Mechanisms underlying cortical resonant states: implications for levodopa-induced dyskinesia

Richter, Ulrike; Halje, Pär; Petersson, Per

doi:10.1515/revneuro-2013-0018

Cited by 19 publications

(23 citation statements)

References 151 publications

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“…In addition, accumulating evidence indicates a role for other brain regions. This includes the cortex, with LIDs correlating with supersensitive excitatory transmission at corticostriatal synapses (Ueno et al, 2014) and high-frequency cortical oscillations (Richter et al, 2013). The cerebellum also plays a role in LIDs possibly via the primary motor cortex (Kishore and Popa, 2014; Kishore et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Bordia

Perez

Heiss

et al. 2016

Neurobiology of Disease

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L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization.

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Section: Discussionmentioning

confidence: 99%

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Bordia

Perez

Heiss

et al. 2016

Neurobiology of Disease

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“…38 Accumulating preclinical experiments indicate a role for the cortex, with LIDs correlating with supersensitive excitatory transmission at corticostriatal synapses 39 and high-frequency cortical oscillations. 40 Additionally, human neuroimaging studies suggest that abnormal dopaminergic modulation of striatocortical networks underlies LIDs, 41 and that alterations in activity of frontal cortex areas were linked to LIDs in PD patients. 42,43 Dyskinetic patients exhibited decreased activity of the right inferior frontal cortex after L-dopa, whereas patients without dyskinesias showed a reverse effect.…”

Section: Discussionmentioning

confidence: 99%

α7 nicotinic receptor agonists reduce levodopa‐induced dyskinesias with severe nigrostriatal damage

et al. 2015

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Background ABT-126 is a novel, safe and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. Here we test the antidyskinetic effect of ABT-126 in MPTP-treated squirrel monkeys with moderate and more severe nigrostriatal damage. Methods Monkeys (n=21, Set 1) were lesioned with MPTP 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n=5), or treated with vehicle (n=6) or ABT-126 (n=10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1-2 times for a total of 3-4 MPTP injections. The antidyskinetic effect of ABT-126, nicotine and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n=23, Set 2) was lesioned with MPTP only 1-2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n=6), ABT-894 (n=6), nicotine (n=5) or vehicle (n=6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured. Results With moderate nigrostriatal damage (MPTP 1-2×), ABT-126 dose-dependently decreased dyskinesias (~60%), with similar results with ABT-894 (~60%) or nicotine (~60%). With more severe damage (MPTP 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism. Conclusion The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early and later stage Parkinson's disease.

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“…This suppression in combination with an activity-dependent broad-band increase in the gamma band created a marked flattening of the power spectrum in the range ~20-60 Hz. However, in conjunction with dyskinetic symptoms, another phenomenon in the form of a strong narrowband oscillation at ~80 Hz emerged (Figure 2B; see also Halje et al 2012, Richter et al 2013, Dupre et al 2015). This oscillation was stable and similar for different electrodes and recordings but was never observed in either the MI or DLS in the lesioned hemisphere during baseline (i.e.…”

Section: Resultsmentioning

confidence: 87%

Untangling cortico-striatal connectivity and cross-frequency coupling in L-DOPA-induced dyskinesia

Belić

Halje

Richter

et al. 2015

Preprint

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We simultaneously recorded local field potentials (LFPs) in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats in order to study the features directly related to pathological states such as parkinsonian state and levodopa-induced dyskinesia. We analyzed the spectral characteristics of the obtained signals and observed that during dyskinesia the most prominent feature was a relative power increase in the high gamma frequency range at around 80 Hz, while for the parkinsonian state it was in the beta frequency range. Here we show that during both pathological states effective connectivity in terms of Granger causality is bidirectional with an accent on the striatal influence on the cortex. In the case of dyskinesia, we also found a high increase in effective connectivity at 80 Hz. In order to further understand the 80-Hz phenomenon, we performed cross-frequency analysis and observed characteristic patterns in the case of dyskinesia but not in the case of the parkinsonian state or the control state. We noted a large decrease in the modulation of the amplitude at 80 Hz by the phase of low frequency oscillations (up to ∼10 Hz) across both structures in the case of dyskinesia. This may suggest a lack of coupling between the low frequency activity of the recorded network and the group of neurons active at ∼80 Hz.

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Mechanisms underlying cortical resonant states: implications for levodopa-induced dyskinesia

Cited by 19 publications

References 151 publications

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

α7 nicotinic receptor agonists reduce levodopa‐induced dyskinesias with severe nigrostriatal damage

Untangling cortico-striatal connectivity and cross-frequency coupling in L-DOPA-induced dyskinesia

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