Parkinson's disease: Mechanisms and models

Corticalgammaoscillations(20280Hz)predictincreasesinfocusedattention,andfailureingammaregulationisahallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons atvariedfrequencies (82200Hz) selectivelyamplifies gamma oscillations. Incontrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.

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Driving fast-spiking cells induces gamma rhythm and controls sensory responses

The basal ganglia: focused selection and inhibition of competing motor programs.

Background In many patients with idiopathic Parkinson's disease, treatment with levodopa is complicated by fluctuations between an “off” period (also referred to as “off medication”), when the medication is not working and the motor symptoms of parkinsonism are present, and an “on” period, when the medication is causing improved mobility (also referred to as “on medication”), often accompanied by debilitating dyskinesias. In animal models of Parkinson's disease, there is overactivity in the subthalamic nucleus, and electrical stimulation of the subthalamic nucleus improves parkinsonism. We therefore sought to determine the efficacy and safety of electrical stimulation of the subthalamic nucleus in patients with Parkinson's disease. Methods We studied 24 patients with idiopathic Parkinson's disease in whom electrodes were implanted bilaterally in the subthalamic nucleus under stereotactic guidance with imaging and electrophysiologic testing of the location. Twenty were followed for at least 12 months. Clin...

https://www.nejm.org/doi/pdf/10.1056/NEJM199810153391603

Electrical Stimulation of the Subthalamic Nucleus in Advanced Parkinson's Disease

Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, and have been proposed to exert opposing influences on motor function. According to this classical model, activation of the 'direct' pathway facilitates movement and activation of the 'indirect' pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct-pathway activation completely rescued deficits in freezing, bradykinesia and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

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Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry

Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.

https://science.sciencemag.org/content/sci/249/4975/1436.full.pdf

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus

1. The neuronal mechanisms underlying the major motor signs of Parkinson's disease were studied in the basal ganglia of parkinsonian monkeys. Three African green monkeys were systemically treated w...

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The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism

Publisher Summary A basic understanding of basal ganglia function in the con­trol of movement can be gleaned from considering the effects of cortical activation on striatal and subthalamic neurons. The basal ganglia are a group of anatomically related sub­cortical nuclei that include the neostriatum (the caudate nucleus and putamen), the ventral striatum, the external and internal segments of the globus pallidus (GPe and GPi, respec­tively), the subthalamic nucleus (STN) and the substantia nigra pars reticulata and compacta (SNr and SNc, respectively). These structures are topographi­cally organized, and are linked to functionally similarly specific cortical and thalamic areas in the form of re-entrant circuits. Of the circuits that involve the basal ganglia, the skeletomotor circuit has received the most attention because it is strongly implicated in the pathophysiology of move­ment disorders. The functions of the motor circuit of the basal ganglia are not known. However, based on findings in diseases with basal ganglia pathology, and on animal experimentation, the basal ganglia are implicated in a large number of behaviors, including self-initiated (internally generated) movements, procedural learning, scaling of movement parameters, and movement sequencing.

Thomas Wichmann

Papers

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus

The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism

Neurotransmitters and Disorders of the Basal Ganglia

Rationale for Surgical Interventions in Movement Disorders