Continuous Theta-Burst Stimulation of the Contralesional Primary Motor Cortex for Promotion of Upper Limb Recovery After Stroke: A Randomized Controlled Trial.

BACKGROUND: Despite improvements in acute stroke therapies and rehabilitation strategies, many stroke patients are left with long-term upper limb motor impairment. We assessed whether an inhibitory repetitive transcranial magnetic stimulation treatment paradigm started within 3 weeks after stroke onset promotes upper limb motor recovery. METHODS: We performed a single-center randomized, sham-controlled clinical trial. Patients with ischemic stroke or intracerebral hemorrhage and unilateral upper limb motor impairment were randomized to 10 daily sessions of active or sham continuous theta-burst stimulation (cTBS) of the contralesional primary motor cortex combined with standard upper limb therapy, started within 3 weeks after stroke onset. The primary outcome was the change in the Action Research Arm Test score from baseline (pretreatment) at 3 months after stroke. Secondary outcomes included the score on the modified Rankin Scale at 3 months and the length of stay at the rehabilitation center. Statistical analyses were performed using mixed models for repeated measures. RESULTS: We enrolled 60 patients between April 2017 and February 2021, of whom 29 were randomized to active cTBS and 31 to sham cTBS. One patient randomized to active cTBS withdrew consent before the intervention and was excluded from the analyses. The mean difference in the change in Action Research Arm Test score from baseline at 3 months poststroke was 9.6 points ([95% CI, 1.2-17.9]; P=0.0244) in favor of active cTBS. Active cTBS was associated with better scores on the modified Rankin Scale at 3 months (OR, 0.2 [95% CI, 0.1-0.8]; P=0.0225) and with an 18 days shorter length of stay at the rehabilitation center than sham cTBS ([95% CI, 0.0-36.4]; P=0.0494). There were no serious adverse events. CONCLUSIONS: Ten daily sessions of cTBS of the contralesional primary motor cortex combined with upper limb training, started within 3 weeks after stroke onset, promote recovery of the upper limb, reduce disability and dependence and leads to earlier discharge from the rehabilitation center. REGISTRATION: URL: https://trialsearch.who.int/; Unique identifier: NTR6133.

Translational Value of Skilled Reaching Assessment in Clinical and Preclinical Studies on Motor Recovery After Stroke.

BACKGROUND: Assessment of skilled reaching enables extensive analysis of upper limb function in clinical and preclinical studies on poststroke outcome. However, translational research if often limited by lack of correspondence between tests of human and rodent motor function. OBJECTIVES: To determine (1) the translational value of skilled reaching performance for preclinical research by comparing the behavioral recovery profiles of skilled reaching characteristics between humans and rats recovering from stroke and (2) the relationship between skilled reaching performance and commonly used clinical outcome measures after stroke. METHODS: Twelve patients with ischemic or hemorrhagic stroke and 17 rats with photothrombotic stroke underwent an equivalent skilled reaching test at different time points, representing early to late subacute stages poststroke. Success scores and a movement element rating scale were used to measure the skilled reaching performance. The Fugl-Meyer Upper Extremity (FM-UE) assessment and the Action Research Arm Test (ARAT) were used as clinical outcome measures. RESULTS: Both species had muscle flaccidity at the early subacute stage after stroke and showed motor recovery following a proximal-distal principle toward the early subacute stage, albeit for rats within a shorter time course. Human skilled reaching scores and FM-UE and ARAT scores in the first 3 months poststroke were significantly correlated (P < .05). CONCLUSIONS: Our study demonstrates that poststroke changes in skilled reaching performance are highly similar between rats and humans and correspond with standard clinical outcome measures. Skilled reaching testing therefore offers an effective and highly translational means for assessment of motor recovery in experimental and clinical stroke settings.

Brain Tissue Conductivity Measurements with MR-Electrical Properties Tomography: An In Vivo Study.

