Burke Medical Research Institute

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

We propose that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. The "vascular depression" hypothesis is supported by the comorbidity of depression, vascular disease, and vascular risk factors and the association of ischemic lesions to distinctive behavioral symptoms. Disruption of prefrontal systems or their modulating pathways by single lesions or by an accumulation of lesions exceeding a threshold are hypothesized to be central mechanisms in vascular depression. The vascular depression concept can generate studies of clinical and heuristic value. Drugs used for the prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurologic recovery from ischemic lesions. Research can clarify the pathways to vascular depression by focusing on the site of the lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.

OBJECTIVE: The aim of the study was to present a systematic review of studies that investigate the effects of robot-assisted therapy on motor and functional recovery in patients with stroke. METHODS: A database of articles published up to October 2006 was compiled using the following Medline key words: cerebral vascular accident, cerebral vascular disorders, stroke, paresis, hemiplegia, upper extremity, arm, and robot. References listed in relevant publications were also screened. Studies that satisfied the following selection criteria were included: (1) patients were diagnosed with cerebral vascular accident; (2) effects of robot-assisted therapy for the upper limb were investigated; (3) the outcome was measured in terms of motor and/or functional recovery of the upper paretic limb; and (4) the study was a randomized clinical trial (RCT). For each outcome measure, the estimated effect size (ES) and the summary effect size (SES) expressed in standard deviation units (SDU) were calculated for motor recovery and functional ability (activities of daily living [ADLs]) using fixed and random effect models. Ten studies, involving 218 patients, were included in the synthesis. Their methodological quality ranged from 4 to 8 on a (maximum) 10-point scale. RESULTS: Meta-analysis showed a nonsignificant heterogeneous SES in terms of upper limb motor recovery. Sensitivity analysis of studies involving only shoulder-elbow robotics subsequently demonstrated a significant homogeneous SES for motor recovery of the upper paretic limb. No significant SES was observed for functional ability (ADL). CONCLUSION: As a result of marked heterogeneity in studies between distal and proximal arm robotics, no overall significant effect in favor of robot-assisted therapy was found in the present meta-analysis. However, subsequent sensitivity analysis showed a significant improvement in upper limb motor function after stroke for upper arm robotics. No significant improvement was found in ADL function. However, the administered ADL scales in the reviewed studies fail to adequately reflect recovery of the paretic upper limb, whereas valid instruments that measure outcome of dexterity of the paretic arm and hand are mostly absent in selected studies. Future research into the effects of robot-assisted therapy should therefore distinguish between upper and lower robotics arm training and concentrate on kinematical analysis to differentiate between genuine upper limb motor recovery and functional recovery due to compensation strategies by proximal control of the trunk and upper limb.

Our goal is to apply robotics and automation technology to assist, enhance, quantify, and document neurorehabilitation. This paper reviews a clinical trial involving 20 stroke patients with a prototype robot-aided rehabilitation facility developed at the Massachusetts Institute of Technology, Cambridge, (MIT) and tested at Burke Rehabilitation Hospital, White Plains, NY. It also presents our approach to analyze kinematic data collected in the robot-aided assessment procedure. In particular, we present evidence 1) that robot-aided therapy does not have adverse effects, 2) that patients tolerate the procedure, and 3) that peripheral manipulation of the impaired limb may influence brain recovery. These results are based on standard clinical assessment procedures. We also present one approach using kinematic data in a robot-aided assessment procedure.

BACKGROUND: Effective rehabilitative therapies are needed for patients with long-term deficits after stroke. METHODS: In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks. RESULTS: At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported. CONCLUSIONS: In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

The Generic Model Organism System Database Project (GMOD) seeks to develop reusable software components for model organism system databases. In this paper we describe the Generic Genome Browser (GBrowse), a Web-based application for displaying genomic annotations and other features. For the end user, features of the browser include the ability to scroll and zoom through arbitrary regions of a genome, to enter a region of the genome by searching for a landmark or performing a full text search of all features, and the ability to enable and disable tracks and change their relative order and appearance. The user can upload private annotations to view them in the context of the public ones, and publish those annotations to the community. For the data provider, features of the browser software include reliance on readily available open source components, simple installation, flexible configuration, and easy integration with other components of a model organism system Web site. GBrowse is freely available under an open source license. The software, its documentation, and support are available at http://www.gmod.org.

