Neural effective connectivity explains subjective fatigue in stroke.

Persistent fatigue is a major debilitating symptom in many psychiatric and neurological conditions, including stroke. Post-stroke fatigue has been linked to low corticomotor excitability. Yet, it remains elusive as to what the neuronal mechanisms are that underlie motor cortex excitability and chronic persistence of fatigue. In this cross-sectional observational study, in two experiments we examined a total of 59 non-depressed stroke survivors with minimal motoric and cognitive impairments using 'resting-state' MRI and single- and paired-pulse transcranial magnetic stimulation. In the first session of Experiment 1, we assessed resting motor thresholds-a typical measure of cortical excitability-by applying transcranial magnetic stimulation to the primary motor cortex (M1) and measuring motor-evoked potentials in the hand affected by stroke. In the second session, we measured their brain activity with resting-state MRI to assess effective connectivity interactions at rest. In Experiment 2 we examined effective inter-hemispheric connectivity in an independent sample of patients using paired-pulse transcranial magnetic stimulation. We also assessed the levels of non-exercise induced, persistent fatigue using Fatigue Severity Scale (FSS-7), a self-report questionnaire that has been widely applied and validated across different conditions. We used spectral dynamic causal modelling in Experiment 1 and paired-pulse transcranial magnetic stimulation in Experiment 2 to characterize how neuronal effective connectivity relates to self-reported post-stroke fatigue. In a multiple regression analysis, we used the balance in inhibitory connectivity between homologue regions in M1 as the main predictor, and have included lesioned hemisphere, resting motor threshold and levels of depression as additional predictors. Our novel index of inter-hemispheric inhibition balance was a significant predictor of post-stroke fatigue in Experiment 1 (ß = 1.524, P = 7.56 × 10-5, confidence interval: 0.921 to 2.127) and in Experiment 2 (ß = 0.541, P = 0.049, confidence interval: 0.002 to 1.080). In Experiment 2, depression scores and corticospinal excitability, a measure associated with subjective fatigue, also significantly accounted for variability in fatigue. We suggest that the balance in inter-hemispheric inhibitory effects between primary motor regions can explain subjective post-stroke fatigue. Findings provide novel insights into neural mechanisms that underlie persistent fatigue.

The effect of motor overflow on bimanual asymmetric force coordination.

Motor overflow, typically described in the context of unimanual movements, refers to the natural tendency for a 'resting' limb to move during movement of the opposite limb and is thought to be influenced by inter-hemispheric interactions and intra-cortical networks within the 'resting' hemisphere. It is currently unknown, however, how motor overflow contributes to asymmetric force coordination task accuracy, referred to as bimanual interference, as there is need to generate unequal forces and corticospinal output for each limb. Here, we assessed motor overflow via motor evoked potentials (MEPs) and the regulation of motor overflow via inter-hemispheric inhibition (IHI) and short-intra-cortical inhibition (SICI) using transcranial magnetic stimulation in the presence of unimanual and bimanual isometric force production. All outcomes were measured in the left first dorsal interosseous (test hand) muscle, which maintained 30% maximal voluntary contraction (MVC), while the right hand (conditioning hand) was maintained at rest, 10, 30, or 70% of its MVC. We have found that as higher forces are generated with the conditioning hand, MEP amplitudes at the active test hand decreased and inter-hemispheric inhibition increased, suggesting reduced motor overflow in the presence of bimanual asymmetric forces. Furthermore, we found that subjects with less motor overflow (i.e., reduced MEP amplitudes in the test hemisphere) demonstrated poorer accuracy in maintaining 30% MVC across all conditions. These findings suggest that motor overflow may serve as an adaptive substrate to support bimanual asymmetric force coordination.

No Polarity-specific Modulation of Prefrontal-to-M1 Interhemispheric Inhibition by Transcranial Direct Current Stimulation Over the Lateral Prefrontal Cortex.

The lateral prefrontal cortex (PFC) plays a variety of crucial roles in higher-order cognitive functions. Previous works have attempted to modulate lateral PFC function by applying non-invasive transcranial direct current stimulation (tDCS) and demonstrated positive effects on performance of tasks involving cognitive processes. The neurophysiological underpinning of the stimulation effects, however, remain poorly understood. Here, we explored the neurophysiological after-effects of tDCS over the lateral PFC by assessing changes in the magnitude of interhemispheric inhibition from the lateral PFC to the contralateral primary motor cortex (PFC-M1 IHI). Using a dual-site transcranial magnetic stimulation paradigm, we assessed PFC-M1 IHI before and after the application of tDCS over the right lateral PFC. We conducted a double-blinded, crossover, and counterbalanced design where 15 healthy volunteers participated in three sessions during which they received either anodal, cathodal, and sham tDCS. In order to determine whether PFC-M1 IHI could be modulated at all, we completed the same assessment on a separate group of 15 participants as they performed visuo-motor reaction tasks that likely engage the lateral PFC. The results showed that tDCS over the right lateral PFC did not modulate the magnitude of PFC-M1 IHI, whereas connectivity changed when Go/NoGo decisions were implemented in reactions during the motor tasks. Although PFC-M1 IHI is sensitive enough to be modulated by behavioral manipulations, tDCS over the lateral PFC does not have substantial modulatory effects on PFC to M1 functional connectivity, or at least not to the degree that can be detected with this measure.

Neurophysiological aftereffects of 10 Hz and 20 Hz transcranial alternating current stimulation over bilateral sensorimotor cortex.

