David A. Cunningham

Rethinking Stimulation of the Brain in Stroke Rehabilitation Why Higher Motor Areas Might Be Better Alternatives for Patients with Greater Impairments

Stimulating the brain to drive its adaptive plastic potential is promising to accelerate rehabilitative outcomes in stroke. The ipsilesional primary motor cortex (M1) is invariably facilitated. However, evidence supporting its efficacy is divided, indicating that we may have overgeneralized its potential. Since the M1 and its corticospinal output are frequently damaged in patients with serious lesions and impairments, ipsilesional premotor areas (PMAs) could be useful alternates instead. We base our premise on their higher probability of survival, greater descending projections, and adaptive potential, which is causal for recovery across the seriously impaired. Using a conceptual model, we describe how chronically stimulating PMAs would strongly affect key mechanisms of stroke motor recovery, such as facilitating the plasticity of alternate descending output, restoring interhemispheric balance, and establishing widespread connectivity. Although at this time it is difficult to predict whether PMAs would be “better,” it is important to at least investigate whether they are reasonable substitutes for the M1. Even if the stimulation of the M1 may benefit those with maximum recovery potential, while that of PMAs may only help the more disadvantaged, it may still be reasonable to achieve some recovery across the majority rather than stimulate a single locus fated to be inconsistently effective across all.

Assessment of Inter-Hemispheric Imbalance Using Imaging and Noninvasive Brain Stimulation in Patients With Chronic Stroke

OBJECTIVEnTo determine how interhemispheric balance in stroke, measured using transcranial magnetic stimulation (TMS), relates to balance defined using neuroimaging (functional magnetic resonance [fMRI], diffusion-tensor imaging [DTI]) and how these metrics of balance are associated with clinical measures of upper-limb function and disability.nnnDESIGNnCross sectional.nnnSETTINGnLaboratory.nnnPARTICIPANTSnPatients with chronic stroke (N = 10; age, 63 ± 9 y) in a population-based sample with unilateral upper-limb paresis.nnnINTERVENTIONSnNot applicable.nnnMAIN OUTCOME MEASURESnInterhemispheric balance was measured with TMS, fMRI, and DTI. TMS defined interhemispheric differences in the recruitment of corticospinal output, size of the corticomotor output maps, and degree of mutual transcallosal inhibition that they exerted on one another. fMRI studied whether cortical activation during the movement of the paretic hand was lateralized to the ipsilesional or to the contralesional primary motor cortex (M1), premotor cortex (PMC), and supplementary motor cortex (SMA). DTI was used to define interhemispheric differences in the integrity of the corticospinal tracts projecting from the M1. Clinical outcomes tested function (upper extremity Fugl-Meyer [UEFM]) and perceived disability in the use of the paretic hand (Motor Activity Log [MAL] amount score).nnnRESULTSnInterhemispheric balance assessed with TMS relates differently to fMRI and DTI. Patients with high fMRI lateralization to the ipsilesional hemisphere possessed stronger ipsilesional corticomotor output maps (M1: r = .831, P = .006; PMC: r = .797, P = .01) and better balance of mutual transcallosal inhibition (r = .810, P = .015). Conversely, we found that patients with less integrity of the corticospinal tracts in the ipsilesional hemisphere show greater corticospinal output of homologous tracts in the contralesional hemisphere (r = .850, P = .004). However, an imbalance in integrity and output do not relate to transcallosal inhibition. Clinically, although patients with less integrity of corticospinal tracts from the ipsilesional hemisphere showed worse impairments (UEFM) (r = -.768, P = .016), those with low fMRI lateralization to the ipsilesional hemisphere had greater perception of disability (MAL amount score) (M1: r = .883, P = .006; PMC: r = .817, P = .007; SMA: r = .633, P = .062).nnnCONCLUSIONSnIn patients with chronic motor deficits of the upper limb, fMRI may serve to mark perceived disability and transcallosal influence between hemispheres. DTI-based integrity of the corticospinal tracts, however, may be useful in categorizing the range of functional impairments of the upper limb. Further, in patients with extensive corticospinal damage, DTI may help infer the role of the contralesional hemisphere in recovery.