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated alpha-tubulin, but not histone, consistent with its HDAC6 selectivity. Tubastatin A also conferred dose-dependent protection in primary cortical neuron cultures against glutathione depletion-induced oxidative stress. Importantly, when given alone at all concentrations tested, this hydroxamate-containing HDAC6-selective compound displayed no neuronal toxicity, thus, forecasting the potential application of this agent and its analogues to neurodegenerative conditions.

Smoothness is characteristic of coordinated human movements, and stroke patients' movements seem to grow more smooth with recovery. We used a robotic therapy device to analyze five different measures of movement smoothness in the hemiparetic arm of 31 patients recovering from stroke. Four of the five metrics showed general increases in smoothness for the entire patient population. However, according to the fifth metric, the movements of patients with recent stroke grew less smooth over the course of therapy. This pattern was reproduced in a computer simulation of recovery based on submovement blending, suggesting that progressive blending of submovements underlies stroke recovery.

As interest in the gut microbiome has grown in recent years, attention has turned to the impact of our diet on our brain. The benefits of a high fiber diet in the colon have been well documented in epidemiological studies, but its potential impact on the brain has largely been understudied. Here, we will review evidence that butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, can improve brain health. Butyrate has been extensively studied as a histone deacetylase (HDAC) inhibitor but also functions as a ligand for a subset of G protein-coupled receptors and as an energy metabolite. These diverse modes of action make it well suited for solving the wide array of imbalances frequently encountered in neurological disorders. In this review, we will integrate evidence from the disparate fields of gastroenterology and neuroscience to hypothesize that the metabolism of a high fiber diet in the gut can alter gene expression in the brain to prevent neurodegeneration and promote regeneration.

Reductions in cerebral metabolism sufficient to impair cognition in normal individuals also occur in Alzheimer's disease (AD). The degree of clinical disability in AD correlates closely to the magnitude of the reduction in brain metabolism. Therefore, we tested whether impairments in tricarboxylic acid (TCA) cycle enzymes of mitochondria correlate with disability. Brains were from patients with autopsy-confirmed AD and clinical dementia ratings (CDRs) before death. Significant (p < 0.01) decreases occurred in the activities of the pyruvate dehydrogenase complex (-41%), isocitrate dehydrogenase (-27%), and the alpha-ketoglutarate dehydrogenase complex (-57%). Activities of succinate dehydrogenase (complex II) (+44%) and malate dehydrogenase (+54%) were increased (p < 0.01). Activities of the other four TCA cycle enzymes were unchanged. All of the changes in TCA cycle activities correlated with the clinical state (p < 0.01), suggesting a coordinated mitochondrial alteration. The highest correlation was with pyruvate dehydrogenase complex (r = 0.77, r2= 0.59). Measures to improve TCA cycle metabolism might benefit AD patients.

Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same "type" exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.

OBJECTIVE: In patients with stroke, the authors tested whether additional sensorimotor training of the paralyzed or paretic upper limb delivered by a robotic device enhanced motor outcome. METHODS: Fifty-six patients with stroke and hemiparesis or hemiplegia received standard poststroke multidisciplinary rehabilitation, and were randomly assigned either to receive robotic training (at least 25 hours) or exposure to the robotic device without training. Outcomes were assessed by the same masked raters, before treatment began and at the end of treatment, with the upper extremity component of the Fugl-Meyer Motor Assessment, the Motor Status score, the Motor Power score, and Functional Independence Measurement. RESULT: The robot treatment and control group had comparable clinical characteristics, lesion size, and pretreatment impairment scores. By the end of treatment, the robot-trained group demonstrated improvement in motor outcome for the trained shoulder and elbow (Motor Power score, p < 0.001; Motor Status score, p < 0. 01) that did not generalize to untrained wrist and hand. The robot-treated group also demonstrated significantly improved functional outcome (Functional Independence Measurement-Motor, p < 0. 01). CONCLUSION: Robot-delivered quantitative and reproducible sensorimotor training enhanced the motor performance of the exercised shoulder and elbow. The robot-treated group also demonstrated improved functional outcome. When added to standard multidisciplinary rehabilitation, robotics provides novel therapeutic strategies that focus on impairment reduction and improved motor performance.

