Joyce L. Chen

Resting State Interhemispheric Motor Connectivity and White Matter Integrity Correlate with Motor Impairment in Chronic Stroke

Functional and structural reorganization in the brain occurs after stroke. The ability to predict motor outcomes may depend on patterns of brain functional and structural connectivity. We tested the hypothesis that alterations in motor transcallosal and corticospinal connections correlate with motor impairment in patients with chronic stroke. Eleven ischemic stroke patients underwent the Upper Extremity Fugl-Meyer (UE-FM) assessment, resting state functional magnetic resonance imaging, and diffusion tensor imaging (DTI). Twelve healthy control subjects underwent DTI. We assessed the temporal coupling in neural activity between interhemispheric motor cortex, and white matter integrity by means of fractional anisotropy (FA), in the transcallosal motor fibers and corticospinal tract. Partial correlation analyses were performed to determine whether these connectivity measures correlate with Upper UE-FM scores. Patients compared to controls had reduced FA in common voxels of transcallosal motor and ipsilesional corticospinal fibers. Within the patient group those with higher interhemispheric motor cortex connectivity and higher FA in the transcallosal motor fibers were less impaired. The results show that markers of functional and structural motor cortex connectivity correlate with motor impairment in the chronic stage of stroke.

Increased resting state connectivity between ipsilesional motor cortex and contralesional premotor cortex after transcranial direct current stimulation with physical therapy

Non-invasive stimulation of the brain using transcranial direct current stimulation (tDCS) during motor rehabilitation can improve the recovery of movements in individuals with stroke. However, the neural substrates that underlie the clinical improvements are not well understood. In this proof-of-principle open-label pilot study, five individuals with stroke received 10 sessions of tDCS while undergoing usual care physical/occupational therapy for the arm and hand. Motor impairment as indexed by the Upper Extremity Fugl Meyer assessment was significantly reduced after the intervention. Resting state fMRI connectivity increased between ipsilesional motor cortex and contralesional premotor cortex after the intervention. These findings provide preliminary evidence that the neural underpinnings of tDCS coupled with rehabilitation exercises, may be mediated by interactions between motor and premotor cortex. The latter, of which has been shown to play an important role in the recovery of movements post-stroke. Our data suggest premotor cortex could be tested as a target region for non-invasive brain-stimulation to enhance connectivity between regions that might be beneficial for stroke motor recovery.

Non-invasive Repeated Therapeutic Stimulation for Aphasia Recovery: A Multilingual, Multicenter Aphasia Trial

Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used in case series and small randomized controlled trials to improve recovery from poststroke aphasia in combination with speech and language therapy. Results of these studies suggest possible clinical efficacy and an excellent safety profile. Therefore, a larger international multicenter proof-of-concept trial was launched, to directly compare the safety and efficacy of rTMS, tDCS, and sham stimulation as adjuvant therapy to speech and language therapy in subacute poststroke aphasia. In the 4 participating centers, subacute stroke patients with aphasia are randomized between 5 and 30xa0days after ischemic stroke to either receive rTMS, tDCS, or sham stimulation in combination with a daily 45xa0minutes speech and language therapy session for 10xa0days. Efficacy is evaluated at 1 and 30xa0days after the last of the 10 treatment sessions using 3 outcome measures, validated in all participating languages: Boston naming test, Token test, and verbal fluency test. Additionally, adverse events are recorded to prove safety. In this study, a total of 90 patients will be recruited, and data analysis will be completed in 2016. This is the first multilingual and multinational randomized and controlled trial in poststroke aphasia and if positive, will add anxa0effective new strategy for early stage poststroke aphasia rehabilitation.

Modulation of cognitive cerebello-cerebral functional connectivity by lateral cerebellar continuous theta burst stimulation

Network connectivity measured with resting state functional magnetic resonance imaging (rsfMRI) has revealed the contribution of distinct cerebellar lobules to an array of brain wide networks sub-serving motor and cognitive processes. As distinct cerebellar lobules form relatively accessible nodes of different brain networks, this raises the possibility for site-specific modulation of network connectivity using non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS). Continuous theta burst transcranial magnetic stimulation (cTBS) induces long-lasting inhibition of cortical areas. Although previous studies have shown that cTBS of the lateral cerebellum modulates motor cortical excitability and improves symptoms in several movement disorders, the effect on cognitive domains has not been examined. We explored the immediate effects of cTBS in a sham-controlled study on the strength of intrinsic functional connectivity between cerebellar and cortical motor and cognitive regions in 12 participants. Lateral cerebellar cTBS significantly decreased functional connectivity with frontal and parietal cognitive regions, while connectivity with motor regions remained unaltered. Sham stimulation had no effect on either motor or cognitive connectivity. These results show that inhibitory cerebellar stimulation reduces intrinsic functional connectivity between different cortical areas, in keeping with the known connectivity pattern of the cerebellum. The results highlight the plasticity of cerebello-cerebral networks and indicate for the first time that this functional connectivity can be downregulated using an inhibitory neurostimulation paradigm. This may shed light on the pathophysiology of network dysfunction and is a potential treatment for cognitive and movement disorders.

