Parkinson Disease: Hallett M

Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, Bronte-Stewart H, Hallett M, Miyasaki J, Stevens J, Weiner WJ, Anonymous00045. · University of Kansas Medical Center, Kansas City, USA. · Neurology. · Pubmed #16606909 No free full text.

Abstract: OBJECTIVE: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS? METHODS: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

Hallett M. · Human Motor Control Section, NINDS, NIH, Bethesda, Maryland 20892-1428, USA. · Mov Disord. · Pubmed #18668625 No free full text.

Abstract: Freezing of gait appears to result from a number of fundamental problems in patients with Parkinson disease. Automaticity is impaired, putting more stress on voluntary mechanisms. Internal drivers of movement are impaired, likely because of deficient basal ganglia function. Deficiency of internal forces to initiate movement is a major factor in freezing. This deficiency gives a greater influence to external or sensory factors. The sensory factors can both help or hinder freezing. Analogous to the problem with set-shifting, there is also some difficulty in regulation of internal versus external factors and in regulation of different external factors.

Nahab FB, Peckham E, Hallett M. · Human Motor Control Section, NINDS/NIH, Bethesda, Maryland 20892-1428, USA. · Pract Neurol. · Pubmed #17636137 No free full text.

Abstract: The diagnosis and management of essential tremor appears deceptively simple. However, isolated mild tremor may be difficult to classify, and if the patients have any additional features the diagnosis is more difficult. Management can be challenging, despite the numerous treatments available, because so many patients are not benefited adequately and some not at all. However, as we gain a better understanding of the disorder, more effective therapies with fewer adverse effects are sure to follow.

Litvan I, Chesselet MF, Gasser T, Di Monte DA, Parker D, Hagg T, Hardy J, Jenner P, Myers RH, Price D, Hallett M, Langston WJ, Lang AE, Halliday G, Rocca W, Duyckaerts C, Dickson DW, Ben-Shlomo Y, Goetz CG, Melamed E. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17483689 No free full text.

Abstract: We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors. Although there is extensive new information on the etiology and pathogenesis of PD, which may advance its treatment, new syntheses of this information are needed. The second part of this two-part, state-of-the-art review by leaders in PD research critically examines the research field to identify areas for which new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part II are genetics, animal models, and oxidative stress.

Litvan I, Halliday G, Hallett M, Goetz CG, Rocca W, Duyckaerts C, Ben-Shlomo Y, Dickson DW, Lang AE, Chesselet MF, Langston WJ, Di Monte DA, Gasser T, Hagg T, Hardy J, Jenner P, Melamed E, Myers RH, Parker D, Price DL. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17413315 No free full text.

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Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Mov Disord. · Pubmed #15372588 No free full text.

Abstract: Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Sohn YH, Hallett M. · Department of Neurology and Brain Research Institute, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, Korea. · Phys Med Rehabil Clin N Am. · Pubmed #15029902 No free full text.

Abstract: Noninvasive electrical stimulation of the human brain first was attempted in the 1950s. In the early 1980s, the first clinical application method of transcranial electrical stimulation was developed. Investigators in the mid-1980s showed that it was possible to stimulate the nerve and the brain using external magnetic stimulation (transcranial magnetic stimulation [TMS]), with little or no pain. TMS now is used commonly in clinical neurology to study central motor conduction time. Depending on the stimulation techniques and parameters, TMS can excite or inhibit brain activity, allowing functional mapping of cortical regions and creation of transient functional lesions. It now is used widely as a research tool to study aspects of human brain physiology, including motor function and the pathophysiology of various brain disorders.

Hallett M. · Human Motor Control Section, National Institute of Neurological Disease Center, National Institutes of Health, Bethesda, Maryland, USA. · Adv Neurol. · Pubmed #12442661 No free full text.

