MPTP induces dystonia and parkinsonism

Perlmutter, Joel S.; Tempel, Lee W.; Black, Kevin J.; Parkinson, David K.; Todd, Richard D.

doi:10.1212/wnl.49.5.1432

Cited by 167 publications

(76 citation statements)

References 14 publications

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“…Thus, dystonia may develop either acutely or delayed (tardive dystonia), in normal individuals treated with dopamine-receptor blocking agents, or can be a sign of other diseases with disturbed dopamine metabolism, such as PD, levodopa-responsive dystonia, or DYT1 [184][185][186][187][188][189]. Transient dystonia has also been observed in monkeys treated with the dopaminergic neurotoxin MPTP [190][191][192].…”

Section: Dystoniamentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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Deep brain stimulation (DBS) is highly effective for both hypo-and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal gangliathalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.

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Section: Dystoniamentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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“…According to this theory, sensorimotor outputs from the GPi and the SNr work to inhibit competing motor programs that interfere with a desired set of movements. 93,94 Abnormally correlated activity within the basal ganglia would then lead to coactivation of competing motor programs and undesirable activation of agonist and antagonist muscle activity. These pathological correlations would also result in an inability to facilitate appropriate motor sequences, leading to further breakdown in focused selection.…”

Section: Effects On Coactivation Of Competing Motor Programsmentioning

confidence: 99%

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

et al. 2008

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Summary:Chronic electrical stimulation of the brain, known as deep brain stimulation (DBS), has become a preferred surgical treatment for medication-refractory movement disorders. Despite its remarkable clinical success, the therapeutic mechanisms of DBS are still not completely understood, limiting opportunities to improve treatment efficacy and simplify selection of stimulation parameters. This review addresses three questions essential to understanding the mechanisms of DBS. 1) How does DBS affect neuronal tissue in the vicinity of the active electrode or electrodes? 2) How do these changes translate into therapeutic benefit on motor symptoms? 3) How do these effects depend on the particular site of stimulation? Early hypotheses proposed that stimulation inhibited neuronal activity at the site of stimulation, mimicking the outcome of ablative surgeries. Recent studies have challenged that view, suggesting that although somatic activity near the DBS electrode may exhibit substantial inhibition or complex modulation patterns, the output from the stimulated nucleus follows the DBS pulse train by direct axonal excitation. The intrinsic activity is thus replaced by high-frequency activity that is time-locked to the stimulus and more regular in pattern. These changes in firing pattern are thought to prevent transmission of pathologic bursting and oscillatory activity, resulting in the reduction of disease symptoms through compensatory processing of sensorimotor information. Although promising, this theory does not entirely explain why DBS improves motor symptoms at different latencies. Understanding these processes on a physiological level will be critically important if we are to reach the full potential of this powerful tool.

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“…A variety of derangements in these pathways have been proposed as the basis for dystonia Perlmutter et al 1997;Vitek 2002). In the model of Vitek, striatal inputs to both pallidal segments are hyperactive.…”

Section: Implications For Alterations In the Direct And Indirect Pathmentioning

confidence: 99%

Spontaneous Pallidal Neuronal Activity in Human Dystonia: Comparison With Parkinson’s Disease and Normal Macaque

Starr¹,

Rau²,

Davis³

et al. 2005

Journal of Neurophysiology

248

183

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. Dystonia is a movement disorder defined by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. To understand the abnormalities in pallidal discharge in dystonia, we have analyzed the spontaneous activity of 453 neurons sampled from the internal or external pallidum (GPi or GPe) of 22 patients with dystonia, 140 neurons from 11 patients with Parkinson's disease (PD), and 157 neurons from two normal non-human primates (NHPs; Macacca mulatta). All recordings were performed without systemic sedation. Mean GPi discharge rate in dystonia was 55.3 Ϯ 1.3 (SE) Hz. This was significantly lower than in the normal NHPs (82.5 Ϯ2.5 Hz) and lower than in PD patients (95.2 Ϯ 2.3 Hz). Mean GPe discharge rate in dystonia (54.0 Ϯ 1.9 Hz) was lower than in the normal NHPs (69.7 Ϯ 3.3 Hz) and was indistinguishable from that in PD patients (56.6 Ϯ 3.5 Hz). Mean GPi discharge rate was inversely correlated with dystonia severity. GPi showed increased oscillatory activity in the 2-to 10-Hz range and increased bursting activity in both dystonia and PD as compared with the normal NHPs. Because the abnormalities in discharge patterns were similar in dystonia compared with PD, we suggest that bursting and oscillatory activity superimposed on a high background discharge rate are associated with parkinsonism, whereas similar bursting and oscillations superimposed on a lower discharge rate are associated with dystonia. Our findings are most consistent with a model of dystonia pathophysiology in which the two striatal cell populations contributing to the direct and indirect intrinsic pathways of the basal ganglia both have increased spontaneous activity.

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MPTP induces dystonia and parkinsonism

Cited by 167 publications

References 14 publications

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

Spontaneous Pallidal Neuronal Activity in Human Dystonia: Comparison With Parkinson’s Disease and Normal Macaque

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