Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease

Kishore, Asha; Joseph, Thomas; Velayudhan, Balu; Popa, Traian; Meunier, Sabine

doi:10.1016/j.clinph.2011.06.034

Cited by 104 publications

(79 citation statements)

References 48 publications

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“…The sensorimotor plastic effects of PAS depend on the coincidence of pre- and post-synaptic neuronal activation within a specific time window (110–112). Using TBS in de novo PD, the LTP- and LTD-like plasticity of the intracortical circuits within M1was shown to be symmetrically and severely impaired even though the motor symptoms were unilateral (29). There was also no correlation of the plasticity loss with motor signs of PD, indicating that that M1 changes were more likely the direct consequence of mesocortical denervation than the indirect consequence of striatal denervation, the latter being more correlated with Parkinsonian signs.…”

Section: Dopaminergic Signaling In Parkinsonism and Levodopa-induced mentioning

confidence: 99%

Cerebellum in Levodopa-Induced Dyskinesias: The Unusual Suspect in the Motor Network

Kishore

Popa

2014

Front. Neurol.

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The exact mechanisms that generate levodopa-induced dyskinesias (LID) during chronic levodopa therapy for Parkinson’s disease (PD) are not yet fully established. The most widely accepted theories incriminate the non-physiological synthesis, release and reuptake of dopamine generated by exogenously administered levodopa in the striatum, and the aberrant plasticity in the cortico-striatal loops. However, normal motor performance requires the correct recruitment of motor maps. This depends on a high level of synergy within the primary motor cortex (M1) as well as between M1 and other cortical and subcortical areas, for which dopamine is necessary. The plastic mechanisms within M1, which are crucial for the maintenance of this synergy, are disrupted both during “OFF” and dyskinetic states in PD. When tested without levodopa, dyskinetic patients show loss of treatment benefits on long-term potentiation and long-term depression-like plasticity of the intracortical circuits. When tested with the regular pulsatile levodopa doses, they show further impairment of the M1 plasticity, such as inability to depotentiate an already facilitated synapse and paradoxical facilitation in response to afferent input aimed at synaptic inhibition. Dyskinetic patients have also severe impairment of the associative, sensorimotor plasticity of M1 attributed to deficient cerebellar modulation of sensory afferents to M1. Here, we review the anatomical and functional studies, including the recently described bidirectional connections between the cerebellum and the basal ganglia that support a key role of the cerebellum in the generation of LID. This model stipulates that aberrant neuronal synchrony in PD with LID may propagate from the subthalamic nucleus to the cerebellum and “lock” the cerebellar cortex in a hyperactive state. This could affect critical cerebellar functions such as the dynamic and discrete modulation of M1 plasticity and the matching of motor commands with sensory information from the environment during motor performance. We propose that in dyskinesias, M1 neurons have lost the ability to depotentiate an activated synapse when exposed to acute pulsatile, non-physiological, dopaminergic surges and become abnormally receptive to unfiltered, aberrant, and non-salient afferent inputs from the environment. The motor program selection in response to such non-salient and behaviorally irrelevant afferent inputs would be abnormal and involuntary. The motor responses are worsened by the lack of normal subcortico–cortical inputs from cerebellum and basal ganglia, because of the aberrant plasticity at their own synapses. Artificial cerebellar stimulation might help re-establish the cerebellar and basal ganglia control over the non-salient inputs to the motor areas during synaptic dopaminergic surges.

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Section: Dopaminergic Signaling In Parkinsonism and Levodopa-induced mentioning

confidence: 99%

Cerebellum in Levodopa-Induced Dyskinesias: The Unusual Suspect in the Motor Network

Kishore

Popa

2014

Front. Neurol.

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“…In another electrophysiological study, plasticity of primary motor cortices (M1) in de novo PD patients and age-matched healthy controls in response to a single dose of L-DOPA has been tested using intermittent versus continuous theta-burst stimulation protocols to induce respectively LTP-and LTDlike plasticity on both M1 cortices [25]. These protocols induced plasticity in M1 of controls while in de novo PD patients no plasticity was measured.…”

Section: Cortexmentioning

confidence: 99%

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

Calabresi

Ghiglieri

Mazzocchetti

et al. 2015

Phil. Trans. R. Soc. B

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The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients.

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“…The negative fi ndings can be partly attributed to altered response to rTMS in PD. Studies investigating plasticity induction in PD patients in general reported ineffectiveness or responses different from healthy populations (Eggers et al 2010 ;Suppa et al 2011 ;Kishore et al 2012a ). A recent study even demonstrated that responses to TBS are highly variable in the healthy population .…”

Section: Rtms Over the Primary Motor Cortex (M1)mentioning

confidence: 93%

Clinical Applications of rTMS in Parkinson’s Disease

Shirota

Hamada

Ugawa³

2015

Therapeutic rTMS in Neurology

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Parkinson's disease (PD) has wide-ranging clinical features, and repetitive transcranial magnetic stimulation (rTMS) therapy has been tried for many aspects of PD. Underlying mechanism of rTMS therapy in PD remains unclear, but several possibilities are proposed such as endogenous dopamine release or restoration of neural plasticity or network activity. Motor symptoms are a cardinal feature of PD, for which evidence suggested moderate effi cacy of rTMS. High-frequency (HF) rTMS over the M1 including less focal stimulation (e.g., leg and bilateral hand M1 rTMS) or over the DLPFC, and low-frequency (LF) rTMS over the SMA were most favorable. Long-term administration of levodopa, a major agent for medical therapy of PD, can induce a motor complication called levodopainduced dyskinesia (LID). Several types of rTMS were reported to be effective for the LID. rTMS has also been tried for non-pharmacological treatment of nonmotor symptoms of PD including depression. A "weak recommendation" in favor of HF rTMS of the left DLPFC can be given for the treatment of depressive symptoms associated with PD. These are examples of growing application of rTMS therapy to PD for symptoms other than the classical motor symptoms. As such, rTMS has a potential to become an important adjunctive treatment for PD. Well-designed large clinical trials are needed to establish its utility in the clinical settings.

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Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease

Cited by 104 publications

References 48 publications

Cerebellum in Levodopa-Induced Dyskinesias: The Unusual Suspect in the Motor Network

Cerebellum in Levodopa-Induced Dyskinesias: The Unusual Suspect in the Motor Network

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

Clinical Applications of rTMS in Parkinson’s Disease

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