Objective The 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. Methods In 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. Results Facilitation 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. Conclusions A preliminary cut-off level of severity separated responders for standard approach vs. facilitation of cPMd. Significance Cut-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.

OBJECTIVE To determine how inter-hemispheric balance in stroke, measured using transcranial magnetic stimulation (TMS), relates to balance defined using neuroimaging (functional magnetic resonance (fMRI) and diffusion tensor imaging (DTI)), and how these metrics of balance are associated with clinical measures of upper limb function and disability. DESIGN Cross-Sectional SETTING Clinical Research Laboratory PARTICIPANTS Ten chronic stroke patients (63±9 years) in a population based sample with unilateral upper-limb paresis. INTERVENTION Not applicable MAIN OUTCOME MEASURES Inter-hemispheric balance was measured with TMS, fMRI and DTI. TMS defined inter-hemispheric differences in recruitment of corticospinal output, the size of the corticomotor output maps and the degree of mutual transcallosal inhibition they exerted upon 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 (M1), premotor (PMC) and supplementary motor cortices (SMA). DTI was used to define inter-hemispheric differences in the integrity of the corticospinal tracts projecting from M1. Clinical outcomes tested function (upper-extremity Fugl-Meyer (UEFM) and the perceived disability in the use of the paretic hand [Motor Activity Log (MAL)]. RESULTS Inter-hemispheric 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 have 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, neither an imbalance in their integrity nor an imbalance of their output relates to transcallosal inhibition. Clinically, while 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) [M1 (r=.883, p=.006), PMC (r=.817, p=.007) and SMA (r=.633, p=.062). CONCLUSIONS In patients with chronic motor deficits of the upper limb, fMRI may serve to mark perceived disability as well as transcallosal influence between hemispheres. DTI-based integrity of 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.

Purpose To 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. Methods In a randomized, double-blinded pilot clinical study, 12 patients with chronic stroke were assigned to receive anodal transcranial direct current stimulation (tDCS) (n = 6) or sham (n = 6) to the ipsilesional higher motor areas during constraint-induced movement therapy. We assessed functional and neurophysiologic outcomes before and after 5 weeks of therapy. Results Only 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. Conclusions Our 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.

Background: Recruitment curves (RCs) acquired using transcranial magnetic stimulation are commonly used in stroke to study physiologic functioning of corticospinal tracts (CST) from M1. However, it is unclear whether CSTs from higher motor cortices contribute as well.Objective: To explore whether integrity of CST from higher motor areas, besides M1, relates to CST functioning captured using RCs.Methods: RCs were acquired for a paretic hand muscle in patients with chronic stroke. Metrics describing gain and overall output of CST were collected. CST integrity was defined by diffusion tensor imaging. For CST emerging from M1 and higher motor areas, integrity (fractional anisotropy) was evaluated in the region of the posterior limb of the internal capsule, the length of CST and in the region of the stroke lesion.Results: We found that output and gain of RC was related to integrity along the length of CST emerging from higher motor cortices but not the M1.Conclusions: Our results suggest that RC parameters in chronic stroke infer function primarily of CST descending from the higher motor areas but not M1. RCs may thus serve as a simple, in-expensive means to assess re-mapping of alternate areas that is generally studied with resource-intensive neuroimaging in stroke.

Stimulating the brain to drive its adaptive plastic potential is promising to accelerate rehabilitative outcomes in stroke. Ipsilesional Primary Motor Cortex (M1) is invariably facilitated. However, evidence supporting its efficacy is divided, indicating we may have over-generalized its potential. Since M1 and its corticospinal output are frequently damaged, in patients with serious lesions and impairments, ipsilesional premotor areas (PMA) could be useful alternates instead. We base our premise on their higher probability of survival, greater descending projections, and an adaptive potential, which is causal for recovery across the seriously impaired. Using a conceptual model, we describe how chronically stimulating PMA would strongly affect key mechanisms of stroke motor recovery, such as facilitating plasticity of alternate descending output, restoring inter-hemispheric balance, and establishing widespread connectivity. Although at this time it is difficult to predict whether PMA would be ‘better’, it is important to at least investigate whether they are reasonable substitutes for M1. Even if stimulation of M1 may benefit those with maximum recovery potential, while that of PMA 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.