Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease

Dong, Jie; Hawes, Sarah; Wu, Jihong; Cai, Huaibin

doi:10.3389/fncir.2021.645287

Cited by 54 publications

(50 citation statements)

References 240 publications

(331 reference statements)

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“…On the other hand, blockade of excitatory glutamatergic transmission decreases CINs activity as expected. These results suggest that GABAergic transmission is also disrupted due to DA depletion (Nitsch and Riesenberg, 1995;Sullivan et al, 2008;Dehorter et al, 2009;Gonzales et al, 2013;Sato et al, 2014;Glajch et al, 2016;Dorst et al, 2020;Dong et al, 2021), provoking an excitatoryinhibitory imbalance that perhaps explains hyperactivity during DA depletion.…”

Section: Synaptic Inputs Contribute To Cholinergic Interneurons Hyper...mentioning

confidence: 92%

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Padilla‐Orozco

Duhne

Fuentes-Serrano

et al. 2022

Front. Synaptic Neurosci.

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Parkinson’s disease is a neurodegenerative ailment generated by the loss of dopamine in the basal ganglia, mainly in the striatum. The disease courses with increased striatal levels of acetylcholine, disrupting the balance among these modulatory transmitters. These modifications disturb the excitatory and inhibitory balance in the striatal circuitry, as reflected in the activity of projection striatal neurons. In addition, changes in the firing pattern of striatal tonically active interneurons during the disease, including cholinergic interneurons (CINs), are being searched. Dopamine-depleted striatal circuits exhibit pathological hyperactivity as compared to controls. One aim of this study was to show how striatal CINs contribute to this hyperactivity. A second aim was to show the contribution of extrinsic synaptic inputs to striatal CINs hyperactivity. Electrophysiological and calcium imaging recordings in Cre-mice allowed us to evaluate the activity of dozens of identified CINs with single-cell resolution in ex vivo brain slices. CINs show hyperactivity with bursts and silences in the dopamine-depleted striatum. We confirmed that the intrinsic differences between the activity of control and dopamine-depleted CINs are one source of their hyperactivity. We also show that a great part of this hyperactivity and firing pattern change is a product of extrinsic synaptic inputs, targeting CINs. Both glutamatergic and GABAergic inputs are essential to sustain hyperactivity. In addition, cholinergic transmission through nicotinic receptors also participates, suggesting that the joint activity of CINs drives the phenomenon; since striatal CINs express nicotinic receptors, not expressed in striatal projection neurons. Therefore, CINs hyperactivity is the result of changes in intrinsic properties and excitatory and inhibitory inputs, in addition to the modification of local circuitry due to cholinergic nicotinic transmission. We conclude that CINs are the main drivers of the pathological hyperactivity present in the striatum that is depleted of dopamine, and this is, in part, a result of extrinsic synaptic inputs. These results show that CINs may be a main therapeutic target to treat Parkinson’s disease by intervening in their synaptic inputs.

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Section: Synaptic Inputs Contribute To Cholinergic Interneurons Hyper...mentioning

confidence: 92%

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Padilla‐Orozco

Duhne

Fuentes-Serrano

et al. 2022

Front. Synaptic Neurosci.

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“…Connections via the thalamus likely have an excitatory effect on the cortex [35]. However, there also exist direct projections from cholinergic neurons in the GPe which have a solely GABAergic effect on the cortex [36]. Hence, while both inhibitory and excitatory projections exist from the GPe to the cortex, in this study we focus on the direct connection and apply periodic high-frequency stimulation, A stim ( t ), to the inhibitory population.…”

Section: Methodsmentioning

confidence: 99%

“…Throughout this paper, we stimulate the models consistently through the inhibitory population due to the GABAergic direct projections from the GPe to the subcortex [36]. However, the 1:2 tongue is still present when stimulating the excitatory population and observing the inhibitory population activity.…”

Section: B5 Stimulating the Excitatory Population Instead Of The Inhi...mentioning

confidence: 99%

Sub-harmonic Entrainment of Cortical Gamma Oscillations to Deep Brain Stimulation in Parkinson’s Disease: Model Based Predictions and Validation in Three Human Subjects

