Orthostatic tremor (OT) is a rare condition characterized by unsteadiness when standing still that is relieved when sitting or walking and is thought to arise from a central generator in the cerebellum or brainstem. OT is considered to be a distinct, discrete condition, and little is known about its demographic characteristics, natural history, associated features, and treatment response. We have reviewed these aspects in 41 OT patients fulfilling current diagnostic criteria, seen at our institution between 1986 and 2001. We classified 31 (75%) as having idiopathic "primary OT" either with (n = 24) or without an associated postural arm tremor. We found that 10 of 41 (25%) cases had additional neurological features, and we defined this group as having "OT plus" syndrome. Of these 10, 6 had parkinsonism; 4 of these had typical Parkinson's disease (PD), 1 had vascular and 1 had drug-induced parkinsonism. Among the remaining 4 patients, 2 had restless legs syndrome (RLS), 1 had tardive dyskinesia, and 1 orofacial dyskinesias of uncertain etiology. One patient with PD and the patient with vascular parkinsonism also had RLS. Age at onset was significantly earlier in the "primary OT" (mean +/- SD, 50.4 +/- 15.1) than in the "OT plus" (61.8 +/- 6.4; z = 2.7; P =.006) group. In 7 of the 10 "OT plus" patients, OT leg symptoms preceded the onset of additional neurological features. OT appeared to be underdiagnosed, and on average, it took 5.7 years from the initial complaints until a diagnosis was made. In general, treatment response to a variety of drugs such as clonazepam, primidone, and levodopa was poor. In most cases, OT symptoms remain relatively unchanged over the years, but in 6 of 41 cases (15%), the condition gradually worsened over the years, and in some of these cases, symptoms spread proximally to involve the trunk and arms. OT may not be a discrete disorder as commonly believed and associated features like parkinsonism present in nearly 25% of cases. Dopaminergic dysfunction may have a role in the pathophysiology of this disorder.

Subthreshold 1 Hz rTMS of the left premotor cortex induces a short-lasting inhibition of corticospinal excitability in the hand area of the ipsilateral motor cortex. This may provide a model for studying the functional interaction between premotor and motor cortex in healthy subjects and patients with movement disorders.

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Atypical parkinsonian syndromes (APS) such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration are characterized by poor response to antiparkinsonian medication and rapid clinical deterioration. We used SPECT and [123I]beta-CIT as a label of dopamine transporters to study the progression of presynaptic dopaminergic degeneration in Parkinson's disease (PD) and APS. Twenty-four PD patients with short disease duration (2.4 +/- 1.5 years), 12 PD patients with long disease duration (9.2 +/- 2.6 years), 10 patients with APS (disease duration 2.1 +/- 1.5 years), and nine patients with essential tremor (ET) underwent sequential [123I]beta-CIT SPECT imaging with an interval of 25.5 +/- 10.3 (13-63) months. The age-related decline of striatal beta-CIT binding was studied cross-sectionally in 30 healthy subjects. The ratio of striatum/cerebellum -1 at 20 hours after tracer injection, reflecting specific-to-nondisplaceable binding, was used as the primary SPECT outcome measure. At scan 1, striatal beta-CIT binding was reduced in PD patients with short disease duration (-42% compared with age-corrected normal values) and long disease duration (-51%), and APS (-36%), but normal in ET. During the observation period striatal beta-CIT binding significantly declined in patients with APS (14.9% per year) and short duration PD (7.1% per year), whereas PD patients with long disease duration and patients with ET showed no significant change of striatal beta-CIT binding between scans 1 and 2. The relative annual reduction from age-corrected normal values at the time of scan 1 was significantly higher in patients with APS than in PD patients with short disease duration (9.6 vs. 4.3%, P = 0.004). These results demonstrate a rapid decline of striatal beta-CIT binding in patients with atypical parkinsonian syndromes, exceeding the reduction in PD. The dopaminergic degeneration in PD appears to slow down during the course of the disease. SPECT with [123I]beta-CIT is a sensitive marker of disease progression in parkinsonian disorders.

Recent studies have shown that low-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsal premotor cortex has a lasting influence on the excitability of specific neuronal subpopulations in the ipsilateral primary motor hand area (M1 HAND ). Here we asked how these premotor to motor interactions are shaped by the intensity and frequency of rTMS and the orientation of the stimulating coil. We confirmed that premotor rTMS at 1 Hz and an intensity of 90% active motor threshold (AMT) produced a lasting decrease in corticospinal excitability probed with single-pulse TMS over the left M1 HAND . Reducing the intensity to 80% AMT increased paired-pulse excitability at an interstimulus interval (ISI) of 7 ms. Opposite effects occurred if rTMS was given at 5 Hz: at 90% AMT, corticospinal excitability increased; at 80% AMT, paired-pulse excitability at ISI = = 7 ms decreased. No effects were seen if rTMS was applied at the same intensities to prefrontal or primary motor cortices. These findings indicate that the intensity of premotor rTMS determines the net effect of conditioning on distinct populations of neurones in the ipsilateral M1 HAND , but it is the frequency of rTMS that determines the direction of the induced change. By selecting the appropriate intensity and frequency, premotor rTMS allows to induce a predictable up-or down-regulation of the excitability in distinct neuronal circuits of human M1 HAND .

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We used PET to examine the pattern and time course of changes produced by repetitive transcranial magnetic stimulation (rTMS) over the dorsal premotor cortex (PMd) in healthy subjects and in patients with primary focal dystonia. Subjects received 1800 stimuli of subthreshold 1 Hz rTMS or sham stimulation to the left PMd. Afterwards, we measured regional cerebral blood flow (rCBF) as a marker of synaptic activity at rest and during performance of freely selected random finger movement. In both groups of subjects, real rTMS caused widespread bilateral decreases in neuronal activity in prefrontal, premotor, primary motor cortex, and left putamen. Conversely, rCBF in the cerebellum increased. Effects were equivalent at rest and during movement, indicating that the pattern of movement-related activation did not change. rTMS-induced changes in neuronal activity lasted for at least 1 h except in the medial aspect of the left globus pallidus. Conditioning effects on neuronal activity were larger in the patients than in the healthy subjects: there was a greater decrease of rCBF in lateral and medial premotor areas, putamen, and thalamus, including the stimulated premotor cortex, and a larger increase in cerebellar rCBF. Our findings indicate that, in healthy subjects and patients with dystonia, a single session of rTMS can produce powerful and widespread changes in regional synaptic activity as indexed by rCBF. Since the greater effects of premotor rTMS were not related to any differences in task performance, increased responsiveness of the motor system to rTMS reveals a physiological trait that characterizes patients with focal arm dystonia.

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