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Berardelli A, Rothwell JC, Thompson PD, Hallett M. · Dipartimento di Scienze Neurologiche, Istituto Neurologico Neuromed IRCCS, Università di Roma La Sapienza, Rome, Italy. · Brain. · Pubmed #11673316 links to  free full text

Abstract: Bradykinesia means slowness of movement and is one of the cardinal manifestations of Parkinson's disease. Weakness, tremor and rigidity may contribute to but do not fully explain bradykinesia. We argue that bradykinesia results from a failure of basal ganglia output to reinforce the cortical mechanisms that prepare and execute the commands to move. The cortical deficit is most apparent in midline motor areas. This leads to particular difficulty with self-paced movements, prolonged reaction times and abnormal pre-movement EEG activity. Movements are often performed with normally timed EMG bursts but the amount of EMG activity is underscaled relative to the desired movement parameters. There are also abnormalities in sensory scaling and sensorimotor integration. The brain appears to be able to compensate to some degree for the basal ganglia deficit. There is overactivity in the lateral premotor areas during task performance and movements can be speeded by giving sensory cues. Attention to movement is also beneficial. However, we propose that the engagement of compensatory processes may also lead to reduced performance in other tasks. For example, patients' problems in performing more than one task at the same time could result from lack of sufficient resources both to compensate for their basal ganglia deficit and to run two tasks simultaneously. Surgical therapies are unlikely to work solely by normalizing basal ganglia output to that seen in healthy individuals. It seems more plausible that surgery removes an interfering signal that allows more efficient compensation by other structures.

Benazzouz A, Hallett M. · Laboratoire de Neurobiologie Preclinique, INSERM U.318, CHRU, Grenoble, France. · Neurology. · Pubmed #11188968 No free full text.

Abstract: Initial observations in patients with tremor treated with deep brain stimulation (DBS) of the thalamus suggested that application of high-frequency stimulation (HFS) had a lesion-like effect. New clinical information from patients treated with DBS of the subthalamic nucleus (STN) and globus pallidus internus (GPi) suggested a more complex mechanism of action. Recent experiments in the rat have shown that HFS of the STN was accompanied by increased release of glutamate and dopamine in the substantia nigra and striatum, respectively. Observations made in the GPi of parkinsonian patients during surgery suggest that stimulation may excite GABA release in axons from afferent connections. Therefore, although depolarization block may remain a major mechanism of action, generation of action potentials and release of neurotransmitters may also be involved in the therapeutic effects of DBS in Parkinson's disease.

Hallett M. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1428, USA. · Ann Neurol. · Pubmed #10762142 No free full text.

Abstract: Levodopa-induced dyskinesias are clinically heterogeneous, both in appearance and timing with respect to dose. Electromyogram observations indicate that levodopa-induced dyskinesias are comprised of irregular bursts of either synchronous or asynchronous neuronal firing in antagonist muscles. Studies of the blink reflex and spontaneous blinking have provided useful neurophysiologic information on brainstem function that is sensitive to changes in brain dopamine concentrations. The blink rate is reduced in Parkinson's disease (PD) and increased with dopamine treatment. The blink rate in patients with levodopa-induced dyskinesias, however, has been shown to be faster than that in optimally treated PD patients and normal individuals. These results suggest that dyskinesias are associated with a relative hyperdopaminergic state. However, there appears to be no correlation of dopaminergic benefit to the parkinsonian symptoms, indicating perhaps that there are several dopaminergic systems, including one responsible for motor function and one for dyskinesia. Alternatively, it may be that the pattern of neural firing influences dyskinesias, while the average firing rate may be responsible for motor benefits.

Mima T, Hallett M. · Human Motor Control Section, Medical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda 20892-1428, Maryland, USA. · J Clin Neurophysiol. · Pubmed #10600018 No free full text.

Abstract: Corticomuscular coherence measured between electroencephalography (EEG), magnetoencephalography, or local field potentials and electromyography (EMG) should be helpful in understanding the cortical control of movement. EEG-EMG coherence and phase spectra depend on the types of EEG derivation and current source density function of EEG appears to be the most appropriate for computation of EEG-EMG coherence. A new model for the interpretation of the phase spectra ("constant phase shift plus constant time lag model") shows that cortical surface negative potentials are phase-locked to EMG firing. There are functional differences of EEG-EMG coherence among the alpha, beta, and gamma bands suggesting differences in their possible generator mechanisms. Since corticomuscular coherence is a noninvasive measure of corticomotoneuronal function in a specific frequency range, clinical application of this method might be very fruitful in tremor research.

Hallett M, Litvan I. · American Academy of Neurology, St. Paul, MN 55116, USA. · Neurology. · Pubmed #10599758 No free full text.

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Benninger DH, Lomarev M, Wassermann EM, Lopez G, Houdayer E, Fasano RE, Dang N, Hallett M. · Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10 Room 7D42 (MSC1428), Center Drive, Bethesda, MD 20892, USA. · Clin Neurophysiol. · Pubmed #19285918 No free full text.

