Broad Therapeutic Time Window for Driving Motor Recovery After TBI Using Activity-Dependent Stimulation.

BACKGROUND: After an acquired injury to the motor cortex, the ability to generate skilled movements is impaired, leading to long-term motor impairment and disability. While rehabilitative therapy can improve outcomes in some individuals, there are no treatments currently available that are able to fully restore lost function. OBJECTIVE: We previously used activity-dependent stimulation (ADS), initiated immediately after an injury, to drive motor recovery. The objective of this study was to determine if delayed application of ADS would still lead to recovery and if the recovery would persist after treatment was stopped. METHODS: Rats received a controlled cortical impact over primary motor cortex, microelectrode arrays were implanted in ipsilesional premotor and somatosensory areas, and a custom brain-machine interface was attached to perform the ADS. Stimulation was initiated either 1, 2, or 3 weeks after injury and delivered constantly over a 4-week period. An additional group was monitored for 8 weeks after terminating ADS to assess persistence of effect. Results were compared to rats receiving no stimulation. RESULTS: ADS was delayed up to 3 weeks from injury onset and still resulted in significant motor recovery, with maximal recovery occurring in the 1-week delay group. The improvements in motor performance persisted for at least 8 weeks following the end of treatment. CONCLUSIONS: ADS is an effective method to treat motor impairments following acquired brain injury in rats. This study demonstrates the clinical relevance of this technique as it could be initiated in the post-acute period and could be explanted/ceased once recovery has occurred.

Biological Efficacy and Safety of Niacinamide in Patients With ADPKD.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst enlargement, leading to kidney failure. Sirtuin-1 is upregulated in ADPKD and accelerates disease progression by deacetylating p53. Niacinamide is a dietary supplement that inhibits sirtuins at high doses. METHODS: We conducted an open-label, single-arm intervention trial (study 1, N = 10), and a randomized, double blinded, placebo-controlled trial (study 2, N = 36) to assess the biological activity and safety of niacinamide. Patients with ADPKD were given 30 mg/kg oral niacinamide or placebo, for 12 months. The primary endpoint was the ratio of acetylated p53 to total p53 protein in peripheral blood mononuclear cells (PBMCs). RESULTS: There was no sustained effect of niacinamide on acetylated/total p53 in either study and no difference between placebo and niacinamide arms. There was no difference in the change in height-adjusted total kidney volume over 12 months between niacinamide and placebo. Niacinamide was generally well tolerated. The most common adverse effects were nausea, diarrhea, gastroesophageal reflux, headache, and acneiform rash but there was no difference in their incidence between niacinamide and placebo. CONCLUSIONS: In conclusion, niacinamide is safe and well-tolerated in patients with ADPKD. However, we were unable to detect a sustained inhibition of sirtuin activity over 12 months of treatment, and there was no signal to suggest a beneficial effect on any efficacy measure.

The Impact of Creative Arts in Alzheimer's Disease and Dementia Public Health Education.

Previous research involving dramatic performances about Alzheimer's disease and dementia perception have targeted health care workers or caretakers. We examined the influence of a theater performance on the emotional affect of a general audience to determine the utility of this type of theater in large-scale public health education efforts. Our study included 147 participants that attended a self-revelatory theater performance based on the social/relationship experiences of those with dementia and those who care for them. This type of theater engages the audience and actors in a dual transformative process, supporting the emotional growth of all involved. Participants completed pre- and post-performance questionnaires regarding their beliefs and feelings surrounding the topic of dementia and the importance of the Arts for educating on issues surrounding dementia care. We tested for change in emotional affect pre- and post-performance using sensitivity and center of gravity statistical analyses. We found a significant change in emotional affect from an initial strong negative affect to slightly more positive/relaxed view after viewing the performance. Findings support self-revelatory theater as a resource to destigmatize preconceived notions of dementia. Large-scale community health education efforts could benefit from using this style of theater to elicit a change in audience perception of disease realities.

A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer's Disease Subjects: Results of a Single-Arm, Pilot Trial.

Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimer's disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective ß estrogen receptor (ERß) agonists benefits these parameters. To assess whether an ERß agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p < 0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study.

Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation.

Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).

Cholecalciferol v. ergocalciferol for 25-hydroxyvitamin D (25(OH)D) repletion in chronic kidney disease: a randomised clinical trial.

Patients with chronic kidney disease (CKD) demonstrate complex mineral metabolism derangements and a high prevalence of vitamin D deficiency. However, the optimal method of 25-hydroxyvitamin D (25(OH)D) repletion is unknown, and trials analysing the comparative efficacy of cholecalciferol and ergocalciferol in this population are lacking. We conducted a randomised clinical trial of cholecalciferol 1250µg (50 000 IU) weekly v. ergocalciferol 1250µg (50 000 IU) weekly for 12 weeks in forty-four non-dialysis-dependent patients with stage 3-5 CKD. The primary outcome was change in total 25(OH)D from baseline to week 12 (immediately after therapy). Secondary analyses included the change in 1,25-dihydroxyvitamin D (1,25(OH)2D), parathyroid hormone (PTH), D2 and D3 sub-fractions of 25(OH)D and 1,25(OH)2D and total 25(OH)D from baseline to week 18 (6 weeks after therapy). Cholecalciferol therapy yielded a greater change in total 25(OH)D (45·0 (sd 16·5) ng/ml) v. ergocalciferol (30·7 (sd 15·3) ng/ml) from baseline to week 12 (P<0·01); this observation partially resulted from a substantial reduction in the 25(OH)D3 sub-fraction with ergocalciferol. However, following cessation of therapy, no statistical difference was observed for total 25(OH)D change from baseline to week 18 between cholecalciferol and ergocalciferol groups (22·4 (sd 12·7) v. 17·6 (sd 8·9) ng/ml, respectively; P=0·17). We observed no significant difference between these therapies with regard to changes in serum PTH or 1,25(OH)2D. Therapy with cholecalciferol, compared with ergocalciferol, is more effective at raising serum 25(OH)D in non-dialysis-dependent CKD patients while active therapy is ongoing. However, levels of 25(OH)D declined substantially in both arms following cessation of therapy, suggesting the need for maintenance therapy to sustain levels.

Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34⁺ cells in a murine model of umbilical cord blood transplantation.

Delayed engraftment and graft failure represent major obstacles to successful umbilical cord blood (UCB) transplantation. Herein, we evaluated the use of hyperbaric oxygen (HBO) therapy as an intervention to improve human UCB stem/progenitor cell engraftment in an immune deficient mouse model. Six- to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34⁺ UCB cell transplant. Irradiated mice were separated into a non-HBO group (where mice remained under normoxic conditions) and the HBO group (where mice received 2 hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Four hours after completing HBO therapy, both groups intravenously received CD34⁺ UCB cells that were transduced with a lentivirus carrying luciferase gene and expanded for in vivo imaging. Mice were imaged and then sacrificed at one of 10 times up to 4.5 months post-transplant. HBO treated mice demonstrated significantly improved bone marrow, peripheral blood, and spleen retention and subsequent engraftment. In addition, HBO significantly improved peripheral, spleen and bone marrow engraftment of human myeloid and B-cell subsets. In vivo imaging demonstrated that HBO mice had significantly higher ventral and dorsal bioluminescence values. These studies suggest that HBO treatment of NSG mice prior to UCB CD34⁺ cell infusion significantly improves engraftment.

A decision algorithm for translating preclinical trial results to enhance recovery after stroke.

A decision algorithm was required to evaluate the first half of a cooperative agreement for preclinical trials to optimize medical device parameters to enhance stroke recovery. Continued funding was contingent upon the midpoint evaluation, called the milestone decision. We developed an algorithm, which summarized our rodent and primate model results. Primary outcomes weighed more heavily than secondary outcomes, and the primate model more heavily than rodent models. By controlling the type I error for this milestone decision, the probability of correctly discontinuing the study if treatment was not beneficial was high (>0.84). Similar algorithms may be adapted for other milestone-driven projects.

Interhemispheric connections of the ventral premotor cortex in a new world primate.

This study describes the pattern of interhemispheric connections of the ventral premotor cortex (PMv) distal forelimb representation (DFL) in squirrel monkeys. Our objectives were to describe qualitatively and quantitatively the connections of PMv with contralateral cortical areas. Intracortical microstimulation techniques (ICMS) guided the injection of the neuronal tract tracers biotinylated dextran amine or Fast blue into PMv DFL. We classified the interhemispheric connections of PMv into three groups. Major connections were found in the contralateral PMv and supplementary motor area (SMA). Intermediate interhemispheric connections were found in the rostral portion of the primary motor cortex, the frontal area immediately rostral and ventral to PMv (FR), cingulate motor areas (CMAs), and dorsal premotor cortex (PMd). Minor connections were found inconsistently across cases in the anterior operculum (AO), posterior operculum/inferior parietal cortex (PO/IP), and posterior parietal cortex (PP), areas that consistently show connections with PMv in the ipsilateral hemisphere. Within-case comparisons revealed that the percentage of PMv connections with contralateral SMA and PMd are higher than the percentage of PMv connections with these areas in the ipsilateral hemisphere; percentages of PMv connections with contralateral M1 rostral, FR, AO, and the primary somatosensory cortex are lower than percentages of PMv connections with these areas in the ipsilateral hemisphere. These studies increase our knowledge of the pattern of interhemispheric connection of PMv. They help to provide an anatomical foundation for understanding PMv's role in motor control of the hand and interhemispheric interactions that may underlie the coordination of bimanual movements.

Neuromuscular electrical stimulation improves severe hand dysfunction for individuals with chronic stroke: a pilot study.

Restoring hand function is difficult post-stroke. We sought to determine if applying neuromuscular electrical stimulation (NMES) was beneficial for reducing severe hand impairments. Subjects with chronic stroke (N=8; 3 Fe, 5 M; 58.3 +/- 6.9 y/o) received 10 sessions of NMES using two different methods applied in a counterbalanced order. In one intervention, we applied NMES (active) in a novel fashion using multiple stimulators on the forearm flexors and extensors to assist subjects with grasping and releasing a tennis ball. In the other intervention, the NMES ('passive') stimulated repeated wrist extension and flexion. Motor performance was assessed prior to and immediately following the interventions and at retention. Upper extremity (UE) Fugl-Myer scores significantly improved (p < 0.002) immediately following either intervention. Significant improvement was also observed in the Modified Ashworth Spasticity Scale (MASS) (p < 0.03), immediately following intervention, primarily due to the NMESpassive treatment (p < 0.034). Subjects performed grasping tasks significantly faster (p < 0.0433) following interventions, with performance speeds on dexterous manipulation increasing approximately 10% for NMESactive immediately following intervention, compared to only 0.1% improvement following NMESpassive. Generally, improvements in motor speed remained 10 days following NMESactive intervention, although slightly diminished. In conclusion, severe hand impairment was reduced after a short duration of NMES therapy in this pilot data set for individuals with chronic stroke. NMES-assisted grasping trended towards greater functional benefit than traditional NMES-activation of wrist flexors/extensors.