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The role of the corticothalamic projection in the ventral motor thalamus remains poorly understood. Therefore, we studied the electrophysiological responses of neurons in the basal ganglia and cerebellar receiving-territories of the motor thalamus (BGMT and CbMT, respectively) using optogenetic activation of corticothalamic projections in awake rhesus macaques. After injections of viral vectors carrying the excitatory opsins ChR2 or C1V1 into the primary motor and premotor cortices of two monkeys, we used optrodes to light activate opsin-expressing neurons in cortex or their terminals in the thalamus while simultaneously recording the extracellular activity of neurons in the vicinity of the stimulation sites. As expected, light activation of opsins in the cerebral cortex evoked robust, short-latency increases in firing of cortical neurons. In contrast, light stimulation of corticothalamic terminals induced small-amplitude, long-latency increases and/or decreases of activity in thalamic neurons. In postmortem material, opsins were found to be expressed in cell bodies and dendrites of cortical neurons and along their corticothalamic projections. At the electron microscopic level, opsin labeling was confined to unmyelinated preterminal axons and small terminals that formed asymmetric synapses with dendrites of projection neurons or GABAergic interneurons in BGMT and CbMT and with neurons in the reticular thalamic nucleus. The morphological features of the transfected terminals, along with the long latency and complex physiological responses of thalamic neurons to their activation, suggest a modulatory role of corticothalamic afferents upon the primate ventral motor thalamus. [ABSTRACT FROM AUTHOR]

Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 μl of a 2.5-mM solution, injected at 0.1-0.2 μl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3-13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential. [ABSTRACT FROM AUTHOR]

The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease. [ABSTRACT FROM AUTHOR]

Abstract: Electrophysiological studies of the effects of electrical brain stimulation have to contend with stimulus artifacts, which complicate both the maintenance of recorded neuron waveforms at recording time, and the post-hoc analysis of the data. The artifacts can be removed by digitally averaging some or all of the (stereotypic) artifact waveforms across artifacts, and then subtracting the resulting template from the recorded waveform at the time of artifact production. Available software-based approaches to this problem are effective but time consuming, and do not help with the problem of maintaining the recording quality at recording time. Alternative hardware-based methods are effective as well, but relatively inflexible and very expensive. We here provide a detailed description of a simple high-performance artifact removal device based on a multi-processor microcontroller as well as analog-to-digital and digital-to-analog converters. This device provides the benefits of self-adapting online-removal of stimulus artifacts for a fraction of the price of the commercially available devices. The device is fully customizable, and can be easily adjusted to various stimulation conditions, as well as AC line noise removal. [Copyright &y& Elsevier]

Abstract: The realization that medications used to treat movement disorders and psychiatric conditions of basal ganglia origin have significant shortcomings, as well as advances in the understanding of the functional organization of the brain, has led to a renaissance in functional neurosurgery, and particularly the use of deep brain stimulation (DBS). Movement disorders are now routinely being treated with DBS of ‘motor’ portions of the basal ganglia output nuclei, specifically the subthalamic nucleus and the internal pallidal segment. These procedures are highly effective and generally safe. Use of DBS is also being explored in the treatment of neuropsychiatric disorders, with targeting of the ‘limbic’ basal ganglia-thalamocortical circuitry. The results of these procedures are also encouraging, but many unanswered questions remain in this emerging field. This review summarizes the scientific rationale and practical aspects of using DBS for neurologic and neuropsychiatric disorders. [Copyright &y& Elsevier]

(1) Background: Non-invasive neuromodulation is a promising alternative to medication or deep-brain stimulation treatment for Parkinson's Disease or essential tremor. In previous work, we developed and tested a wearable system that modulates tremor via the non-invasive, electrical stimulation of peripheral nerves. In this article, we examine the proper range and the effects of various stimulation parameters for phase-locked stimulation. (2) Methods: We recruited nine participants with essential tremor. The subjects performed a bean-transfer task that mimics an eating activity to elicit kinetic tremor while using the wearable stimulation system. We examined the effects of stimulation with a fixed duty cycle, at different stimulation amplitudes and frequencies. The epochs of stimulation were locked to one of four phase positions of ongoing tremor, as measured with an accelerometer. We analyzed stimulation-evoked changes of the frequency and amplitude of tremor. (3) Results: We found that the higher tremor amplitude group experienced a higher rate of tremor power reduction (up to 65%) with a higher amplitude of stimulation when the stimulation was applied at the ±peak of tremor phase. (4) Conclusions: The stimulation parameter can be adjusted to optimize tremor reduction, and this study lays the foundation for future large-scale parameter optimization experiments for personalized peripheral nerve stimulation. [ABSTRACT FROM AUTHOR]

Abstract: The motor signs of Parkinson’s disease are thought to result in large part from a reduction of the level of dopamine in the basal ganglia. Over the last few years, many of the functional and anatomical consequences of dopamine loss in these structures have been identified, both in the basal ganglia and in related areas in thalamus and cortex. This knowledge has contributed significantly to our understanding of the link between the degeneration of dopamine neurons in the midbrain and the development of parkinsonism. This review discusses the evidence that implicates electrophysiologic changes (including altered discharge rates, increased incidence of burst firing, interneuronal synchrony, oscillatory activity, and altered sensorimotor processing) in basal ganglia, thalamus, and cortex, in parkinsonism. From these studies, parkinsonism emerges as a complex network disorder, in which abnormal activity in groups of neurons in the basal ganglia strongly affects the excitability, oscillatory activity, synchrony and sensory responses of areas of the cerebral cortex that are involved in the planning and execution of movement, as well as in executive, limbic or sensory functions. Detailed knowledge of these changes will help us to develop more effective and specific symptomatic treatments for patients with Parkinson’s disease. [Copyright &y& Elsevier]

These experiments re-examined the notion that reduced activity in the external pallidal segment (GPe) results in the abnormalities of neuronal discharge in the subthalamic nucleus (STN) and the internal pallidal segment (GPi) and in the development of parkinsonian motor signs. Extracellular recording in two rhesus monkeys, which had been rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed that the average neuronal discharge rate decreased in GPe but increased in STN and GPi. After MPTP, neurons in all three nuclei tended to discharge in oscillatory bursts. In addition, GABA release in STN (measured with microdialysis) was reduced, indicative of reduced activity along the GPe-STN pathway. Finally, the concentration of glutamic acid dehydrogenase (GAD; measured with autoimmunoradiography) was increased in GPe and GPi, likely reflecting increased striatal input and increased activity of local axon collaterals, respectively. Surprisingly, GAD protein in STN remained unchanged, indicating that the usual assumption that GAD levels are determined primarily by the overall activity of GABAergic elements may be too simplistic. The results from the MPTP-treated animals were compared with results obtained in a second group of three animals with ibotenic acid lesions of GPe. GPe lesions resulted in increased discharge in STN and GPi, comparable with the changes seen after MPTP but did not induce oscillatory bursting and had no behavioral effects. The results indicate that a mere reduction of GPe activity does not produce parkinsonism. Other changes, such as altered discharge patterns in STN and GPi, may play an important role in the generation of parkinsonism. [ABSTRACT FROM AUTHOR]

Conventional models propose that activity levels in two neuronal pathways, which have opposing effects on movement, become imbalanced in Parkinson’s disease. Analyses in mice point to a more complex reality. [ABSTRACT FROM AUTHOR]