GABAergic changes in the thalamocortical circuit in Parkinson's disease

Nuland, A.J.M. van; Ouden, H.E.M. den; Zach, Heidemarie; Dirkx, Michiel F.; Asten, Jack J.A. van; Scheenen, Tom W. J.; Toni, Ivan; Cools, Roshan; Helmich, Rick C.

doi:10.1002/hbm.24857

Cited by 53 publications

(38 citation statements)

References 68 publications

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“…For patients only, each day started with a measurement of their motor symptoms (using the UPDRS motor scale), followed by administration of medication (or placebo). Next all participants underwent a combination of functional MRI and anatomical scans that lasted ∼2 h ( Dirkx et al , 2019; van Nuland et al ., 2020, submitted for publication ). After a short break, participants performed the behavioural task (outside the scanner).…”

Section: Methodsmentioning

confidence: 99%

Effects of dopamine on reinforcement learning in Parkinson’s disease depend on motor phenotype

Nuland

Helmich

Dirkx³

et al. 2020

Brain

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Parkinson’s disease is clinically defined by bradykinesia, along with rigidity and tremor. However, the severity of these motor signs is greatly variable between individuals, particularly the presence or absence of tremor. This variability in tremor relates to variation in cognitive/motivational impairment, as well as the spatial distribution of neurodegeneration in the midbrain and dopamine depletion in the striatum. Here we ask whether interindividual heterogeneity in tremor symptoms could account for the puzzlingly large variability in the effects of dopaminergic medication on reinforcement learning, a fundamental cognitive function known to rely on dopamine. Given that tremor-dominant and non-tremor Parkinson’s disease patients have different dopaminergic phenotypes, we hypothesized that effects of dopaminergic medication on reinforcement learning differ between tremor-dominant and non-tremor patients. Forty-three tremor-dominant and 20 non-tremor patients with Parkinson’s disease were recruited to be tested both OFF and ON dopaminergic medication (200/50 mg levodopa-benserazide), while 22 age-matched control subjects were recruited to be tested twice OFF medication. Participants performed a reinforcement learning task designed to dissociate effects on learning rate from effects on motivational choice (i.e. the tendency to ‘Go/NoGo’ in the face of reward/threat of punishment). In non-tremor patients, dopaminergic medication improved reward-based choice, replicating previous studies (Frank et al., 2004; Cools et al., 2006). In contrast, in tremor-dominant patients, dopaminergic medication improved learning from punishment. Formal modelling showed divergent computational effects of dopaminergic medication as a function of Parkinson’s disease motor phenotype, with a modulation of motivational choice bias and learning rate in non-tremor and tremor patients, respectively. This finding establishes a novel cognitive/motivational difference between tremor and non-tremor Parkinson’s disease patients, and highlights the importance of considering motor phenotype in future work.

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Section: Methodsmentioning

confidence: 99%

Effects of dopamine on reinforcement learning in Parkinson’s disease depend on motor phenotype

Nuland

Helmich

Dirkx³

et al. 2020

Brain

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“…However, our finding provides strong evidence that the cerebellum should be considered as a primary site for systems-level compensation in the disorder [ 5 ]. Considering the neuroprotective role of GABAergic inhibition [ 51 ], future intervention studies are necessary to test how the modulation of GABAergic mechanisms changes PD cognitive symptoms, and to establish whether GABA plays a compensatory or pathophysiological role in Parkinson’s disease. This is of clinical relevance since pharmacologically boosting GABAergic neurotransmission in PD patients modulates aberrant neuronal network oscillations at beta frequency [ 52 ], which seems to restore cognitive functions, at least in stroke patients.…”

Section: Discussionmentioning

confidence: 99%

Cerebellar GABA Levels and Cognitive Interference in Parkinson’s disease and Healthy Comparators

Piras

Vecchio

Assogna

et al. 2020

JPM

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The neuroanatomical and molecular substrates for cognitive impairment in Parkinson Disease (PD) are far from clear. Evidence suggests a non-dopaminergic basis, and a crucial role for cerebellum in cognitive control in PD. We investigated whether a PD cognitive marker (response inhibition) was differently controlled by g-amino butyric acid (GABA) and/or by glutamate-glutamine (Glx) levels in the cerebellum of idiopathic PD patients, and healthy comparators (HC). Magnetic resonance spectroscopy of GABA/Glx (MEGA-PRESS acquisition sequence) was performed at 3 Tesla, and response inhibition assessed by the Stroop Word-Color Test (SWCT) and the Wisconsin Card Sorting Test (WCST). Linear correlations between cerebellar GABA/Glx levels, SWCT time/error interference effects and WCST perseverative errors were performed to test differences between correlation coefficients in PD and HC. Results showed that higher levels of mean cerebellar GABA were associated to SWCT increased time and error interference effects in PD, and the contrary in HC. Such effect dissociated by hemisphere, while correlation coefficients differences were significant in both right and left cerebellum. We conclude that MRS measured levels of cerebellar GABA are related in PD patients with decreased efficiency in filtering task-irrelevant information. This is crucial for developing pharmacological treatments for PD to potentially preserve cognitive functioning.

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“…It is generally thought that bradykinesia results from the loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent striatal dopamine depletion [ 142 ]. However, it has recently been suggested that GABA plays a modulatory role in the pathophysiology of PD that is independent of dopaminergic medication [ 143 , 144 , 145 ]. In addition, the GABA A R/Cl − , HCO 3 − ATPase from rat brain is involved in the phenol-induced manifestations of both head-twitching and tremors [ 94 ].…”

Section: The β3 Subunit and Human Diseasesmentioning

confidence: 99%

Intricacies of GABAA Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology

Menzikov

Morozov

Kubatiev

2021

IJMS

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Neuronal intracellular chloride ([Cl−]i) is a key determinant in γ-aminobutyric acid type A (GABA)ergic signaling. γ-Aminobutyric acid type A receptors (GABAARs) mediate both inhibitory and excitatory neurotransmission, as the passive fluxes of Cl− and HCO3− via pores can be reversed by changes in the transmembrane concentration gradient of Cl−. The cation–chloride co-transporters (CCCs) are the primary systems for maintaining [Cl−]i homeostasis. However, despite extensive electrophysiological data obtained in vitro that are supported by a wide range of molecular biological studies on the expression patterns and properties of CCCs, the presence of ontogenetic changes in [Cl−]i—along with the consequent shift in GABA reversal potential—remain a subject of debate. Recent studies showed that the β3 subunit possesses properties of the P-type ATPase that participates in the ATP-consuming movement of Cl− via the receptor. Moreover, row studies have demonstrated that the β3 subunit is a key player in GABAAR performance and in the appearance of serious neurological disorders. In this review, we discuss the properties and driving forces of CCCs and Cl−, HCO3−ATPase in the maintenance of [Cl−]i homeostasis after changes in upcoming GABAAR function. Moreover, we discuss the contribution of the β3 subunit in the manifestation of epilepsy, autism, and other syndromes.

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GABAergic changes in the thalamocortical circuit in Parkinson's disease

Cited by 53 publications

References 68 publications

Effects of dopamine on reinforcement learning in Parkinson’s disease depend on motor phenotype

Effects of dopamine on reinforcement learning in Parkinson’s disease depend on motor phenotype

Cerebellar GABA Levels and Cognitive Interference in Parkinson’s disease and Healthy Comparators

Intricacies of GABAA Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology

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