Altered plasticity of the human motor cortex in Parkinson's disease

Ueki, Yoshino; Mima, Tatsuya; Kotb, Mamdouh Ali; Sawada, Hideyuki; Saiki, Hidemoto; Ikeda, Akio; Begum, Tahamina; Reza, Faruque; Nakagawa, Takashi; Fukuyama, Hidenao

doi:10.1002/ana.20692

Cited by 192 publications

(134 citation statements)

References 86 publications

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“…The absence of the PAS response on the more affected side is in line with previous studies in patients with more advanced PD, 18,19 who show decreased response to PAS in the "off " state that normalizes with L-dopa. 18 The reduced response to PAS is explained as being secondary to abnormal basal ganglia output 20 or to result from reduced dopamine at the cortical level.…”

Section: Resultssupporting

confidence: 91%

Functional reorganization of sensorimotor cortex in early Parkinson disease

et al. 2012

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Objective: Compensatory reorganization of the nigrostriatal system is thought to delay the onset of symptoms in early Parkinson disease (PD). Here we sought evidence that compensation may be a part of a more widespread functional reorganization in sensorimotor networks, including primary motor cortex. Methods:Several neurophysiologic measures known to be abnormal in the motor cortex (M1) of patients with advanced PD were tested on the more and less affected side of 16 newly diagnosed and drug-naive patients with PD and compared with 16 age-matched healthy participants. LTP-like effects were probed using a paired associative stimulation protocol. We also measured short interval intracortical inhibition, intracortical facilitation, cortical silent period, and input/output curves. Results:The less affected side in patients with PD had preserved intracortical inhibition and a larger response to the plasticity protocol compared to healthy participants. On the more affected side, there was no response to the plasticity protocol and inhibition was reduced. There was no difference in input/output curves between sides or between patients with PD and healthy participants. Conclusions:Increased motor cortical plasticity on the less affected side is consistent with a functional reorganization of sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side. The rate of change in paired associative stimulation response over time could be developed into a surrogate marker of disease progression in PD. Neurology ® 2012;78:1441-1448 GLOSSARY ADM ϭ abductor digiti minimi; AMT ϭ active motor threshold; APB ϭ abductor pollicis brevis; CS ϭ conditioning stimulus; CSP ϭ cortical silent period; DaT ϭ dopamine transporter; I/O ϭ input/output; ICF ϭ intracortical facilitation; ISI ϭ interstimulus interval; LTP ϭ long-term potentiation; MEP ϭ motor evoked potential; PAS ϭ paired associative stimulation; PD ϭ Parkinson disease; RMT ϭ resting motor threshold; SICI ϭ short-latency intracortical inhibition; TMS ϭ transcranial magnetic stimulation; UPDRS ϭ Unified Parkinson's Disease Rating Scale.Motor signs in Parkinson disease (PD) appear when striatal dopamine is depleted beyond a critical threshold of ϳ60%-80%.1 Neuropathologic and neuroimaging evidence suggests that presynaptic and synaptic changes in the nigrostriatal system compensate for dopamine deficiency.1-6 Indeed, given the extent of preclinical dopaminergic denervation, 7 it is conceivable that compensatory changes extend also beyond the nigrostriatal portion of the motor circuit.Patients with clinically asymmetric PD represent a valuable model to study compensatory reorganization within the motor system since functional changes that prevent motor symptom progression are likely to be more evident on the less affected side. A previous [ 18 F]-fluorodeo...

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Section: Resultssupporting

confidence: 91%

Functional reorganization of sensorimotor cortex in early Parkinson disease

et al. 2012

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“…Impaired PAS-induced LTP-like plasticity is typically observed in disorders associated with a dysfunctional dopaminergic system such as Parkinson's disease (Morgante et al, 2006;Ueki et al, 2006;Schwingenschuh et al, 2010) or schizophrenia (Frantseva et al, 2008), or a deficient central cholinergic system such as Alzheimer's disease (Battaglia et al, 2007), whereas exaggerated PASinduced LTP-like plasticity can be observed in states of increased endogenous central cholinergic tone such as dystonia (Quartarone et al, 2003(Quartarone et al, , 2008Weise et al, 2006;Schwingenschuh et al, 2010).…”

