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

Abstract

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 (n = 20) 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 30 min, twice a day for 3 days a week for 5 weeks. 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

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

“…The variance may emerge from the choice of DTI analysis as previously mentioned. Here we measure integrity along the entire length of tract using a method less affected by confounds from the lesion (details 47, 48,49 ). Hence, we may have been able to witness the ‘detailed’ degeneration of the tracts even in less impaired patients.…”

Invasive Neurostimulation in Stroke Rehabilitation

“…Our speculation aligns with the success of noninvasive cortical stimulation that is less focal. Using transcranial magnetic stimulation (TMS) [31], or transcranial direct current stimulation (tDCS), as in Bolognini et al [32], or in our ongoing study [33], a>5-point gain in Fugl-Meyer assessment is noted within a few weeks. Thus, it is important to realize the perfect balance between focality and potency of stimulation, as well as the drawbacks of the surgical process itself, which can take a toll on patients' function, attenuating gains in rehabilitation.…”

“…Their contribution evidently emerges from substantial (~60 %) and independent projections to corticospinal pathways [56], extensive reciprocal connections with M1 [57], and dense transcallosal connections with their homologues [57]. Although we currently explore how stimulating higher motor areas potentiates vicariation [33], a recent rodent model by Boychuk et al [30] may offer some translational insight. They have discussed that stimulating distributed regions in the periphery of ipsilesional motor cortices is more efficacious than focal stimulation in the interior of M1.…”

“…Although clinical trials set specific criteria (Fugl-Meyer score between 20 and 50), a minimal score of 20 [17][18][19][20] can be achieved if patients only possess proximal upper limb control without much hand function or vice versa. Specifying criteria for wrist/hand (as in [29]) or extension (such as in [75] and in our work [5,33]) may increase the chances that patients with viable ipsilesional motor systems would be enrolled. This is because finger extension is the most important predictor of dexterity [76], and is strongly indicative of functioning corticospinal pathways [29].…”

Challenges in Recruitment for the Study of Noninvasive Brain Stimulation in Stroke: Lessons from Deep Brain Stimulation

“…While tDCS was applied during rehabilitation of the paretic upper limb with the intent of augmenting therapeutic benefit, transcranial magnetic stimulation (TMS) was utilized for evaluating plasticity (NCT01539096). Details of this trial are provided in Plow et al 17 This trial was chosen because it represents the most common indication for use of NIBS in stroke, affecting rehabilitative outcomes of the paretic upper limb. Inclusion and exclusion criteria were based on published recommendations for TMS, 45 tDCS, 18 and magnetic resonance imaging (MRI) 46 (Table 1).…”