Anodal Transcranial Direct Current Stimulation over the Vertex Enhances Leg Motor Cortex Excitability Bilaterally.

In many studies, anodal transcranial Direct Current Stimulation (tDCS) is applied near the vertex to simultaneously facilitate leg motor cortex (M1) of both hemispheres and enhance recovery of gait and balance in neurological disorders. However, its effect on the excitability of leg M1 in either hemisphere is not well known. In this double-blind sham-controlled study, corticospinal excitability changes induced in leg M1 of both hemispheres by anodal (2 mA for 20 minutes) or sham tDCS (for 20 min) over the vertex were evaluated. Peak amplitudes of Transcranial Magnetic Stimulation (TMS) induced motor evoked potentials (MEPs) were measured over the contralateral Tibialis Anterior (TA) muscle before and up to 40 min after tDCS in 11 normal participants. Analysis of data from all participants found significant overall increase in the excitability of leg M1 after tDCS. However, in individual subjects there was variability in observed effects. In 4 participants, 20 min of tDCS increased mean MEPs of TAs on both sides; in 4 participants there was increased mean MEP only on one side and in 3 subjects there was no change. It's not known if the benefits of tDCS in improving gait and balance are dependent on excitability changes induced in one or both leg M1; such information may be useful to predict treatment outcomes.

SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial.

BACKGROUND: Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer , Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. METHODS: The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1-5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. DISCUSSION: SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC. TRIAL REGISTRATION: EudraCT Number: 2015-004062-29 (entered Dec 7, 2015) ISRCTN registry number: 16332228 (registered on Feb 3, 2016).

Does Action Observation Training With Immediate Physical Practice Improve Hemiparetic Upper-Limb Function in Chronic Stroke?

BACKGROUND: The mirror neuron network provides a neural mechanism to prime the motor system through action observation in stroke survivors. OBJECTIVE: To examine whether action observation training with immediate physical practice improves upper-limb function in chronic stroke. METHODS: In a within-subject design, 14 chronic stroke survivors were assessed at baseline, then participated in 2 weeks of relaxation-sham plus physical practice (control) and reassessed. Thereafter, they participated in 2 weeks of action observation training coupled with immediate physical practice (intervention), followed by a final assessment. Duration of each action observation video sequence (priming exposure) was 30 s followed immediately by practice of the observed motor skill. RESULTS: There were significant improvements in control and intervention phases on primary outcome measures--Upper Extremity Fugl-Meyer Motor Assessment (FMA) and Functional Test of the Hemiparetic Upper Extremity (FTHUE)--as well as secondary outcome measures of self-perceptions of arm use. Gains in the primary outcomes were greater during the intervention phase (action observation + physical practice; FMA, 10.64; FTHUE level, 0.79, and tasks, 1.57) than during the control phase (relaxation-sham plus physical practice; FMA, 6.64; FTHUE level, 0.43, and tasks, 1.00). Interviews with participants highlighted the added value of watching an actor perform the movement before physically attempting to perform the action. CONCLUSIONS: This study provides preliminary evidence of the additive value of action observation plus physical practice over relaxation-sham plus physical practice. There appears to be capacity for further recovery of upper-limb function in chronic stroke that persists at least in the short term.