EMG activity and neuronal activity in the internal globus pallidus (GPi) and their interaction are different between hemiballismus and apomorphine induced dyskinesias of Parkinson's disease (AID).

The nature of electromyogram (EMG) activity and its relationship to neuronal activity in the internal globus pallidus (GPi) have not previously been studied in hyperkinetic movement disorders. We now test the hypothesis that GPi spike trains are cross-correlated with EMG activity during apomorphine-induced dyskinesias of Parkinson's disease (AID), and Hemiballism. We have recorded these two signals during awake stereotactic pallidal surgeries and analyzed them by cross-correlation of the raw signals and of peaks of activity occurring in those signals. EMG signals in Hemiballism usually consist of 'sharp' activity characterized by peaks of activity with low levels of activity between peaks, and by co-contraction between antagonistic muscles. Less commonly, EMG in Hemiballism shows 'non-sharp' EMG activity with substantial EMG activity between peaks; 'non-sharp' EMG activity is more common in AID. Therefore, these hyperkinetic disorders show substantial differences in peripheral (EMG) activity, although both kinds of activity can occur in both disorders. Since GPi spike×EMG spectral and time domain functions demonstrated inconsistent cross-correlation in both disorders, we studied peaks of activity in GPi neuronal and in EMG signals. The peaks of GPi activity commonly show prolonged cross-correlation with peaks of EMG activity, which suggests that GPi peaks are related to the occurrence of EMG peaks, perhaps by transmission of GPi activity to the periphery. In Hemiballism, the presence of direct GPi peak×EMG peak cross-correlations at the site where lesions relieve these disorders is evidence that gradual changes in peak GPi neuronal activity are directly involved in Hemiballism.

Ventral intermediate thalamic stimulation in complex tremor syndromes.

BACKGROUND/AIMS: We report on deep brain stimulation (DBS) in the ventral intermediate part of the thalamus in 4 patients with complex tremor syndromes, 2 classified as Holmes tremor (HT) and 2 as thalamic tremor (TT). RESULTS: Three out of 4 patients showed intraoperative improvement and underwent DBS implantation. One patient with TT without intraoperative improvement was not provided with an implant. A sustained beneficial effect was present after a follow-up ranging from 20 months to 7 years, although there was partial persistence of the intentional tremor and of proximal myoclonic-dystonic movements. The mean global clinical impression score was 2. In 1 HT patient the benefit persisted after battery failure. CONCLUSION: The study confirms that ventral intermediate thalamic DBS can provide long-term efficacy for HT and TT. While the patients experienced considerable and lasting functional improvement, the effect was incomplete and not all elements of their complex movement disorders were equally suppressed.

Internal pallidal neuronal activity during mild drug-related dyskinesias in Parkinson's disease: decreased firing rates and altered firing patterns.

The neuronal basis of hyperkinetic movement disorders has long been unclear. We now test the hypothesis that changes in the firing pattern of neurons in the globus pallidus internus (GPi) are related to dyskinesias induced by low doses of apomorphine in patients with advanced Parkinson's disease (PD). During pallidotomy for advanced PD, the activity of single neurons was studied both before and after administration of apomorphine at doses just adequate to induce dyskinesias (21 neurons, 17 patients). After the apomorphine injection, these spike trains demonstrated an initial fall in firing from baseline. In nine neurons, the onset of on was simultaneous with that of dyskinesias. In these spike trains, the initial fall in firing rate preceded and was larger than the fall at the onset of on with dyskinesias. Among the three neurons in which the onset of on occurred before that of dyskinesias, the firing rate did not change at the time of onset of dyskinesias. After injection of apomorphine, dyskinesias during on with dyskinesias often fluctuated between transient periods with dyskinesias and those without. Average firing rates were not different between these two types of transient periods. Transient periods with dyskinesias were characterized by interspike interval (ISI) independence, stationary spike trains, and higher variability of ISIs. A small but significant group of neurons demonstrated recurring ISI patterns during transient periods of on with dyskinesias. These results suggest that mild dyskinesias resulting from low doses of apomorphine are related to both low GPi neuronal firing rates and altered firing patterns.

Deep brain stimulation of the VIM thalamic nucleus modifies several features of essential tremor.