Functional somatotopy revealed across multiple cortical regions using a model of complex motor task

The primary motor cortex (M1) possesses a functional somatotopic structure-representations of adjacent within-limb joints overlap to facilitate coordination while maintaining discrete centers for individuated movement. We examined whether similar organization exists across other sensorimotor cortices. Twenty-four right-handed healthy subjects underwent functional magnetic resonance imaging (fMRI) while tracking complex targets with flexion/extension at right finger, elbow and ankle separately. Activation related to each joint at false discovery rate of 0.005 served as its representation across multiple regions. Within each region, we identified the center of mass (COM) for each representation, and the overlap between the representations of within-limb (finger and elbow) and between-limb joints (finger and ankle). Somatosensory (S1) and premotor cortices (PMC) demonstrated greater distinction of COM and minimal overlap for within- and between-limb representations. In contrast, M1 and supplementary motor area (SMA) showed more integrative somatotopy with higher sharing for within-limb representations. Superior and inferior parietal lobule (SPL and IPL) possessed both types of structure. Some clusters exhibited extensive overlap of within- and between-limb representations, while others showed discrete COMs for within-limb representations. Our results help to infer hierarchy in motor control. Areas such as S1 may be associated with individuated movements, while M1 may be more integrative for coordinated motion; parietal associative regions may allow switch between both modes of control. Such hierarchy creates redundant opportunities to exploit in stroke rehabilitation. The use of complex rather than traditionally used simple movements was integral to illustrating comprehensive somatotopic structure; complex tasks can potentially help to understand cortical representation of skill and learning-related plasticity.

Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of-concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms

PURPOSEnTo demonstrate, in a proof-of-concept study, whether potentiating ipsilesional higher motor areas (premotor cortex and supplementary motor area) augments and accelerates recovery associated with constraint induced movement.nnnMETHODSnIn a randomized, double-blinded pilot clinical study, 12 patients with chronic stroke were assigned to receive anodal transcranial direct current stimulation (tDCS) (nu200a=u200a6) or sham (nu200a=u200a6) to the ipsilesional higher motor areas during constraint-induced movement therapy. We assessed functional and neurophysiologic outcomes before and after 5 weeks of therapy.nnnRESULTSnOnly patients receiving tDCS demonstrated gains in function and dexterity. Gains were accompanied by an increase in excitability of the contralesional rather than the ipsilesional hemisphere.nnnCONCLUSIONSnOur proof-of-concept study provides early evidence that stimulating higher motor areas can help recruit the contralesional hemisphere in an adaptive role in cases of greater ipsilesional injury. Whether this early evidence of promise translates to remarkable gains in functional recovery compared to existing approaches of stimulation remains to be confirmed in large-scale clinical studies that can reasonably dissociate stimulation of higher motor areas from that of the traditional primary motor cortices.

It Takes Two: Noninvasive Brain Stimulation Combined With Neurorehabilitation

The goal of postacute neurorehabilitation is to maximize patient function, ideally by using surviving brain and central nervous system tissue when possible. However, the structures incorporated into neurorehabilitative approaches often differ from this target, which may explain why the efficacy of conventional clinical treatments targeting neurologic impairment varies widely. Noninvasive brain stimulation (eg, transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS]) offers the possibility of directly targeting brain structures to facilitate or inhibit their activity to steer neural plasticity in recovery and measure neuronal output and interactions for evaluating progress. The latest advances as stereotactic navigation and electric field modeling are enabling more precise targeting of patients residual structures in diagnosis and therapy. Given its promise, this supplement illustrates the wide-ranging significance of TMS and tDCS in neurorehabilitation, including in stroke, pediatrics, traumatic brain injury, focal hand dystonia, neuropathic pain, and spinal cord injury. TMS and tDCS are still not widely used and remain poorly understood in neurorehabilitation. Therefore, the present supplement includes articles that highlight ready clinical application of these technologies, including their comparative diagnostic capabilities relative to neuroimaging, their therapeutic benefit, their optimal delivery, the stratification of likely responders, and the variable benefits associated with their clinical use because of interactions between pathophysiology and the innate reorganization of the patients brain. Overall, the supplement concludes that whether provided in isolation or in combination, noninvasive brain stimulation and neurorehabilitation are synergistic in the potential to transform clinical practice.