More Feedback Is Better than Less: Learning a Novel Upper Limb Joint Coordination Pattern with Augmented Auditory Feedback

Motor learning is a process whereby the acquisition of new skills occurs with practice, and can be influenced by the provision of feedback. An important question is what frequency of feedback facilitates motor learning. The guidance hypothesis assumes that the provision of less augmented feedback is better than more because a learner can use his/her own inherent feedback. However, it is unclear whether this hypothesis holds true for all types of augmented feedback, including for example sonified information about performance. Thus, we aimed to test what frequency of augmented sonified feedback facilitates the motor learning of a novel joint coordination pattern. Twenty healthy volunteers first reached to a target with their arm (baseline phase). We manipulated this baseline kinematic data for each individual to create a novel target joint coordination pattern. Participants then practiced to learn the novel target joint coordination pattern, receiving either feedback on every trial i.e., 100% feedback (n = 10), or every other trial, i.e., 50% feedback (n = 10; acquisition phase). We created a sonification system to provide the feedback. This feedback was a pure tone that varied in intensity in proportion to the error of the performed joint coordination relative to the target pattern. Thus, the auditory feedback contained information about performance in real-time (i.e., “concurrent, knowledge of performance feedback”). Participants performed the novel joint coordination pattern with no-feedback immediately after the acquisition phase (immediate retention phase), and on the next day (delayed retention phase). The root-mean squared error (RMSE) and variable error (VE) of joint coordination were significantly reduced during the acquisition phase in both 100 and 50% feedback groups. There was no significant difference in VE between the groups at immediate and delayed retention phases. However, at both these retention phases, the 100% feedback group showed significantly smaller RMSE than the 50% group. Thus, contrary to the guidance hypothesis, our findings suggest that the provision of more, concurrent knowledge of performance auditory feedback during the acquisition of a novel joint coordination pattern, may result in better skill retention.

The use of augmented auditory feedback to improve arm reaching in stroke: a case series

Abstract Purpose: After practice, augmented feedback is the most important factor that facilitates motor learning. We assess the potential effectiveness of two types of augmented auditory feedback on the re-learning of arm reaching in individuals with stroke: (a) real-time knowledge of performance (KP) feedback and (b) rhythmic cueing in the form of knowledge of results (KR) feedback. Method: Five participants with stroke underwent short-term practice, reaching with their affected arm with KP, KR and no feedback, on separate days. We assessed range of motion of the upper extremity (shoulder, elbow) and trunk, mean error and variability of the performed trajectory, and movement time, before and after training. Results: All participants benefitted from practice with feedback, though the effects varied across participants and feedback type. In three participants, KP feedback increased elbow extension and reduced compensatory trunk flexion. In four participants, KR feedback reduced movement time taken to perform the reach. Of note, one participant benefitted mostly from KP feedback, which increased shoulder flexion and elbow extension, and decreased compensatory trunk flexion and mean error. Conclusions: Within day practice with augmented auditory feedback improves reaching in individuals with stroke. This warrants further investigation with longer practice periods in a larger sample size. Implications for Rehabilitation After practice, augmented feedback is the second most important factor that facilitates motor learning. Music-based augmented auditory feedback has potential to enhance reaching abilities in individuals with stroke. Future studies are warranted to evaluate the long-term effectiveness of this feedback over a longer training period in a larger sample size.

Regulation of the activins-follistatins-inhibins axis by energy status: Impact on reproductive function

BACKGROUNDnWe have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA.nnnMETHODSnThe AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months.nnnRESULTSnThe circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles.nnnCONCLUSIONSnWe demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.

Post-stroke Fatigue and Depressive Symptoms Are Differentially Related to Mobility and Cognitive Performance

