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

Does inhibitory repetitive transcranial magnetic stimulation augment functional task practice to improve arm recovery in chronic stroke?

Introduction. Restoration of upper extremity (UE) functional use remains a challenge for individuals following stroke. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive modality that modulates cortical excitability and is being explored as a means to potentially ameliorate these deficits. The purpose of this study was to evaluate, in the presence of chronic stroke, the effects of low-frequency rTMS to the contralesional hemisphere as an adjuvant to functional task practice (FTP), to improve UE functional ability. Methods. Twenty-two individuals with chronic stroke and subsequent moderate UE deficits were randomized to receive 16 sessions (4 times/week for 4 weeks) of either real-rTMS or sham-rTMS followed by 1-hour of paretic UE FTP. Results. No differences in UE outcomes were revealed between the real-rTMS and sham-rTMS intervention groups. After adjusting for baseline differences, no differences were revealed in contralesional cortical excitability postintervention. In a secondary analysis, data pooled across both groups revealed small, but statistically significant, improvements in UE behavioral measures. Conclusions. rTMS did not augment changes in UE motor ability in this population of individuals with chronic stroke. The chronicity of our participant cohort and their degree of UE motor impairment may have contributed to inability to produce marked effects using rTMS

Interhemispheric Interactions between the Human Primary Somatosensory Cortices

In the somatosensory domain it is still unclear at which processing stage information reaches the opposite hemispheres. Due to dense transcallosal connections, the secondary somatosensory cortex (S2) has been proposed to be the key candidate for interhemispheric information transfer. However, recent animal studies showed that the primary somatosensory cortex (S1) might as well account for interhemispheric information transfer. Using paired median nerve somatosensory evoked potential recordings in humans we tested the hypothesis that interhemispheric inhibitory interactions in the somatosensory system occur already in an early cortical processing stage such as S1. Conditioning right S1 by electrical median nerve (MN) stimulation of the left MN (CS) resulted in a significant reduction of the N20 response in the target (left) S1 relative to a test stimulus (TS) to the right MN alone when the interstimulus interval between CS and TS was between 20 and 25 ms. No such changes were observed for later cortical components such as the N20/P25, N30, P40 and N60 amplitude. Additionally, the subcortically generated P14 response in left S1 was also not affected. These results document the existence of interhemispheric inhibitory interactions between S1 in human subjects in the critical time interval of 20–25 ms after median nerve stimulation

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

Exploring the role of interhemispheric inhibition in musculoskeletal pain

The overarching aim of this thesis was to determine whether: i) interhemispheric inhibition (IHI) is altered in response to unilateral musculoskeletal pain; and ii) a relationship exists between altered IHI (if any) and the development of bilateral sensorimotor dysfunction. To achieve this, three studies were conducted. These studies provided novel insight into IHI in experimentally induced acute muscle pain and chronic lateral elbow pain. The body of work in this thesis provides an original contribution to the field of musculoskeletal pain that deepens our understanding of IHI, and its potential association with changes in sensorimotor function in the unaffected limb, in unilateral conditions. Study 1 demonstrated a reduction in IHI from the affected to unaffected M1 but no change in IHI from the affected to unaffected S1 was observed in Study 2. In both studies, increased sensitivity to pressure was observed on the affected and unaffected sides. No change in IHI between M1s, and no differences in sensorimotor function were observed between individuals with chronic LE and healthy controls in Study 3. Taken together, the findings presented in this thesis suggest that IHI between M1s is reduced in response to acute muscle pain and altered IHI could contribute to the development of bilateral sensorimotor symptoms soon after pain onset. Conversely, IHI between S1s is preserved in response to acute muscle pain. In a clinical chronic musculoskeletal pain population, IHI is also preserved. However, further research is needed to determine whether the degree of change in IHI is related to various features of clinical pain such as pain severity, or the severity of bilateral sensorimotor dysfunction. The studies in this thesis are amongst the first to investigate: i) IHI in response to musculoskeletal pain of varying durations; and ii) the relationship between altered IHI and the development of bilateral sensorimotor dysfunction. Longitudinal studies that follow individuals from an initial episode of acute musculoskeletal pain to recovery, or to the development of chronic musculoskeletal pain, are required to further explore the relationship between IHI and the development of bilateral sensorimotor symptoms in unilateral musculoskeletal pain conditions

Stratifying chronic stroke patients based on the influence of contralesional motor cortices: an inter-hemispheric inhibition study

Objective: A recent “bimodal-balance recovery” model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships. Methods: Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5 week-rehabilitation (n=21). Results: Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40-46). Patients less impaired than UEFM=43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM=43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n=14), more-impaired patients showed further IHI reduction. Conclusions: A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation. Significance: The criterion may be used to stratify patients to design targeted, precision treatments

Physiological and behavioural consequences of network breakdown in brain injury

Traumatic brain injury (TBI) is a major public health problem with a huge unmet need for effective long-term care. Advances in MRI technology using diffusion tensor imaging (DTI) have demonstrated structural abnormalities in patients with TBI, often not seen on conventional brain imaging. The structural and neuropsychological consequences are described in existing research. The aim of this thesis is to identify whether there are physiological and behavioural consequences of TBI, which may be contributing to the observed problems in daily activities associated with this condition. This will help to understand the devastating functional impact following TBI, and its neurorehabilitation needs. This thesis initially develops a study protocol to investigate the physiology in TBI. Initial work explores physiology in thirty four healthy individuals using transcranial magnetic stimulation (TMS) to produce a study protocol that can be used in the patient group. This examined a selection of pathways, including the assessment of callosal physiology using a twin coil TMS method to assess for interhemispheric inhibition. This protocol was used to assess seventeen TBI patients, and compared to healthy controls, and demonstrated that callosal transfer is physiologically different between the two groups. The behavioural consequences of callosal transfer were then explored through the development of a bimanual tapping task in twenty nine healthy participants. The behavioural consequences were then assessed in the same group of TBI patients, and compared to the control group. The TBI patients had comparable mean performance. However, the variability in performance was the main difference between the two groups. The MRI DTI metrics were then investigated in the TBI and control groups. A relationship between the physiology, behaviour and microstructure was then explored. Through this series of investigations this thesis hopes to increase existing understanding of the consequences of brain injury