Effectiveness and neural mechanisms associated with tDCS delivered to premotor cortex in stroke rehabilitation: study protocol for a randomized controlled trial

BackgroundMore than 60% of stroke survivors experience residual deficits of the paretic upper limb/hand. Standard rehabilitation generates modest gains. Stimulation delivered to the surviving Primary Motor Cortex in the stroke-affected hemisphere has been considered a promising adjunct. However, recent trials challenge its advantage. We discuss our pilot clinical trial that aims to address factors implicated in divergent success of the approach. We assess safety, feasibility and efficacy of targeting an alternate locus during rehabilitation- the premotor cortex. In anticipating variance across patients, we measure neural markers differentiating response from non-response.Methods/DesignIn a randomized, sham-controlled, double-blinded pilot clinical study, patients with chronic stroke (nu2009=u200920) are assigned to receive transcranial direct current stimulation delivered to the premotor cortex or sham during rehabilitation of the paretic arm/hand. Patients receive the designated intervention for 30xa0min, twice a day for 3xa0days a week for 5xa0weeks. We assess hand function and patients’ reports of use of paretic hand. A general linear mixed methods model will analyze changes from pre- to post-intervention. Responders and non-responders will be compared upon baseline level of function, and neural substrates, including function and integrity of output tracts, bi-hemispheric balance, and lesion profile. Incidence of adverse events will be compared using Fisher’s Exact test, while rigor of blinding will be assessed with Chi-square analysis to ascertain feasibility.DiscussionVariable success of cortical stimulation in rehabilitation can be related to gaps in theoretical basis and clinical investigation. Given that most patients with severe deficits have damage to the primary motor cortex or its output pathways, it would be futile to target stimulation to this site. We suggest targeting premotor cortex because it contributes substantially to descending output, a role that is amplified with greater damage to the motor cortex. With regards to clinical investigation, paired cortical stimulation in rehabilitation has been compared to rehabilitation alone in unblinded trials or to unconvincing sham conditions. Transcranial direct current stimulation, a noninvasive technique of brain stimulation, which offers a more effective placebo and has a favorable safety-feasibility profile, may improve scientific rigor. Neural markers of response would help inform patient selection for future clinical trials so we can address limitations of recent negative studies.Trial registrationNCT01539096

Models to tailor brain stimulation therapies in stroke

A great challenge facing stroke rehabilitation is the lack of information on how to derive targeted therapies. As such, techniques once considered promising, such as brain stimulation, have demonstrated mixed efficacy across heterogeneous samples in clinical studies. Here, we explain reasons, citing its one-type-suits-all approach as the primary cause of variable efficacy. We present evidence supporting the role of alternate substrates, which can be targeted instead in patients with greater damage and deficit. Building on this groundwork, this review will also discuss different frameworks on how to tailor brain stimulation therapies. To the best of our knowledge, our report is the first instance that enumerates and compares across theoretical models from upper limb recovery and conditions like aphasia and depression. Here, we explain how different models capture heterogeneity across patients and how they can be used to predict which patients would best respond to what treatments to develop targeted, individualized brain stimulation therapies. Our intent is to weigh pros and cons of testing each type of model so brain stimulation is successfully tailored to maximize upper limb recovery in stroke.

Age-Related Weakness of Proximal Muscle Studied with Motor Cortical Mapping: A TMS Study

Aging-related weakness is due in part to degeneration within the central nervous system. However, it is unknown how changes to the representation of corticospinal output in the primary motor cortex (M1) relate to such weakness. Transcranial magnetic stimulation (TMS) is a noninvasive method of cortical stimulation that can map representation of corticospinal output devoted to a muscle. Using TMS, we examined age-related alterations in maps devoted to biceps brachii muscle to determine whether they predicted its age-induced weakness. Forty-seven right-handed subjects participated: 20 young (22.6±0.90 years) and 27 old (74.96±1.35 years). We measured strength as force of elbow flexion and electromyographic activation of biceps brachii during maximum voluntary contraction. Mapping variables included: 1) center of gravity or weighted mean location of corticospinal output, 2) size of map, 3) volume or excitation of corticospinal output, and 4) response density or corticospinal excitation per unit area. Center of gravity was more anterior in old than in young (p<0.001), though there was no significant difference in strength between the age groups. Map size, volume, and response density showed no significant difference between groups. Regardless of age, center of gravity significantly predicted strength (βu200a=u200a−0.34, pu200a=u200a0.005), while volume adjacent to the core of map predicted voluntary activation of biceps (βu200a=u200a0.32, pu200a=u200a0.008). Overall, the anterior shift of the map in older adults may reflect an adaptive change that allowed for the maintenance of strength. Laterally located center of gravity and higher excitation in the region adjacent to the core in weaker individuals could reflect compensatory recruitment of synergistic muscles. Thus, our study substantiates the role of M1 in adapting to aging-related weakness and subtending strength and muscle activation across age groups. Mapping from M1 may offer foundation for an examination of mechanisms that preserve strength in elderly.

