Task-specific training in Huntington disease: a randomized controlled feasibility trial.

BACKGROUND: Task-specific training may be a suitable intervention to address mobility limitations in people with Huntington disease (HD). OBJECTIVE: The aim of this study was to assess the feasibility and safety of goal-directed, task-specific mobility training for individuals with mid-stage HD. DESIGN: This study was a randomized, blinded, feasibility trial; participants were randomly assigned to control (usual care) and intervention groups. SETTING: This multisite study was conducted in 6 sites in the United Kingdom. PATIENTS: Thirty individuals with mid-stage HD (13 men, 17 women; mean age=57.0 years, SD=10.1) were enrolled and randomly assigned to study groups. INTERVENTION: Task-specific training was conducted by physical therapists in participants' homes, focusing on walking, sit-to-stand transfers, and standing, twice a week for 8 weeks. Goal attainment scaling was used to individualize the intervention and monitor achievement of personal goals. MEASUREMENTS: Adherence and adverse events were recorded. Adjusted between-group comparisons on standardized outcome measures were conducted at 8 and 16 weeks to determine effect sizes. RESULTS: Loss to follow-up was minimal (n=2); adherence in the intervention group was excellent (96.9%). Ninety-two percent of goals were achieved at the end of the intervention; 46% of the participants achieved much better than expected outcomes. Effect sizes on all measures were small. LIMITATIONS: Measurements of walking endurance were lacking. CONCLUSIONS: The safety of and excellent adherence to a home-based, task-specific training program, in which most participants exceeded goal expectations, are encouraging given the range of motivational, behavioral, and mobility issues in people with HD. The design of the intervention in terms of frequency (dose), intensity (aerobic versus anaerobic), and specificity (focused training on individual tasks) may not have been sufficient to elicit any systematic effects. Thus, a larger-scale trial of this specific intervention does not seem warranted.

Motivational modulation of bradykinesia in Parkinson's disease off and on dopaminergic medication.

Motivational influence on bradykinesia in Parkinson's disease may be observed in situations of emotional and physical stress, a phenomenon known as paradoxical kinesis. However, little is known about motivational modulation of movement speed beyond these extreme circumstances. In particular, it is not known if motivational factors affect movement speed by improving movement preparation/initiation or execution (or both) and how this effect relates to the patients' medication state. In the present study, we tested if provision of motivational incentive through monetary reward would speed-up movement initiation and/or execution in Parkinson's disease patients and if this effect depended on dopaminergic medication. We studied the effect of monetary incentive on simple reaction time in 11 Parkinson's disease patients both "off" and "on" dopaminergic medication and in 11 healthy participants. The simple reaction time task was performed across unrewarded and rewarded blocks. The initiation time and movement time were quantified separately. Anticipation errors and long responses were also recorded. The prospect of reward improved initiation times in Parkinson's disease patients both "off" and "on" dopaminergic medication, to a similar extent as in healthy participants. However, for "off" medication, this improvement was associated with increased frequency of anticipation errors, which were eliminated by dopamine replacement. Dopamine replacement had an additional, albeit small effect, on reward-related improvement of movement execution. Motivational strategies are helpful in overcoming bradykinesia in Parkinson's disease. Motivational factors may have a greater effect on bradykinesia when patients are "on" medication, as dopamine appears to be required for overcoming speed-accuracy trade-off and for improvement of movement execution. Thus, medication status should be an important consideration in movement rehabilitation programmes for patients with Parkinson's disease.

Motivation and movement: the effect of monetary incentive on performance speed.

From observation of human behavior, we know that speed of movement initiation and execution can be influenced by motivational factors, for example we walk faster when in a hurry (sense of urgency) or write faster during an exam (potential reward of good results). However, there is scant experimental evidence for the motivational modulation of movement in man. Experiments in non-human primates have demonstrated shortening of reaction times in response to reward. However, it is not clear how reward might affect performance of reaction time (RT) tasks in humans, and specifically whether warned and unwarned simple and uncued and precued choice RTs are similarly or differentially affected by reward. The effect of monetary incentive on total time (TT, (RT + MT)) was assessed in 16 healthy participants using four paradigms: warned simple RT (wSRT), unwarned simple RT (uSRT), uncued choice RT (uCRT), and precued choice RT (pCRT). wSRT, uSRT, and pCRT tasks all allow advance preparation and preprogramming of the movement, whereas uCRT does not. We found a significant effect of monetary incentive in shortening TTs in wSRT, uSRT, and pCRT tasks, but no effect on the uCRT task. These results demonstrate that monetary incentive can speed up movement initiation and execution in human participants, but only in tasks where preprogramming of the response is possible. This suggests that in reaction time tasks such as these, monetary incentive is having its effect by enhancing preparation of preprogrammed movement, but has little effect when movements cannot be specified in advance. These "RT and reward" tasks provide a useful paradigm for investigation into the effects of monetary incentive on reaction times in man and to study motivational modulation of movement speed in health and disease.