BACKGROUND: Pharmacologic interventions (e.g., beta blockers) and thalamic lesions have failed to alter the pathophysiology of essential tremor (ET) beyond a reduction in tremor amplitude. Deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus successfully reduces tremor rating scores. It is unknown how VIM DBS alters the pathophysiologic characteristics of ET. OBJECTIVE: To determine the effects of VIM DBS on the neurophysiologic characteristics of ET. METHODS: Hand tremor and EMG activity of forearm extensor and flexor muscles were recorded in six patients with ET ON-DBS and OFF-DBS and from six age- and sex-matched control subjects. Hand tremor was assessed across different inertial loads. The amplitude, frequency, regularity, and tremor-EMG coherence were analyzed. RESULTS: VIM DBS reduced the amplitude, increased the frequency, decreased the regularity, and reduced the 1 to 8 Hz tremor-EMG coherence of ET. ON-DBS, patients with ET had greater tremor amplitude, lower frequency, more regularity, and greater tremor-EMG coherence compared to control subjects. CONCLUSIONS: Whereas pharmacologic and thalamic lesions have previously failed to change characteristics of ET beyond amplitude reduction, VIM DBS modified multiple features of ET. The changes in ET after VIM DBS provide strong evidence for clinical efficacy.

Recognition and treatment of response fluctuations in Parkinson's disease: review article.

Patients with Parkinson's disease (PD) by definition benefit from treatment with the dopamine precursor levodopa. However, after 5 years of therapy 50% of patients experience motor response complications (MRC's): the benefit from each dose becomes shorter (wearing-off fluctuations), more unpredictable (on-off fluctuations) and associated with involuntary movements (dyskinesias). In addition these patients suffer from fluctuations in motor function that are inherent to the disease itself. Recent findings have lead to the suggestion that hyperfunction of NMDA receptors on striatal efferent neurons, as a consequence of chronic non-physiologic dopaminergic stimulation, contributes to the pathogenesis of MRC's. In PD patients blockade of striatal glutamate receptors with several NMDA-antagonists improve MRC's. With progression of PD the severity and complexity of MRC's magnify, obfuscating their pattern and their relation to the medication cycle. Only through detailed history taking and patient education will the physician be able to clarify the situation and establish a rational, targeted approach to the treatment of patients with advanced PD complicated by motor fluctuations and dyskinesias.

Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine.

OBJECTIVE: To examine the acute effects of the NMDA receptor antagonist amantadine on motor and cognitive function in Huntington's disease (HD). BACKGROUND: Chorea in HD and in the levodopa-induced dyskinesias of PD may be clinically indistinguishable. In PD, hyperphosphorylation of NMDA receptors expressed on striatal medium spiny neurons contributes to peak-dose dyskinesias, and drugs that block these receptors can diminish chorea severity. Because these spiny neurons are the primary target of the neurodegenerative process in HD, sensitization of NMDA receptors on residual striatal neurons might also participate in the generation of motor dysfunction in HD. METHODS: To evaluate this possibility, 24 patients with HD entered a double-blind placebo-controlled crossover study of amantadine with two 2-week arms. RESULTS: Chorea scores were lower with amantadine (usually 400 mg/d) than placebo, with a median reduction in extremity chorea at rest of 36% (p = 0.04) for all 22 evaluable patients and of 56% in the 10 individuals with the highest plasma drug levels. Improvement correlated with plasma amantadine concentrations (p = 0.01) but not CAG repeat length. Parkinsonian rating scores did not worsen and there was no consistent change in cognitive measures. Adverse event profile was benign. CONCLUSIONS: Results suggest that NMDA receptor supersensitivity may contribute to the clinical expression of choreiform dyskinesias in HD and that selective antagonists at that site can safely confer palliative benefit.

Tremor-frequency (3-6 Hz) activity in the sensorimotor arm representation of the internal segment of the globus pallidus in patients with Parkinson's disease.

Neurons in the internal segment of the globus pallidus (GPi) oscillate at approximately the frequency of parkinsonian tremor. However, the correlation of that activity with tremor has not previously been studied. We now describe the relationship between single neuron activity in the arm sensorimotor portion of GPi and upper extremity tremor in patients with Parkinson's disease. There was a significant concentration of power in the tremor-frequency range (3-6 Hz) for 11/44 GPi neurons. However, pallidal tremor-frequency activity correlated significantly with electromyogram (EMG) activity during tremor for only a single GPi neuron. These data are most consistent with the hypothesis that the output of neurons in GPi is transformed in thalamus by a non-linear mechanism, before transmission via the cortex to the spinal motorneurons that drive movement.

Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease.