Neurophysiological correlates of aging-related muscle weakness

Muscle weakness associated with aging implicates central neural degeneration. However, role of the primary motor cortex (M1) is poorly understood, despite evidence that gains in strength in younger adults are associated with its adaptations. We investigated whether weakness of biceps brachii in aging analogously relates to processes in M1. We enrolled 20 young (22.6 ± 0.87 yr) and 28 old (74.79 ± 1.37 yr) right-handed participants. Using transcranial magnetic stimulation, representation of biceps in M1 was identified. We examined the effect of age and sex on strength of left elbow flexion, voluntary activation of biceps, corticospinal excitability and output, and short-interval intracortical and interhemispheric inhibition. Interhemispheric inhibition was significantly exaggerated in the old (P = 0.047), while strength tended to be lower (P = 0.075). Overall, women were weaker (P < 0.001). Processes of M1 related to strength or voluntary activation of biceps, but only in older adults. Corticospinal excitability was lower in weaker individuals (r = 0.38), and corticospinal output, intracortical inhibition and interhemispheric inhibition were reduced too in individuals who poorly activated biceps (r = 0.43, 0.54 and 0.38). Lower intracortical inhibition may reflect compensation for reduced corticospinal excitability, allowing weaker older adults to spread activity in M1 to recruit synergists and attempt to sustain motor output. Exaggerated interhemispheric inhibition, however, conflicts with previous evidence, potentially related to greater callosal damage in our older sample, our choice of proximal vs. distal muscle and differing influence of measurement of inhibition in rest vs. active states of muscle. Overall, age-specific relation of M1 to strength and muscle activation emphasizes that its adaptations only emerge when necessitated, as in a weakening neuromuscular system in aging.

Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation

OBJECTIVEnThe standard approach to brain stimulation in stroke is based on the premise that ipsilesional M1 (iM1) is important for motor function of the paretic upper limb, while contralesional cortices compete with iM1. Therefore, the approach typically advocates facilitating iM1 and/or inhibiting contralesional M1 (cM1). But, this approach fails to elicit much improvement in severely affected patients, who on account of extensive damage to ipsilesional pathways, cannot rely on iM1. These patients are believed to instead rely on the undamaged cortices, especially the contralesional dorsal premotor cortex (cPMd), for support of function of the paretic limb. Here, we tested for the first time whether facilitation of cPMd could improve paretic limb function in severely affected patients, and if a cut-off could be identified to separate responders to cPMd from responders to the standard approach to stimulation.nnnMETHODSnIn a randomized, sham-controlled crossover study, fifteen patients received the standard approach of stimulation involving inhibition of cM1 and a new approach involving facilitation of cPMd using repetitive transcranial magnetic stimulation (rTMS). Patients also received rTMS to control areas. At baseline, impairment [Upper Extremity Fugl-Meyer (UEFMPROXIMAL, max=36)] and damage to pathways [fractional anisotropy (FA)] was measured. We measured changes in time to perform proximal paretic limb reaching, and neurophysiology using TMS.nnnRESULTSnFacilitation of cPMd generated more improvement in severely affected patients, who had experienced greater damage and impairment than a cut-off value of FA (0.5) and UEFMPROXIMAL (26-28). The standard approach instead generated more improvement in mildly affected patients. Responders to cPMd showed alleviation of interhemispheric competition imposed on iM1, while responders to the standard approach showed gains in ipsilesional excitability in association with improvement.nnnCONCLUSIONSnA preliminary cut-off level of severity separated responders for standard approach vs. facilitation of cPMd.nnnSIGNIFICANCEnCut-offs identified here could help select candidates for tailored stimulation in future studies so patients in all ranges of severity could potentially achieve maximum benefit in function of the paretic upper limb.