Tau (tau) is a major constituent of paired helical filaments (PHF) found in Alzheimer's disease. The current study examines the possibility that the distinct properties of PHF-associated tau proteins (tau PHF) result from post-translational modifications of normal soluble tau (tau s). Following hydrofluoric acid (HF) treatment, tau PHF proteins are heat- and acid-stable, soluble in 2-(N-morpholino)ethanesulfonic acid buffers and display the same molecular weight, pI, and immunochemical properties as normal tau s. Alkaline phosphatase treatment of dissociated PHF results in similar, although less extensive, electrophoretic changes and a reduction in PHF-1 immunoreactivity. Therefore, phosphorylation of normal tau s appears to be responsible for the distinct properties of tau PHF. Although our results suggest that all of the normal tau isoforms are in PHF, the relative abundance of individual tau species differs in HF-treated PHF and tau s samples. Moreover, the loss of PHF following HF treatment suggests that post-translational modifications contribute to the structural stability of PHF.

In 1991, a novel robot, MIT-MANUS, was introduced to study the potential that robots might assist in and quantify the neuro-rehabilitation of motor function. MIT-MANUS proved an excellent tool for shoulder and elbow rehabilitation in stroke patients, showing in clinical trials a reduction of impairment in movements confined to the exercised joints. This successful proof of principle as to additional targeted and intensive movement treatment prompted a test of robot training examining other limb segments. This paper focuses on a robot for wrist rehabilitation designed to provide three rotational degrees-of-freedom. The first clinical trial of the device will enroll 200 stroke survivors. Ultimately 160 stroke survivors will train with both the proximal shoulder and elbow MIT-MANUS robot, as well as with the novel distal wrist robot, in addition to 40 stroke survivor controls. So far 52 stroke patients have completed the robot training (ongoing protocol). Here, we report on the initial results on 36 of these volunteers. These results demonstrate that further improvement should be expected by adding additional training to other limb segments.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage leads to disability or death with few established treatments. Adverse outcomes after intracerebral hemorrhage result from irreversible damage to neurons resulting from primary and secondary injury. Secondary injury has been attributed to hemoglobin and its oxidized product hemin from lysed red blood cells. The aim of this study was to identify the underlying cell death mechanisms attributable to secondary injury by hemoglobin and hemin to broaden treatment options. METHODS: We investigated cell death mechanisms in cultured neurons exposed to hemoglobin or hemin. Chemical inhibitors implicated in all known cell death pathways were used. Identified cell death mechanisms were confirmed using molecular markers and electron microscopy. RESULTS: Chemical inhibitors of ferroptosis and necroptosis protected against hemoglobin- and hemin-induced toxicity. By contrast, inhibitors of caspase-dependent apoptosis, protein or mRNA synthesis, autophagy, mitophagy, or parthanatos had no effect. Accordingly, molecular markers of ferroptosis and necroptosis were increased after intracerebral hemorrhage in vitro and in vivo. Electron microscopy showed that hemin induced a necrotic phenotype. Necroptosis and ferroptosis inhibitors each abrogated death by >80% and had similar therapeutic windows in vitro. CONCLUSIONS: Experimental intracerebral hemorrhage shares features of ferroptotic and necroptotic cell death, but not caspase-dependent apoptosis or autophagy. We propose that ferroptosis or necroptotic signaling induced by lysed blood is sufficient to reach a threshold of death that leads to neuronal necrosis and that inhibition of either of these pathways can bring cells below that threshold to survival.