Alpha (8-12 Hz) and beta (13-30 Hz) oscillations are believed to be involved in motor control. Their modulation with transcranial alternating current stimulation (tACS) has been shown to alter motor behavior and cortical excitability. The aim of the present study was to determine whether tACS applied bilaterally over sensorimotor cortex at 10 Hz and 20 Hz modulates interhemispheric interactions and corticospinal excitability. Thirty healthy volunteers participated in a randomized, cross-over, sham-controlled, double-blind protocol. Sham and active tACS (10 Hz, 20 Hz, 1 mA) were applied for 20 min over bilateral sensorimotor areas. The physiological effects of tACS on corticospinal excitability and interhemispheric inhibition were assessed with transcranial magnetic stimulation. Physiological mirror movements were assessed to measure the overflow of motor activity to the contralateral M1 during voluntary muscle contraction. Bilateral 10 Hz tACS reduced corticospinal excitability. There was no significant effect of tACS on physiological mirror movements and interhemispheric inhibition. Ten Hz tACS was associated with response patterns consistent with corticospinal inhibition in 57% of participants. The present results indicate that application of tACS at the alpha frequency can induce aftereffects in sensorimotor cortex of healthy individuals.

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.

The Effect of Dual-Hemisphere Transcranial Direct Current Stimulation Over the Parietal Operculum on Tactile Orientation Discrimination.

The parietal operculum (PO) often shows ipsilateral activation during tactile object perception in neuroimaging experiments. However, the relative contribution of the PO to tactile judgment remains unclear. Here, we examined the effect of transcranial direct current stimulation (tDCS) over bilateral PO to test the relative contributions of the ipsilateral PO to tactile object processing. Ten healthy adults participated in this study, which had a double-blind, sham-controlled, cross-over design. Participants discriminated grating orientation during three tDCS and sham conditions. In the dual-hemisphere tDCS conditions, anodal and cathodal electrodes were placed over the left and right PO. In the uni-hemisphere tDCS condition, anodal and cathodal electrodes were applied over the left PO and contralateral orbit, respectively. In the tDCS and sham conditions, we applied 2 mA for 15 min and for 15 s, respectively. Computational models of electric fields (EFs) during tDCS indicated that the strongest electric fields were located in regions in and around the PO. Compared with the sham condition, dual-hemisphere tDCS improved the discrimination threshold of the index finger contralateral to the anodal electrode. Importantly, dual-hemisphere tDCS with the anodal electrode over the left PO yielded a decreased threshold in the right finger compared with the uni-hemisphere tDCS condition. These results suggest that the ipsilateral PO inhibits tactile processing of grating orientation, indicating interhemispheric inhibition (IHI) of the PO.

Transcranial Direct Current Stimulation Over the Primary and Secondary Somatosensory Cortices Transiently Improves Tactile Spatial Discrimination in Stroke Patients.

In healthy subjects, dual hemisphere transcranial direct current stimulation (tDCS) over the primary (S1) and secondary somatosensory cortices (S2) has been found to transiently enhance tactile performance. However, the effect of dual hemisphere tDCS on tactile performance in stroke patients with sensory deficits remains unknown. The purpose of this study was to investigate whether dual hemisphere tDCS over S1 and S2 could enhance tactile discrimination in stroke patients. We employed a double-blind, crossover, sham-controlled experimental design. Eight chronic stroke patients with sensory deficits participated in this study. We used a grating orientation task (GOT) to measure the tactile discriminative threshold of the affected and non-affected index fingers before, during, and 10 min after four tDCS conditions. For both the S1 and S2 conditions, we placed an anodal electrode over the lesioned hemisphere and a cathodal electrode over the opposite hemisphere. We applied tDCS at an intensity of 2 mA for 15 min in both S1 and S2 conditions. We included two sham conditions in which the positions of the electrodes and the current intensity were identical to that in the S1 and S2 conditions except that current was delivered for the initial 15 s only. We found that GOT thresholds for the affected index finger during and 10 min after the S1 and S2 conditions were significantly lower compared with each sham condition. GOT thresholds were not significantly different between the S1 and S2 conditions at any time point. We concluded that dual-hemisphere tDCS over S1 and S2 can transiently enhance tactile discriminative task performance in chronic stroke patients with sensory dysfunction.

Dual-hemisphere transcranial direct current stimulation improves performance in a tactile spatial discrimination task.

OBJECTIVE: The aim of this study was to test the hypothesis that dual-hemisphere transcranial direct current stimulation (tDCS) over the primary somatosensory cortex (S1) could improve performance in a tactile spatial discriminative task, compared with uni-hemisphere or sham tDCS. METHODS: Nine healthy adults participated in this double-blind, sham-controlled, and cross-over design study. The performance in a grating orientation task (GOT) in the right index finger was evaluated before, during, immediately after and 30min after the dual-hemisphere, uni-hemisphere (1mA, 20min), or sham tDCS (1mA, 30s) over S1. In the dual-hemisphere and sham conditions, anodal tDCS was applied over the left S1, and cathodal tDCS was applied over the right S1. In the uni-hemisphere condition, anodal tDCS was applied over the left S1, and cathodal tDCS was applied over the contralateral supraorbital front. RESULTS: The percentage of correct responses on the GOT during dual-hemisphere tDCS was significantly higher than that in the uni-hemisphere or sham tDCS conditions when the grating width was set to 0.75mm (all p<0.05). CONCLUSIONS: Dual-hemisphere tDCS over S1 improved performance in a tactile spatial discrimination task in healthy volunteers. SIGNIFICANCE: Dual-hemisphere tDCS may be a useful strategy to improve sensory function in patients with sensory dysfunctions.