OBJECTIVE: This study assessed the effects of the N-methyl-D-aspartate (NMDA) antagonist dextromethorphan (DM) on levodopa-induced dyskinesias in Parkinson's disease (PD). BACKGROUND: Recent experimental evidence suggests that increased synaptic efficacy of NMDA receptors expressed on basal ganglia neurons may play a role in the pathophysiology of levodopa-induced motor response complications. METHODS: DM was given to six PD patients with motor fluctuations in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week study arm, patients received several brief i.v. levodopa infusions while parkinsonian symptoms and dyskinesias were frequently scored. Levodopa dose-response curves for antiparkinsonian and dyskinetic effects were then compared for each study arm. RESULTS: With DM, average and maximum dyskinesia scores improved by >50%, without compromising the antiparkinsonian response magnitude or duration of levodopa, although in some subjects the levodopa threshold dose was slightly higher with DM than with placebo. CONCLUSIONS: These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptors can ameliorate levodopa-associated dyskinesias.

A trial of dextromethorphan in parkinsonian patients with motor response complications.

The effects of the NMDA antagonist dextromethorphan (DM) on levodopa-associated dyskinesias and motor fluctuations were studied in patients with advanced Parkinson's disease. During initial open-label dose escalation, 6 of 18 patients reported a beneficial effect at their individually determined optimal DM dose (range, 60-120 mg/day). The 12 remaining patients either experienced reversible side effects, particularly mild drowsiness, or decreased levodopa efficacy, and were therefore excluded from the study. The six responders entered the double-blind, placebo-controlled, crossover study with two 2-week arms separated by 1 week wash-out. On the last day of each arm, motor ratings were performed every 20 minutes for 8 consecutive hours. In addition, motor complications and Activities of Daily Living (ADL) were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and patient diaries. With DM, dyskinesias improved by 25% according to physician's ratings and by 40% according to UPDRS interviews, without compromising the anti-Parkinson effect of levodopa. Motor fluctuations and ADL scores also improved significantly. Although the narrow therapeutic index of DM limits its clinical usefulness, these findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate levodopa-associated motor complications.

Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease.

OBJECTIVE: To determine the effects of the N-methyl-D-aspartate (NMDA) antagonist amantadine on levodopa-associated dyskinesias and motor fluctuations in Parkinson's disease (PD). BACKGROUND: NMDA receptor blockade can ameliorate levodopa-induced dyskinesias in primates and PD patients. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was recently found to possess NMDA antagonistic properties. METHODS: Eighteen patients with advanced PD participated in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week treatment arm, parkinsonian and dyskinesia scores were obtained during a steady-state intravenous levodopa infusion. Motor fluctuations and dyskinesias were also documented with patient-kept diaries and Unified Parkinson's Disease Rating Scale (UPDRS) interviews. RESULTS: In the 14 patients completing this trial, amantadine reduced dyskinesia severity by 60% (p = 0.001) compared to placebo, without altering the antiparkinsonian effect of levodopa. Motor fluctuations occurring with patients' regular oral levodopa regimen also improved according to UPDRS and patient-kept diaries. CONCLUSIONS: These findings suggest that amantadine given as adjuvant to levodopa can markedly improve motor response complications and support the view that hyperfunction of NMDA receptors contributes to the pathogenesis of levodopa-associated motor complications.

Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson's disease.

In animal models of Parkinson's disease (PD), glutamate antagonists diminish levodopa (LD)-associated motor fluctuations and dyskinesias. We sought to investigate if these preclinical observations can be extended to the human disease, by evaluating the effects of three non-competitive NMDA antagonists (dextrorphan, dextromethorphan and amantadine) on the motor response to LD in patients with advanced PD. In four separate trials, adjuvant therapy with these drugs reduced LD-induced dyskinesias and motor fluctuations. These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate LD associated motor response complications.

Apomorphine responses in Parkinson's disease and the pathogenesis of motor complications.

We studied the contribution of basal ganglia circuitry downstream from the nigrostriatal dopaminergic system to the pathogenesis of levodopa associated motor complications by means of an apomorphine dose-response paradigm in 28 parkinsonian patients grouped according to their clinical response to levodopa therapy. With progression from the dopa-naive to the severely fluctuating dyskinetic state, apomorphine response duration shortened, the dose-response slope steepened, and the therapeutic window narrowed. Because apomorphine acts independently of the integrity of presynaptic dopaminergic neurons, our results suggest that postsynaptic alterations account mainly for the appearance of response complications. The present findings support the possibility, raised by animal model studies, that motor response complications arise as a consequence of altered signal transduction mechanisms in striatal medium-sized neurons.