SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment.

BACKGROUND: Physical exercise, cognitive training, and vitamin D are low cost interventions that have the potential to enhance cognitive function and mobility in older adults, especially in pre-dementia states such as Mild Cognitive Impairment (MCI). Aerobic and progressive resistance exercises have benefits to cognitive performance, though evidence is somewhat inconsistent. We postulate that combined aerobic exercise (AE) and progressive resistance training (RT) (combined exercise) will have a better effect on cognition than a balance and toning control (BAT) intervention in older adults with MCI. We also expect that adding cognitive training and vitamin D supplementation to the combined exercise, as a multimodal intervention, will have synergistic efficacy. METHODS: The SYNERGIC trial (SYNchronizing Exercises, Remedies in GaIt and Cognition) is a multi-site, double-blinded, five-arm, controlled trial that assesses the potential synergic effect of combined AE and RT on cognition and mobility, with and without cognitive training and vitamin D supplementation in older adults with MCI. Two-hundred participants with MCI aged 60 to 85 years old will be randomized to one of five arms, four of which include combined exercise plus combinations of dual-task cognitive training (real vs. sham) and vitamin D supplementation (3 × 10,000 IU/wk. vs. placebo) in a quasi-factorial design, and one arm which receives all control interventions. The primary outcome measure is the ADAS-Cog (13 and plus modalities) measured at baseline and at 6 months of follow-up. Secondary outcomes include neuroimaging, neuro-cognitive performance, gait and mobility performance, and serum biomarkers of inflammation (C reactive protein and interleukin 6), neuroplasticity (brain-derived neurotropic factor), endothelial markers (vascular endothelial growth factor 1), and vitamin D serum levels. DISCUSSION: The SYNERGIC Trial will establish the efficacy and feasibility of a multimodal intervention to improve cognitive performance and mobility outcomes in MCI. These interventions may contribute to new approaches to stabilize and reverse cognitive-mobility decline in older individuals with MCI. TRIAL REGISTRATION: Identifier: NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676 .

'Priming' the brain to generate rapid upper-limb reactions.

Evoked autonomic nervous system (ANS) activity may be an important modulator of rapid reactions, generated in the face of urgency and may serve to augment the parallel somatosensory processing to adjust speed of processing. The primary objective of the current study was to temporally pair auditory stimuli with whole body perturbations to determine if conditioning could 'prime' the central nervous system (CNS) to respond faster and with greater ANS reactivity to the auditory stimulus alone. Healthy young participants (n = 19) were seated in a custom chair, which tilted backwards upon the release of an electromagnet and were instructed to reach to grasp a handle located in front of their arm as fast as possible following an auditory cue. Three conditions were completed in the following order: (1) baseline-auditory cue alone (5 trials); (2) paired-auditory cue, followed by a chair tilt 110 ms later (20 trials); and (3) post-pairing-auditory cue alone (5 trials). Participants were not informed of the switch from paired to auditory-only stimuli in the first trial of the post-pairing task condition. Reaction time was measured using electromyography, and autonomic nervous system activity was monitored via the electrodermal response (EDR). The first trial post-pairing had significantly faster reaction time (Δ = 21 ms) and significantly greater EDR amplitude compared to the last trial prior to pairing (baseline). The amplitude of contraction and overall time to handle contact were not significantly different between the first trial post-pairing and the last trial prior to pairing. This study demonstrates that the CNS can be 'primed' to generate rapid reactions and an elevated autonomic response in the absence of whole body instability. This indicates that afferent volume generated following whole body instability is not the only determinant of rapid reactions and emphasizes the importance of physiologic measures of autonomic activity with respect to stimulus-evoked reaction time.

Transient inhibition of primary motor cortex suppresses hand muscle responses during a reactive reach to grasp.

Rapid balance reactions such as compensatory reach to grasp represent important response strategies following unexpected loss of balance. While it has been assumed that early corrective actions arise from subcortical networks, recent research has prompted speculation about the potential role of cortical involvement. With reach to grasp reactions there is evidence of parallels in the control of perturbation-evoked reaching versus rapid voluntary reaching. However, the potential role of cortical involvement in such rapid balance reactions remains speculative. To test if cortical motor regions are involved we used continuous theta burst stimulation (cTBS) to temporarily suppress the hand area of primary motor cortex (M1) in participants involved in two reaching conditions: (1) rapid compensatory perturbation-evoked reach to grasp and (2) voluntary reach to grasp in response to an auditory cue. We hypothesized that following cTBS to the left M1 hand area we would find diminished EMG responses in the reaching (right) hand for both compensatory and voluntary movements. To isolate balance reactions to the upper limb participants were seated in an elevated tilt-chair with a stable handle positioned in front of their right shoulder. The chair was held vertical by a magnet and triggered to fall backward randomly. To regain balance, participants were instructed to reach for the handle as quickly as possible with the right hand upon chair release. Intermixed with perturbation trials, participants were also required to reach for the same handle but in response to an auditory tone. Muscle activity was recorded from several muscles of the right arm/hand using electromyography. As expected, movement time and muscle onsets were much faster following perturbation versus auditory-cued reaching. The novel finding from our study was the reduced amplitude of hand muscle activity post-cTBS for both perturbation-cued and auditory-cued reaches. Moreover, this reduction was specific to the cTBS-targeted hand with no effect on remaining arm muscles. These findings support the idea that cortical networks contribute to both volitional and perturbation-evoked reaches and provide evidence for M1involvement in driving early arm responses toward a target following sudden loss of balance.