The comorbidity of psychiatric diagnoses was examined with the Diagnostic Interview Schedule in 62 women who participated in a 10-year follow-up study of anorexia nervosa. Sixty-two age- and sex-matched controls, their parents, and parents of the anorectic probands were also interviewed with the Diagnostic Interview Schedule. There was a statistically significant comorbidity of the affective and anxiety disorders with anorexia nervosa. The first-degree relatives of the anorectic probands had significantly more alcoholism and total number of psychiatric diagnoses compared with the first-degree relatives of controls. There were two mothers with bulimia nervosa, two cases of anorexia nervosa and two of bulimia nervosa in other first-degree relatives of anorectic probands, and no cases of eating disorders in the first-degree relatives of controls.

OBJECTIVE: The goals of this longitudinal investigation were 1) to study the rate of development of irreversible dementia in elderly depressed patients with a dementia syndrome that subsided after improvement of depression and 2) to compare it with that of depressed, never-demented patients. METHOD: The subjects were 57 elderly patients consecutively hospitalized for major depression. At entry into the study, 23 subjects also met criteria for "reversible dementia," while 34 were without dementia. After a systematic clinical evaluation, the subjects were followed up at approximately yearly intervals for an average of 33.8 months. RESULTS: Irreversible dementia developed significantly more frequently in the depressed group with reversible dementia (43%) than in the group with depression alone (12%). Survival analysis showed that the group with reversible dementia had a 4.69-times higher chance of having developed dementia at follow-up than the patients with depression alone. No clinical characteristics at entry into the study were found to discriminate the subjects who developed irreversible dementia during the follow-up period from those who remained nondemented. CONCLUSIONS: These findings suggest that geriatric depression with reversible dementia is a clinical entity that includes a group of patients with early-stage dementing disorders. Therefore, identification of a reversible dementia syndrome is an indication for a thorough diagnostic workup and frequent follow-ups in order to identify treatable neurological disorders.

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), however, the means by which neurodegeneration occurs remains obscure. There is evidence that mutant Htt interacts with transcription factors leading to reduced histone acetylation. We report that administration of the histone deacetylase inhibitor phenylbutyrate after onset of symptoms in a transgenic mouse model of HD significantly extends survival and attenuates both gross brain and neuronal atrophy. Administration of phenylbutyrate increased brain histone acetylation and decreased histone methylation levels as assessed by both immunocytochemistry and Western blots. Phenylbutyrate increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum. These results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and therefore represents a very promising therapeutic approach for HD.

BACKGROUND: Previous results with the planar robot MIT-MANUS demonstrated positive benefits in trials with over 250 stroke patients. Consistent with motor learning, the positive effects did not generalize to other muscle groups or limb segments. Therefore we are designing a new class of robots to exercise other muscle groups or limb segments. This paper presents basic engineering aspects of a novel robotic module that extends our approach to anti-gravity movements out of the horizontal plane and a pilot study with 10 outpatients. Patients were trained during the initial six-weeks with the planar module (i.e., performance-based training limited to horizontal movements with gravity compensation). This training was followed by six-weeks of robotic therapy that focused on performing vertical arm movements against gravity. The 12-week protocol includes three one-hour robot therapy sessions per week (total 36 robot treatment sessions). RESULTS: Pilot study demonstrated that the protocol was safe and well tolerated with no patient presenting any adverse effect. Consistent with our past experience with persons with chronic strokes, there was a statistically significant reduction in tone measurement from admission to discharge of performance-based planar robot therapy and we have not observed increases in muscle tone or spasticity during the anti-gravity training protocol. Pilot results showed also a reduction in shoulder-elbow impairment following planar horizontal training. Furthermore, it suggested an additional reduction in shoulder-elbow impairment following the anti-gravity training. CONCLUSION: Our clinical experiments have focused on a fundamental question of whether task specific robotic training influences brain recovery. To date several studies demonstrate that in mature and damaged nervous systems, nurture indeed has an effect on nature. The improved recovery is most pronounced in the trained limb segments. We have now embarked on experiments that test whether we can continue to influence recovery, long after the acute insult, with a novel class of spatial robotic devices. This pilot results support the pursuit of further clinical trials to test efficacy and the pursuit of optimal therapy following brain injury.