First in vivo brain conductivity reconstructions using Helmholtz MR-Electrical Properties Tomography (MR-EPT) have been published. However, a large variation in the reconstructed conductivity values is reported and these values differ from ex vivo conductivity measurements. Given this lack of agreement, we performed an in vivo study on eight healthy subjects to provide reference in vivo brain conductivity values. MR-EPT reconstructions were performed at 3 T for eight healthy subjects. Mean conductivity and standard deviation values in the white matter, gray matter and cerebrospinal fluid (σWM, σGM, and σCSF) were computed for each subject before and after erosion of regions at tissue boundaries, which are affected by typical MR-EPT reconstruction errors. The obtained values were compared to the reported ex vivo literature values. To benchmark the accuracy of in vivo conductivity reconstructions, the same pipeline was applied to simulated data, which allow knowledge of ground truth conductivity. Provided sufficient boundary erosion, the in vivo σWM and σGM values obtained in this study agree for the first time with literature values measured ex vivo. This could not be verified for the CSF due to its limited spatial extension. Conductivity reconstructions from simulated data verified conductivity reconstructions from in vivo data and demonstrated the importance of discarding voxels at tissue boundaries. The presented σWM and σGM values can therefore be used for comparison in future studies employing different MR-EPT techniques.

EEG Functional Connectivity is a Weak Predictor of Causal Brain Interactions.

In recent years there has been an explosion of research evaluating resting-state brain functional connectivity (FC) using different modalities. However, the relationship between such measures of FC and the underlying causal brain interactions has not been well characterized. To further characterize this relationship, we assessed the relationship between electroencephalography (EEG) resting state FC and propagation of transcranial magnetic stimulation (TMS) evoked potentials (TEPs) at the sensor and source level in healthy participants. TMS was applied to six different cortical regions in ten healthy individuals (9 male; 1 female), and effects on brain activity were measured using simultaneous EEG. Pre-stimulus FC was assessed using five different FC measures (Pearson's correlation, mutual information, weighted phase lag index, coherence and phase locking value). Propagation of the TEPs was quantified as the root mean square (RMS) of the TEP voltage and current source density (CSD) at the sensor and source level, respectively. The relationship between pre-stimulus FC and the spatial distribution of TEP activity was determined using a generalized linear model (GLM) analysis. On the group level, all FC measures correlated significantly with TEP activity over the early (15-75 ms) and full range (15-400 ms) of the TEP at the sensor and source level. However, the predictive value of all FC measures is quite limited, accounting for less than 10% of the variance of TEP activity, and varies substantially across participants and stimulation sites. Taken together, these results suggest that EEG functional connectivity studies in sensor and source space should be interpreted with caution.

A novel concurrent TMS-fMRI method to reveal propagation patterns of prefrontal magnetic brain stimulation.

Major depressive disorder (MDD) is a severe mental disorder associated with high morbidity and mortality rates, which remains difficult to treat, as both resistance and recurrence rates are high. Repetitive transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) provides a safe and effective treatment for selected patients with treatment-resistant MDD. Little is known about the mechanisms of action of TMS provided to the left DLPFC in MDD and we can currently not predict who will respond to this type of treatment, precluding effective patient selection. In order to shed some light on the mechanism of action, we applied single pulse TMS to the left DLPFC in 10 healthy participants using a unique TMS-fMRI set-up, in which we could record the direct effects of TMS. Stimulation of the DLPFC triggered activity in a number of connected brain regions, including the subgenual anterior cingulate cortex (sgACC) in four out of nine participants. The sgACC is of particular interest, because normalization of activity in this region has been associated with relief of depressive symptoms in MDD patients. This is the first direct evidence that TMS pulses delivered to the DLPFC can propagate to the sgACC. The propagation of TMS-induced activity from the DLPFC to sgACC may be an accurate biomarker for rTMS efficacy. Further research is required to determine whether this method can contribute to the selection of patients with treatment resistant MDD who will respond to rTMS treatment.