Between-limb synchronization for control of standing balance in individuals with stroke.

BACKGROUND: During standing, forces and moments exerted at the feet serve to maintain stability in the face of constant centre-of-mass movement. These actions are temporally synchronized in healthy individuals. Stroke is typically a unilateral injury resulting in increased sensori-motor impairment in the contra-lesional compared with the ipsi-lesional lower-limb, which could lead to reduced between-limb synchronization for control of standing balance. The purpose of this study is to investigate between-limb synchronization of standing balance control in individuals with stroke; a potentially important index of control of upright stability. METHODS: Twenty healthy controls and 33 individuals with unilateral stroke were assessed. Stability was assessed during a 30-second quiet standing trial by measuring data from two force plates (one per foot). Limb-specific centre of pressure was calculated. Between-limb synchronization was defined as the coefficient of the correlation between the left and right foot for both the antero-posterior and medio-lateral centre of pressure time series. Synchronization, weight-bearing symmetry, and root mean square of the total centre of pressure excursion were compared between controls and stroke participants. FINDINGS: Stroke participants swayed more, were more asymmetric, and had less between-limb synchronization than healthy controls. Among individuals with stroke, reduced between-limb synchronization was related to increased postural sway in the medio-lateral direction and increased weight-bearing asymmetry. INTERPRETATION: Individuals with stroke have reduced temporal synchronization of centre of pressure fluctuations under the feet when controlling quiet standing. The clinical significance of reduced synchronization remains to be determined, although it appears linked to increased medio-lateral sway and weight-bearing asymmetry.

Rehabilitation of reaching and grasping function in severe hemiplegic patients using functional electrical stimulation therapy.

OBJECTIVE: The aim of this study was to establish the efficacy of a therapeutic intervention based on functional electrical stimulation (FES) therapy to improve reaching and grasping function after severe hemiplegia due to stroke. METHODS: A total of 21 subjects with acute stroke were randomized into 2 groups, FES plus conventional occupational and physiotherapy (FES group) or only conventional therapy (control group) 5 days a week for 12 to 16 weeks. A third group of 7 subjects with chronic hemiplegia (at least 5 months poststroke) received only FES therapy (chronic group) and pre-post training changes were compared. FES was applied to proximal and then distal muscle groups during specific motor tasks. At baseline and at the end of treatment, grasping function was assessed using the Rehabilitation Engineering Laboratory Hand Function Test, along with more standard measures of rehabilitation outcome. RESULTS: The FES group improved significantly more than the control group in terms of object manipulation, palmar grip torque, pinch grip pulling force, Barthel Index, Upper Extremity Fugl-Meyer scores, and Upper Extremity Chedoke-McMaster Stages of Motor Recovery. The chronic stroke subjects demonstrated improvements in most categories, but the changes were not statistically significant. CONCLUSIONS: FES therapy with upper extremity training may be an efficacious intervention in the rehabilitation of reaching and grasping function during acute stroke rehabilitation.

Somatosensory gating and recovery from stroke involving the thalamus.

BACKGROUND AND PURPOSE: In the undamaged brain, sensory input to the cortex is intricately controlled via sensory gating mechanisms. Given the role of corticothalamic pathways in this control, it was hypothesized that in patients recovering from thalamic stroke there would be evidence of disrupted sensory gating and that efficient control of cortical sensory inputs would emerge during recovery. METHODS: Four patients were tested serially after stroke from 1 to 24 weeks after injury. Perceptual thresholds, somatosensory evoked potential amplitudes, and functional MRI activations under specific somatosensory stimulation conditions were measured. RESULTS: All patients demonstrated comparable results, revealing disrupted threshold detection to vibrotactile stimuli in the presence of a concurrent competing, contralateral input. In contrast, threshold detection was comparable between the affected and unaffected sides when there were no competing stimuli. This compromised capacity to inhibit competing sensory inputs was paralleled by a reduction in the measured activation of cortical representation in the stroke-affected hemisphere (functional MRI and somatosensory evoked potential) during bilateral stimulation. After recovery, perceptual detection improvements during bilateral stimulation were paralleled by enhancements of primary somatosensory cortical activation in the stroke-affected hemisphere. CONCLUSIONS: These results provide insight into potential mechanisms that contribute to sensory gating and suggest that the ability to control sensory input through effective gating mechanisms, in addition to primary somatosensory representation, may be important for poststroke sensory recovery.