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Neurodegeneration
Published in Ibrahim Natalwala, Ammar Natalwala, E Glucksman, MCQs in Neurology and Neurosurgery for Medical Students, 2022
Ibrahim Natalwala, Ammar Natalwala, E Glucksman
The motor cortex and the supplementary motor area predominantly project excitatory glutamatergic fibres to the spinal cord (lateral corticospinal tract), striatum and thalamus. The striatum consists of the caudate nucleus and the putamen, separated anatomically by the internal capsule. It comprises chiefly medium spiny neurones which are inherently inhibitory (GABAergic). The striatum projects inhibitory fibres to the globus pallidus interna (GPi) and substantia nigra pars reticularis (SNr). This pathway is known as the direct pathway since the GPi and SNr inhibit the thalamus (via the inhibitory ansa lenticularis projections) and hence if the striatum inhibits them, the thalamus is allowed to transmit excitatory output to the cerebral cortex and striatum (positive feedback loop).
Assessing Paediatric Development in Psychiatry
Published in Cathy Laver-Bradbury, Margaret J.J. Thompson, Christopher Gale, Christine M. Hooper, Child and Adolescent Mental Health, 2021
The basal ganglia nuclei are essential partners of the motor system. As a unit they are responsible for preventing unwanted movements from being instigated, along with allowing the current constellation of motor signals, already occurring between the cortex and the spine, to continue to be relayed, unimpeded. The indirect pathway is responsible for the former, the direct pathway, the latter.
Brain Motor Centers and Pathways
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
There are three feedback loops between the cerebral cortex and the basal ganglia, through the thalamus. the direct pathway is a positive feedback loop that facilitates movement, whereas the indirect and hyperdirect pathways are negative feedback loops that hinder movement. Some of the well-known clinical disorders of the basal ganglia can be correlated with neuronal activity in these loops.
Developments in the mechanistic understanding and clinical application of deep brain stimulation for Parkinson’s disease
Published in Expert Review of Neurotherapeutics, 2022
Francesco Bove, Danilo Genovese, Elena Moro
Recent studies have raised the alternative explanation according to which DBS could dissociate input and output signals, producing a functional deafferentation of the targeted structure from afferent and toward efferent structures [22,39]. The theorized mechanism is the reduction of hyperactivity along the hyperdirect and indirect pathways (indirectly measured with the abolition of cortically evoked early and late excitation of GPi in experimental PD models), preserving the function of the direct pathway [16]. The so-called ‘disruption hypothesis’ can also unknot a long-standing paradox: interrupting the information flow through the stimulated structure, DBS ultimately produces effects comparable with lesion therapies, without inhibiting the target as postulated in previous studies [16,26,40]. According to this latter model, high-frequency DBS exerts its effects through a complex interplay of inhibitory and excitatory events, modulating neural activity in afferent and efferent brain regions to restore function [41].
Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan
Published in Expert Opinion on Pharmacotherapy, 2018
Makio Takahashi, Masaki Fujita, Naoko Asai, Mayumi Saki, Akihisa Mori
Adenosine A2A receptors are highly localized to the striatum, globus pallidus external segment (GPe), and accumbens [9]. The basal ganglia-thalamo-cortical circuit was proposed to help understand the mechanisms involved in the motor symptoms in PD. A key feature of this neuronal circuit is the presence of two output pathways from the striatum: i) the striato-nigral pathway (direct pathway) regulated by dopamine D1 receptors; and ii) the striato-pallidal pathway controlled by dopamine D2 receptors (indirect pathway). Both pathways should be well balanced via dopaminergic input from the SNpc to ensure good motor control. A lack of dopaminergic inputs to those pathways occurs in PD, leading to an imbalance of the two pathways resulting in the decreased excitatory activity of the direct pathway and increased inhibitory activity of the indirect pathway, which causes motor dysfunction via the uncoordinated balance of the basal ganglia circuit [10]. To date, studies have revealed that A2A receptor activation selectively increases the excitability of the indirect pathway via receptors in the striatum and GPe, mainly expressed by GABAergic interneurons (medium spiny neurons) [11,12]. Adenosine A2A receptor signals counteract dopaminergic D2 receptor function in the same indirect pathway, suggesting it is involved in the motor abnormalities observed in PD [13,14]. Indeed, selective adenosine A2A receptor agonists produce motor deficits in rodents and non-human primates, which are ameliorated by adenosine A2A receptor antagonists and vice versa [15,16].
The adenosine A2A receptor is a therapeutic target in neurological, heart and oncogenic diseases
Published in Expert Opinion on Therapeutic Targets, 2022
Rafael Franco, Alejandro Lillo, Gemma Navarro, Irene Reyes-Resina
It served to formulate the hypothesis that pharmacological manipulation of the adenosinergic system could be useful in PD. In fact, the direct pathway mainly contains neurons expressing D1 dopamine and A1 Ado receptors and the indirect pathway mainly contains neurons expressing D2 dopamine and A2A Ado receptors. Unfortunately, PD also courses with non-motor symptoms, mainly neuropsychiatric for which there are no good animals models [46]. Evidence at the preclinical level shows that A2AR antagonists may be useful in combating some of the non-motor symptoms accompanying PD patients. On the one hand, mice that are knockout for the ADORA2A gene, which codes for the A2AR, display aggressiveness [20], whereas daytime sleep disturbances in PD patients can be addressed by A2AR antagonists by a mechanism similar to that exerted by caffeine [31] On the other hand, a limited open-label prospective study with a limited number of PD patients, 15, show that istradefylline may be efficacious against depression in some of the patients. Authoritative reviews on the possibility that A2AR antagonists may be efficacious to treat the non-motor symptoms of parkinsonian patients may be found in the literature [28,47–50]. A recent untargeted metabolomics study in rat serum and brain indicates that anti-depressive actions of A2AR antagonists may be related to effects on lipid and amino acid metabolisms [51], thus suggesting that some of the metabolites highlighted in the study could be biomarkers of the actions of these drugs and/or of depression