Abstract: OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating Parkinson's disease (PD), but the best values for rTMS parameters are not established. Fifty Hertz rTMS may be superior to 25 Hz rTMS investigated so far. The objective of this study was to determine if 50 Hz rTMS could be delivered safely in PD patients since current safety limits are exceeded. METHODS: Fifty Hertz rTMS was applied with a circular coil on the primary motor cortex (M1). Stimulation intensity was first tested at 60% rest motor threshold [RMT] and 0.5 s train duration and then increased in 0.5 s steps to 2 s, and by 10% steps to 90% RMT. Multi-channel electromyography (EMG) was recorded to control for signs of increasing time-locked EMG activity including correlates of the spread of excitation and after-discharges, or an increase of M1 excitability. Pre- and post-50 Hz rTMS assessments included EEG, Unified Parkinson Disease Rating Scale (UPDRS), Grooved Pegboard Test, Serial Reaction Time Task (SRTT), Folstein Mini-Mental Status Examination (MMSE) and Verbal Fluency to control for motor and cognitive side effects. RESULTS: Ten PD patients were investigated. Multi-channel EMG showed no signs of increased time-locked EMG activity including correlates of the spread of excitation and after-discharges, or increased M1 excitability in 9 patients. A PD patient with bi-temporal spikes in the pre-testing EEG had clinical and EMG correlates of spread of excitation at 90% RMT, but no seizure activity. Pre- and post-50 Hz assessment showed no changes. No adverse events were observed. Fifty Hertz rTMS was well tolerated except by 1 patient who wished to terminate the study due to facial muscle stimulation. CONCLUSION: Fifty Hertz rTMS at an intensity of 90% RMT for 2 s appears safe in patients with PD, but caution should be taken for patients with paroxysmal EEG activity. For this reason, comprehensive screening should include EEG before higher-frequency rTMS is applied. SIGNIFICANCE: This is the first study to investigate safety of 50 Hz rTMS in humans.

Wu T, Long X, Zang Y, Wang L, Hallett M, Li K, Chan P. · Key Laboratory on Neurodegenerate Disorder of Ministry of Education, Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, #45 Changchun Street, Beijing, China. · Hum Brain Mapp. · Pubmed #18649351 No free full text.

Abstract: Resting state brain activity in Parkinson's disease (PD) can give clues to the pathophysiology of the disorder, and might be helpful in diagnosis, but it has never been explored using functional MRI (fMRI). In the current study, we used a regional homogeneity (ReHo) method to investigate PD-related modulations of neural activity in the resting state. FMRIs were acquired in 22 patients with PD at both before and after levodopa administration, as well as in 22 age- and sex-matched normal controls. In the PD group compared with the healthy controls, we found ReHo decreased in extensive brain regions, including the putamen, thalamus, and supplementary motor area; and increased in some other areas, including the cerebellum, primary sensorimotor cortex, and premotor area. The ReHo off medication was negatively correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) in the putamen and some other regions, and was positively correlated with the UPDRS in the cerebellum. Administration of levodopa relatively normalized ReHo. Our findings demonstrate that neural activity in the resting state is changed in patients with PD. This change is secondary to dopamine deficiency, and related to the severity of the disease. The different neuronal activity at the baseline state should be considered in explaining fMRI findings obtained during tasks.

Battaglia F, Ghilardi MF, Quartarone A, Bagnato S, Girlanda P, Hallett M. · Department of Physiology and Pharmacology, CUNY School of Medicine, New York, New York 10031, USA. · Mov Disord. · Pubmed #17078045 No free full text.

Abstract: We investigated the hypothesis that Parkinsons's disease (PD) is associated with abnormal plasticity of the neuronal circuits mediating blink reflex. We induced long-term potentiation (LTP)-like plasticity in trigeminal wide dynamic range neurons of the blink reflex circuit by pairing an high-frequency train of electrical stimuli over the right supraorbital nerve (SO) coincident with the R2 response elicited by a preceding SO stimulus. The facilitation of the R2 response after the induction protocol was markedly decreased in patients relative to controls. Treatment with dopaminergic drugs normalized the LTP-like plasticity of the R2 response. We conclude that nigrostriatal denervation disrupts LTP-like plasticity in the trigeminal reflex circuit.