Sermon

Olaru

Ansó

et al. 2022

Preprint

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BackgroundEntrainment of brain oscillations has been hypothesised as a potential mechanism of neuromodulation. While neuromodulation has been shown to be an effective therapy for a variety of pathologies, there is no algorithmic approach to programming neurostimulators for specific neurological disorders. This is due in part to the lack of understanding of the effects of stimulation on neuronal rhythms. Counterintuitively, cortical finely-tuned gamma oscillations around 75Hz have been reported to be entrained at 65Hz during 130Hz deep brain stimulation (DBS) in patients with Parkinson’s disease (PD).Objective/MethodsHere, we demonstrate that these observations are consistent with 1:2 entrainment, which is a special case of sub-harmonic entrainment predicted by synchronisation theory. We fit a coupled neuronal population model to selected features characterising a PD patient’s off-stimulation finely-tuned gamma rhythm recorded through electrocorticography.ResultsOur model predicts the patient-specific regions of entrainment (Arnold tongues) in the stimulation frequency/amplitude space. We show that the resulting patient-specific neural circuit model exhibits 1:2 entrainment when stimulation is provided at 130Hz. Furthermore, we verify keys features of the 1:2 Arnold tongue with follow-up recordings from the same patient, such as the loss of 1:2 entrainment beyond a certain stimulation amplitude.ConclusionOur results reveal that periodic DBS in patients can lead to counter-intuitive patterns of neuronal entrainment across stimulation parameters, and that these responses can be predicted by modelling. Should entrainment prove to be an important mechanism of therapeutic stimulation, our modelling framework may reduce the parameter space that clinicians must consider when programming devices for optimal benefit.HighlightsEntrainment of cortical gamma oscillation at half stimulation frequency in patients with Parkinson’s disease is predicted by synchronisation theory.A Wilson-Cowan model, fitted to off-stimulation patient data, predicts a 1:2 synchronisation region biased towards lower stimulation frequencies where 1:2 entrainment will be lost at increased stimulation amplitudes.The fitted model also predicts that power spectral density of the 1:2 entrained frequency will be largest at lower stimulation frequencies and amplitudes.Observations of 1:2 entrainment at variable stimulation parameters for the same patient as the model was fitted to, are in line with the predictions from the model.

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“…Resting-state functional Magnetic Resonance Imaging (rs-fMRI) detects the intrinsic or spontaneous brain fluctuations of the blood oxygen level-dependent signal (Cohen et al, 2008;Fox & Raichle, 2007), which provides a powerful approach to investigate the functional variations and explore the neurotransmitter-related alterations. The functional connectivity (FC) between basal ganglia and cerebral cortex is an indirect index of dopaminergic activity and is verified to be related to the clinical severity of PD (Dong et al, 2021;Montgomery, 2015;Obeso et al, 2000;Rolinski et al, 2015Rolinski et al, , 2016. Basal forebrain (BF) provides the principal source of ACh for cerebral cortex in brain (Geula & Slevin, 1989;Mesulam, 2013;Sparks et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Cholinergic relevant functional reactivity is associated with dopamine responsiveness of tremor in Parkinson’s disease

Zhou

Guo

et al. 2022

Brain Imaging and Behavior

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Tremor in Parkinson’s disease (PD) has distinct responsiveness to dopamine, which is supposed not be exclusively related to dopamine deficiency but has a close relationship with cholinergic system. This phenomenon indicates that cholinergic system may be an important regulatory for distinct dopamine responsiveness of parkinsonian tremor. Through investigating the alterations of cholinergic and dopaminergic network during levodopa administration, we aimed at exploring the mechanisms of differed dopamine responsiveness of parkinsonian tremor. Fifty-two PD patients with tremor were enrolled. MRI scanning, UPDRS III and its sub-symptom scores were collected in OFF and ON status (dopaminergic challenge test). Then, patients were divided into two groups (dopamine-resistant tremor and dopamine-responsive tremor) according to the tremor change rate median score. Dopaminergic and cholinergic network were obtained. LASSO regression was conducted to identify functional connectivity with distinct reactivity during levodopa administration between groups. Afterwards, detailed group comparisons, interaction and correlation analyses were performed. The reactivity of cholinergic connectivity showed the highest possibility to distinguish two groups, especially connectivity of right basal forebrain 123 to right parietal operculum cortex (R.BF123-R.PO). After levodopa administration, connectivity of R.BF123-R.PO was decreased for dopamine-responsive tremor while which remained unchanged for dopamine-resistant tremor. The reactivity of R.BF123-R.PO was negatively correlated with tremor change rate. Reduced cholinergic connectivity to parietal operculum may be an underlying mechanism for the responsive tremor in PD and the distinct cholinergic reactivity of parietal operculum to levodopa may be a core pathophysiology for the differed DA responsiveness of tremor in PD.

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Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease

Cited by 54 publications

References 240 publications

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Sub-harmonic Entrainment of Cortical Gamma Oscillations to Deep Brain Stimulation in Parkinson’s Disease: Model Based Predictions and Validation in Three Human Subjects

Cholinergic relevant functional reactivity is associated with dopamine responsiveness of tremor in Parkinson’s disease

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