Background: Fatigue and depressive symptoms are common and often inter-related stroke sequelae. This study investigates how they are related, directly or indirectly, to mobility and cognitive outcomes within 6 months of stroke. Methods: Participants were recruited from 4 stroke centers in Ontario, Canada. Post-stroke fatigue was assessed using the Fatigue Assessment Scale (FAS). Depressive symptoms were screened using the Center for Epidemiological Studies Scale for Depression (CES-D). Factor analyses were used to construct scores from mobility (distance traveled during a 2-min walk test, Chedoke-McMaster Stroke Assessment leg score, and Berg Balance Scale total score) and cognitive (Montreal Cognitive Assessment, Trail-Making Tests A and B, and five-word free recall) tests. Direct associations were assessed in linear regression models and indirect effects were assessed in path models. Covariates were age, sex, education, antidepressant use, days since stroke, and stroke severity (National Institute of Health Stroke Severity Scale score). Results: Fatigue and depressive symptoms were highly correlated (r > 0.51, p < 0.0001). Depressive symptoms were associated with cognition (β = −0.184, p = 0.04) and indirectly with mobility, mediated by fatigue (indirect effect = −0.0142, 95% CI: −0.0277 to −0.0033). Fatigue was associated with mobility (β = −0.253, p = 0.01), and indirectly with cognition, mediated by depressive symptoms (indirect effect = −0.0113, 95% CI: −0.0242 to −0.0023). Conclusions: Fatigue and depressive symptoms are related distinctly to cognitive and mobility impairments post-stroke. Fatigue was associated with poorer lower limb motor function, and with cognition indirectly via depressive symptoms.

Variability in stroke motor outcome is explained by structural and functional integrity of the motor system

Biomarkers that represent the structural and functional integrity of the motor system enable us to better assess motor outcome post-stroke. The degree of overlap between the stroke lesion and corticospinal tract (CST Injury) is a measure of the structural integrity of the motor system, whereas the left-to-right motor cortex resting state connectivity (LM1-RM1 rs-connectivity) is a measure of its functional integrity. CST Injury and LM1-RM1 rs-connectivity each individually correlate with motor outcome post-stroke, but less is understood about the relationship between these biomarkers. Thus, this study investigates the relationship between CST Injury and LM1-RM1 rs-connectivity, individually and together, with motor outcome. Twenty-seven participants with upper limb motor deficits post-stroke completed motor assessments and underwent MRI at one time point. CST Injury and LM1-RM1 rs-connectivity were derived from T1-weighted and resting state functional MRI scans, respectively. We performed hierarchical multiple regression analyses to determine the contribution of each biomarker in explaining motor outcome. The interaction between CST Injury and LM1-RM1 rs-connectivity does not significantly contribute to the variability in motor outcome. However, inclusion of both CST Injury and LM1-RM1 rs-connectivity explains more variability in motor outcome, than either alone. We suggest both biomarkers provide distinct information about an individual’s motor outcome.

Neural coupling between contralesional motor and frontoparietal networks correlates with motor ability in individuals with chronic stroke

Movement is traditionally viewed as a process that involves motor brain regions. However, movement also implicates non-motor regions such as prefrontal and parietal cortex, regions whose integrity may thus be important for motor recovery after stroke. Importantly, focal brain damage can affect neural functioning within and between distinct brain networks implicated in the damage. The aim of this study is to investigate how resting state connectivity (rs-connectivity) within and between motor and frontoparietal networks are affected post-stroke in correlation with motor outcome. Twenty-seven participants with chronic stroke with unilateral upper limb deficits underwent motor assessments and magnetic resonance imaging. Participants completed the Chedoke-McMaster Stroke Assessment as a measure of arm (CMSA-Arm) and hand (CMSA-Hand) impairment and the Action Research Arm Test (ARAT) as a measure of motor function. We used a seed-based rs-connectivity approach defining the motor (seed=contralesional primary motor cortex (M1)) and frontoparietal (seed=contralesional dorsolateral prefrontal cortex (DLPFC)) networks. We analyzed the rs-connectivity within each network (intra-network connectivity) and between both networks (inter-network connectivity), and performed correlations between: a) intra-network connectivity and motor assessment scores; b) inter-network connectivity and motor assessment scores. We found: a) Participants with high rs-connectivity within the motor network (between M1 and supplementary motor area) have higher CMSA-Hand stage (z=3.62, p=0.003) and higher ARAT score (z=3.41, p=0.02). Rs-connectivity within the motor network was not significantly correlated with CMSA-Arm stage (z=1.83, p>0.05); b) Participants with high rs-connectivity within the frontoparietal network (between DLPFC and mid-ventrolateral prefrontal cortex) have higher CMSA-Hand stage (z=3.64, p=0.01). Rs-connectivity within the frontoparietal network was not significantly correlated with CMSA-Arm stage (z=0.93, p=0.03) or ARAT score (z=2.53, p=0.05); and c) Participants with high rs-connectivity between motor and frontoparietal networks have higher CMSA-Hand stage (rs=0.54, p=0.01) and higher ARAT score (rs=0.54, p=0.009). Rs-connectivity between the motor and frontoparietal networks was not significantly correlated with CMSA-Arm stage (rs=0.34, p=0.13). Taken together, the connectivity within and between the motor and frontoparietal networks correlate with motor outcome post-stroke. The integrity of these regions may be important for an individuals motor outcome. Motor-frontoparietal connectivity may be a potential biomarker of motor recovery post-stroke.