Zeuner KE, Molloy FM, Shoge RO, Goldstein SR, Wesley R, Hallett M. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1428, USA. · Mov Disord. · Pubmed #14639668 No free full text.

Abstract: We investigated the effects of ethanol and diazepam on the central, mechanical, and mechanical reflex components of tremor in patients with essential tremor (ET). A double-blind crossover study (ethanol or diazepam) was conducted on 2 separate days. Dose of ethanol or diazepam was calculated in each individual according to height, weight, and age in 10 patients with ET. The postural tremor amplitude at the wrist was recorded using a three-dimensional accelerometer placed on the dorsum of the hand. Electromyogram (EMG) was recorded with surface electrodes placed on the forearm extensors and flexors. To separate central and mechanical (reflex) components, a 500-g weight was placed on the dorsum of the hand during a second tremor measurement. Tremor recordings were done at baseline and 30, 60, 90, and 120 minutes after drug ingestion. Ethanol and diazepam blood levels were measured at baseline and after 20, 40, 80, and 120 minutes. Blood ethanol and diazepam levels were highest after 40 and 80 minutes. The amplitude of the central component 60 minutes after ingestion of ethanol was decreased significantly (P = 0.029) compared with diazepam. Our findings suggest that the improvement in tremor after ethanol ingestion was due, at least in part, to an effect on a central oscillator.

Catalan MJ, Ishii K, Honda M, Samii A, Hallett M. · Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1428, USA. · Brain. · Pubmed #10094257 links to  free full text

Abstract: To study the difficulty that patients with Parkinson's disease have in performing long sequential movements, we used H2(15)O PET to assess the regional cerebral blood flow (rCBF) associated with the performance of simple repetitive movements, well-learned sequential finger movements of varying length and self-selected movements. Sequential finger movements in the Parkinson's disease patients were associated with an activation pattern similar to that found in normal subjects, but Parkinson's disease patients showed relative overactivity in the precuneus, premotor and parietal cortices. Increasing the complexity of movements resulted in increased rCBF in the premotor and parietal cortices of normal subjects; the Parkinson's disease patients showed greater increases in these same regions and had additional significant increases in the anterior supplementary motor area (SMA)/cingulate. Performance of self-selected movements induced significant activation of the anterior SMA/cingulate in normal subjects but not in Parkinson's disease patients. We conclude that in Parkinson's disease patients more cortical areas are recruited to perform sequential finger movements; this may be the result of increasing corticocortical activity to compensate for striatal dysfunction.

Goker-Alpan O, Lopez G, Vithayathil J, Davis J, Hallett M, Sidransky E. · Section on Molecular Neurogenetics, National Human Genome Research Institute, National Institutes of Health, 35 Convent Dr, MSC 3708, Bldg 35, Room 1A213, Bethesda, MD 20892-3708, USA. · Arch Neurol. · Pubmed #18852351 links to  free full text

Abstract: BACKGROUND: Mutations in the glucocerebrosidase gene (GBA) result in Gaucher disease and can be associated with a phenotype characterized by adult-onset progressive neurologic deterioration and parkinsonism. OBJECTIVE: To define the clinical and neurologic spectrum of parkinsonian manifestations associated with GBA mutations. Design, Setting, and Patients A prospective case series of 10 patients (7 men and 3 women) with parkinsonism and GBA mutations evaluated at the National Institutes of Health Clinical Center. MAIN OUTCOME MEASURES: The GBA genotypes were identified by means of DNA sequencing. Tests evaluating neurologic, motor, cognitive, ocular, and olfactory functions were performed and the results were analyzed by a single team. RESULTS: Genotyping identified GBA mutations N370S, L444P, and c.84dupG and recombinant alleles. The mean age at onset of parkinsonian manifestations was 49 years (range, 39-65 years), disease duration was 7.8 years (range, 1.2-16.0 years), and Unified Parkinson Disease Rating Scale part III score was 26.3 (range, 13-38). Half of the patients reported cognitive changes later in the disease course. Six patients were diagnosed as having Parkinson disease, 3 as having Lewy body dementia, and 1 as having a "Parkinson plus" syndrome. The most frequent nonmotor finding was olfactory dysfunction. Atypical manifestations included myoclonus, electroencephalographic abnormalities, and seizures. CONCLUSIONS: In the homozygous and heterozygous states, GBA mutations are associated with a spectrum of parkinsonian phenotypes ranging from Parkinson disease, mostly of the akinetic type, to a less common phenotype characteristic of Lewy body dementia.

