm impairment.

Use of transcranial magnetic stimulation in the treatment of selected movement disorders

Abstract Transcranial magnetic stimulation (TMS) is a valuable technique for assessing the underlying neurophysiology associated with various neuropathologies, and is a unique tool for establishing potential neural mechanisms responsible for disease progression. Recently, repetitive TMS (rTMS) has been advanced as a potential therapeutic technique to treat selected neurologic disorders. In healthy individuals, rTMS can induce changes in cortical excitability. Therefore, targeting specific cortical areas affected by movement disorders theoretically may alter symptomology. This review discusses the evidence for the efficacy of rTMS in Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. It is hoped that gaining a more thorough understanding of the timing and parameters of rTMS in individuals with neurodegenerative disorders may advance both clinical care and research into the most effective uses of this technology.