Section: Clinical Perspectivementioning

confidence: 99%

Neuromodulatory Neurotransmitters Influence LTP-Like Plasticity in Human Cortex: A Pharmaco-TMS Study

Korchounov

Ziemann

2011

Neuropsychopharmacol

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Long-term potentiation (LTP) of synaptic efficacy is considered a fundamental mechanism of learning and memory. At the cellular level a large body of evidence demonstrated that the major neuromodulatory neurotransmitters dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) influence LTP magnitude. Noninvasive brain stimulation protocols provide the opportunity to study LTP-like plasticity at the systems level of human cortex. Here we applied paired associative stimulation (PAS) to induce LTP-like plasticity in the primary motor cortex of eight healthy subjects. In a double-blind, randomized, placebo-controlled, crossover design, the acute effects of a single oral dose of the neuromodulatory drugs cabergoline (DA agonist), haloperidol (DA antagonist), methylphenidate (indirect NE agonist), prazosine (NE antagonist), tacrine (ACh agonist), and biperiden (ACh antagonist) on PAS-induced LTP-like plasticity were examined. The antagonists haloperidol, prazosine, and biperiden depressed significantly the PAS-induced LTP-like plasticity observed under placebo, whereas the agonists cabergoline, methylphenidate, and tacrine had no effect. Findings demonstrate that antagonists in major neuromodulatory neurotransmitter systems suppress LTP-like plasticity at the systems level of human cortex, in accord with evidence of their modulating action of LTP at the cellular level. This provides further supportive evidence for the known detrimental effects of these drugs on LTP-dependent mechanisms such as learning and memory.

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“…Animal studies have revealed an inverted U-shaped dose-response curve of dopamine on cognition (Williams and Goldman-Rakic, 1995;Granon et al, 2000;Seamans and Yang, 2004). Interestingly, PAS-induced plasticity is absent in ParkinsonЈs disease patients off medication, but restituted by dopaminergic agents (Ueki et al, 2006). However, only dosage dependency of dopamine on tDCS-induced plasticity (Monte-Silva et al, 2010), but not associative plasticity, has been explored so far.…”

Section: Introductionmentioning

confidence: 99%

Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans

Thirugnanasambandam

Grundey²,

Paulus³

et al. 2011

J. Neurosci.

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Dopamine is one of the major neuromodulators in the CNS, which is involved in learning and memory processes. A nonlinear, inverted U-shaped dose-response curve of its effects on cognition has been observed in animal studies. The basis for this nonlinear effect might be a similar effect of dopamine on neuroplasticity. Whereas it has been shown that dopamine affects paired associative stimulation (PAS)-induced plasticity, which might reflect learning-related processes to a larger degree than other noninvasive plasticity induction protocols in the human motor cortex in principle, its dose-dependency has not been explored previously. We studied the effect of different dosages of the dopamine precursor L-DOPA on motor cortex plasticity induced by facilitatory and inhibitory PAS of the motor cortex in 12 healthy humans. They received 25, 100, or 200 mg of L-DOPA or placebo medication combined with either excitability-enhancing or -diminishing PAS. Cortical excitability level was monitored before and for up to 2 d after plasticity induction by assessment of transcranial magnetic stimulation-induced motor-evoked potentials. Low-dose L-DOPA abolished the aftereffects of PAS and medium-dose L-DOPA prolonged facilitatory plasticity. High-dose L-DOPA reversed the excitability enhancement accomplished by facilitatory PAS to diminution. Thus, the results show a clear nonlinear effect of L-DOPA dosage on associative plasticity, different from that on nonfocal plasticity. This might help to explain dopaminergic effect on cognition and could be relevant for understanding the pathophysiology and treatment of neuropsychiatric diseases accompanied by alterations of the dopaminergic system.

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Altered plasticity of the human motor cortex in Parkinson's disease

Cited by 192 publications

References 86 publications

Functional reorganization of sensorimotor cortex in early Parkinson disease

Functional reorganization of sensorimotor cortex in early Parkinson disease

Neuromodulatory Neurotransmitters Influence LTP-Like Plasticity in Human Cortex: A Pharmaco-TMS Study

Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans

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