Cropley VL, Fujita M, Bara-Jimenez W, Brown AK, Zhang XY, Sangare J, Herscovitch P, Pike VW, Hallett M, Nathan PJ, Innis RB. · Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-0135, USA. · Psychiatry Res. · Pubmed #18504119 No free full text.

Abstract: Frontostriatal cognitive dysfunction is common in Parkinson disease (PD), but the explanation for its heterogeneous expressions remains unclear. This study examined the dopamine system within the frontostriatal circuitry with positron emission tomography (PET) to investigate pre- and post-synaptic dopamine function in relation to the executive processes in PD. Fifteen non-demented PD patients and 14 healthy controls underwent [(18)F]FDOPA (for dopamine synthesis) and [(11)C]NNC 112 (for D(1) receptors) PET scans and cognitive testing. Parametric images of [(18)F]FDOPA uptake (K(i)) and [(11)C]NNC 112 binding potential (BP(ND)) were calculated using reference tissue models. Group differences in K(i) and BP(ND) were assessed with both volume of interest and statistical parametric mapping, and were correlated with cognitive tests. Measurement of [(18)F]FDOPA uptake in cerebral cortex was questionable because of higher K(i) values in white than adjacent gray matter. These paradoxical results were likely to be caused by violations of the reference tissue model assumption rendering interpretation of cortical [(18)F]FDOPA uptake in PD difficult. We found no regional differences in D(1) receptor density between controls and PD, and no overall differences in frontostriatal performance. Although D(1) receptor density did not relate to frontostriatal cognition, K(i) decreases in the putamen predicted performance on the Wisconsin Card Sorting Test in PD only. These results suggest that striatal dopamine denervation may contribute to some frontostriatal cognitive impairment in moderate stage PD.

Wu T, Hallett M. · Beijing Institute of Geriatrics, State Key Laboratory of Cognitive Neuroscience and Learning, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China. · J Neurol Neurosurg Psychiatry. · Pubmed #18006652 No free full text.

Abstract: BACKGROUND: Patients with Parkinson's disease (PD) have great difficulty in performing two tasks simultaneously, but the neural contribution to this problem has not been identified. In the current study, we investigated the pathophysiology of dual task performance in PD. METHODS: We studied 15 patients with PD and 14 healthy controls. Functional MRIs were obtained before and after practicing dual tasks with different complexities. RESULTS: After practice, 12 normal subjects performed all dual tasks correctly. Twelve patients performed the simpler dual tasks correctly. However, only 3 patients could perform the more complex dual task correctly. Dual tasks activated similar brain regions in both groups. The bilateral precuneus was additionally activated during performance of dual tasks compared with the component tasks in both groups. Patients had greater activity in the cerebellum, premotor area, parietal cortex, precuneus and prefrontal cortex compared with normal subjects. CONCLUSIONS: Difficulty in performing two tasks simultaneously in patients with PD is probably due to limited attentional resources, defective central executive function and less automaticity in performing the tasks. Practice can diminish dual task interference and improve performance in patients with PD.

Goldstein DS, Imrich R, Peckham E, Holmes C, Lopez G, Crews C, Hardy J, Singleton A, Hallett M. · Clinical Neurocardiology Section, National Institutes on Neurological Disorders and Stroke, National Institute on Aging, NIH, Bethesda, MD 20892-1620, USA. · Neurology. · Pubmed #17625107 No free full text.

Abstract: BACKGROUND: Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. METHODS: Here we report results of cardiac sympathetic neuroimaging by 6-[(18)F]fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[(18)F] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common genetic abnormality identified so far in familial PD. RESULTS: The patient had no detectable 6-[(18)F] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[(18)F] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. CONCLUSION: This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process.

Zeuner KE, Peller M, Knutzen A, Holler I, Münchau A, Hallett M, Deuschl G, Siebner HR. · Department of Neurology, Christian Albrechts University Kiel, Kiel, Germany. · Mov Disord. · Pubmed #17230462 No free full text.