Endothelial, sympathetic, and cardiac function in inherited (6R)-L-erythro-5,6,7,8-tetrahydro-L-biopterin deficiency.

BACKGROUND: (6R)-5,6,7,8-Tetrahydro-l-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by GCH1. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in GCH1 in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans. METHODS AND RESULTS: In 16 DOPA-responsive dystonia patients with mutations predicted to affect GTPCH-1 expression or function and in age- and sex-matched control subjects, we measured plasma biopterin and nitrogen oxides by high-performance liquid chromatography and the Griess reaction, respectively, endothelial function by brachial artery flow-mediated dilation (FMD), sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response. Cardiac function and structure were assessed by echocardiography. Plasma biopterin was lower in patients (5.76±0.53 versus 8.43±0.85 nmol/L, P=0.03), but plasma NO(2)(-)/NO(3)(-) (NOx) (median, 9.06 [interquartile range, 5.35 to 11.04] versus 8.40 [interquartile range, 5.28 to 11.44] µmol/L, P=1) and FMD were not lower (7.7±0.8% versus 7.9±0.9%, P=0.91). In patients but not control subjects, FMD was insensitive to nitric oxide synthase inhibition (FMD at baseline, 6.7±2.1%; FMD during l-NMMA infusion, 6.2±2.5, P=0.68). The heart rate at rest was higher in patients, but the heart rate and blood pressure response to sympathetic stimulation did not differ in patients and control subjects despite lower concentrations of norepinepherine (264±8 pg/mL versus 226±9 pg/mL, P=0.006) and epinephrine (33.8±5.2 pg/mL versus 17.8±4.6 pg/mL, P=0.03) in patients. There was also no difference in cardiac function and structure. CONCLUSIONS: Sympathetic, cardiac, and endothelial functions are preserved in patients with GCH1 mutations despite a neurological phenotype, reduced plasma biopterin, and norepinepherine and epinephrine concentrations. Lifelong endogenous BH4 deficiency may elicit developmental adaptation through mechanisms that are inaccessible during acquired BH4 deficiency in adulthood.

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease presenting with voluntary gaze difficulties, early falls, and Parkinsonism. Neuronal loss, associated with intracellular neurofibrillary tangles and activated microglia, is found targeting the basal ganglia, brainstem nuclei, and frontal cortex. [11C](R)-PK11195 PET is a marker of peripheral benzodiazepine binding sites (PBBS) expressed by activated microglia. We have used [11C](R)-PK11195 PET to demonstrate in vivo the degree and distribution of the glial response to the degenerative process in four patients with PSP. Compared to normal age-matched controls, the PSP patient group showed significantly increased mean [11C](R)-PK11195 binding in the basal ganglia, midbrain, the frontal lobe, and the cerebellum. Two of the patients were rescanned after 6 to 10 months and during that time the level of microglial activation remained stable. [11C](R)-PK11195 PET reveals a pattern of increased microglial activation in PSP patients involving cortical and subcortical regions that corresponds well with the known distribution of neuropathological changes. [11C](R)-PK11195 PET, therefore, may help in characterizing in vivo the underlying disease activity in PSP.

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration.

Corticobasal degeneration (CBD) is a neurodegenerative parkinsonian disorder of unknown cause that shows considerable clinical heterogeneity. In CBD, activated microglia have been shown to be associated closely with the extensive tau pathology found in the affected basal ganglia, brainstem nuclei, and cortical regions. We report on the use of [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) (PK11195) positron emission tomography (PET), a marker of peripheral benzodiazepine binding sites (PBBS) that are expressed by activated microglia, to demonstrate in vivo the degree and distribution of glial response to the degenerative process in 4 patients with CBD. Compared with normal age-matched controls, the CBD patient group showed significantly increased mean [(11)C](R)-PK11195 binding in the caudate nucleus, putamen, substantia nigra, pons, pre- and postcentral gyrus, and the frontal lobe. [11C](R)-PK11195 PET reveals a pattern of increased microglial activation in CBD patients involving cortical regions and the basal ganglia that corresponds well with the known distribution of neuropathological changes, which may therefore help to characterize in vivo the underlying disease activity in CBD.