Abstract: Writer's cramp is a task-specific hand dystonia affecting handwriting. Clinical scores such as the Arm Dystonia Disability Scale (ADDS) or Writer's Cramp Rating Scale (WCRS) as well as kinematic analysis of handwriting movements have been used to assess functional impairment in affected patients. In 21 patients with writer's cramp and healthy controls, we analyzed the kinematics of writing and cyclic drawing movements. We rated the severity of dystonia using the ADDS and WCRS and correlated the clinical scores with movement kinematics. Mean stroke frequency was significantly reduced in dystonic patients. Drawing movements showed more frequently a decrease in stroke frequency than handwriting movements. During circle drawing, mean vertical peak velocity was more variable in patients relative to controls, indicating an impaired ability to reproduce the same kinematic pattern over time. An increase in vertical writing pressure was only observed during handwriting but not during circle drawing and may reflect a compensatory effort to stabilize the pencil. Kinematic measures and individual ADDS and WCRS scores did not correlate with each other. The lack of correlation is not surprising as ADDS, WCRS, and kinematic analysis probe different aspects of motor impairment. The ADDS characterizes how dystonia affects a set of fine manual tasks, whereas the WCRS scores the manifestation of dystonia during handwriting. Therefore, the clinical scores and kinematic analysis of handwriting provide complementary insights into motor impairment. Future studies need to address which combination of clinical scores and kinematic measures are most appropriate to quantify impairment in writer's cramp.

Lomarev MP, Kanchana S, Bara-Jimenez W, Iyer M, Wassermann EM, Hallett M. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1428, USA. · Mov Disord. · Pubmed #16211618 No free full text.

Abstract: The objective of this study is to assess the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) for gait and bradykinesia in patients with Parkinson's disease (PD). In a double-blind placebo-controlled study, we evaluated the effects of 25 Hz rTMS in 18 PD patients. Eight rTMS sessions were performed over a 4-week period. Four cortical targets (left and right motor and dorsolateral prefrontal cortex) were stimulated in each session, with 300 pulses each, 100% of motor threshold intensity. Left motor cortex (MC) excitability was assessed using motor evoked potentials (MEPs) from the abductor pollicis brevis. During the 4 weeks, times for executing walking and complex hand movements tests gradually decreased. The therapeutic rTMS effect lasted for at least 1 month after treatment ended. Right-hand bradykinesia improvement correlated with increased MEP amplitude evoked by left MC rTMS after individual sessions, but improvement overall did not correlate with MC excitability. rTMS sessions appear to have a cumulative benefit for improving gait, as well as reducing upper limb bradykinesia in PD patients. Although short-term benefit may be due to MC excitability enhancement, the mechanism of cumulative benefit must have another explanation.

Wu T, Hallett M. · Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Brain. · Pubmed #15958505 links to  free full text

Abstract: Patients with Parkinson's disease have great difficulty performing learned movements automatically. The neural contribution to the problem has not been identified. In the current study, we used functional magnetic resonance imaging (fMRI) to investigate the underlying neural mechanisms of movement automaticity in Parkinson's disease patients. Fifteen patients with Parkinson's disease were recruited. Three patients were finally excluded because they could not achieve automaticity. The remaining 12 patients were aged from 52 to 67 years, with a mean age of 61.2 years. Controls included 14 age-matched normal subjects. The subjects were asked to practise four tasks, including two self-initiated, self-paced sequences of finger movements with different complexity until they could perform the tasks automatically. Two dual tasks were used to evaluate automaticity. For dual tasks, subjects performed a visual letter-counting task simultaneously with the sequential movements. Twelve normal subjects performed all sequences automatically. All patients performed sequences correctly; 12 patients could perform the simpler sequence automatically; and only 3 patients could perform the more complex sequence automatically. fMRI results showed that for both groups, sequential movements activated similar brain regions before and after automaticity was achieved. No additional activity was observed in the automatic condition. In normal subjects, many areas had reduced activity at the automatic stage, whereas in patients, only the bilateral superior parietal lobes and left insular cortex were less activated. Patients had greater activity in the cerebellum, premotor area, parietal cortex, precuneus and prefrontal cortex compared with normal subjects while performing automatic movements. We conclude that Parkinson's disease patients can achieve automaticity after proper training, but with more difficulty. Our study is the first to demonstrate that patients with Parkinson's disease require more brain activity to compensate for basal ganglia dysfunction in order to perform automatic movements.