In order to evaluate the specific interactions between cortical oscillations and basal ganglia–spiking activity under normal and parkinsonian conditions, we examined the relationship between frontal cortex electroencephalographic (EEG) signals and simultaneously recorded neuronal activity in the internal and external segments of the pallidum or the subthalamic nucleus (STN) in 3 rhesus monkeys. After we made recordings in the normal state, hemiparkinsonism was induced with intracarotid injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in one animal, followed by additional recordings. Spiking activity in the pallidum and STN was associated with significant shifts in the level of EEG synchronization. We also found that the spectral power of beta- and gamma-band EEG rhythms covaried positively before the basal ganglia spikes but did not covary or covaried negatively thereafter. In parkinsonism, changes in cortical synchronization and phase coherence were reduced in EEG segments aligned to STN spikes, whereas both were increased in data segments aligned to pallidal spikes. Spiking-related changes in beta/gamma-band covariance were reduced. The findings indicate that basal ganglia and cortex interact in the processing of cortical rhythms that contain oscillations across a broad range of frequencies and that this interaction is severely disrupted in parkinsonism.
The availability of suitable animal models and the opportunity to record electrophysiologic data in movement disorder patients undergoing neurosurgical procedures has allowed researchers to investigate parkinsonism-related changes in neuronal firing patterns in the basal ganglia and associated areas of the thalamus and cortex. These studies have shown that parkinsonism is associated with increased activity in the basal ganglia output nuclei, along with increases in burst discharges, oscillatory firing and synchronous firing patterns throughout the basal ganglia. Computational approaches have the potential to play an important role in the interpretation of these data. Such efforts can provide a formalized view of neuronal interactions in the network of connections between the basal ganglia, thalamus, and cortex, allow for the exploration of possible contributions of particular network components to parkinsonism, and potentially result in new conceptual frameworks and hypotheses that can be subjected to biological testing. It has proven very difficult, however, to integrate the wealth of the experimental findings into coherent models of the disease. In this review, we provide an overview of the abnormalities in neuronal activity that have been associated with parkinsonism. Subsequently, we discuss some particular efforts to model the pathophysiologic mechanisms that may link abnormal basal ganglia activity to the cardinal parkinsonian motor signs and may help to explain the mechanisms underlying the therapeutic efficacy of deep brain stimulation for Parkinson's disease. We emphasize the logical structure of these computational studies, making clear the assumptions from which they proceed and the consequences and predictions that follow from these assumptions. Parkinsonism has been linked with changes in neuronal firing patterns in the basal ganglia (BG) and associated areas of the thalamus and cortex. We provide an overview of these findings and discuss some efforts to use computational models to understand these relationships as well as the therapeutic effects of deep brain stimulation (DBS). In particular, several modeling studies that we consider focus on the idea that DBS works by regularizing BG outputs. For example, models show how parkinsonian basal ganglia outputs may compromise thalamocortical relay of excitatory inputs (curly brackets), while DBS- induced regularization may restore relay fidelity, and these ideas lead to predictions about the importance of particular BG outputs in the emergence of parkinsonian signs and of particular DBS properties in alleviating these signs.
Although the existence of a massive projection from the caudal intralaminar nuclei of the thalamus [i.e. the centromedian (CM) and parafascicular nuclei] to the striatum is well documented, the effects of CM activation upon striatal cells remain poorly understood. Therefore, we studied the effects of electrical stimulation of CM on the electrophysiological activity of striatal neurons, and on striatal levels of γ-aminobutyric acid (GABA) and acetylcholine in rhesus monkeys. Striatal cells did not respond to single-pulse stimulation (bipolar biphasic stimulation, 175-500 μA), but the large majority of recorded neurons responded to burst stimulation (100 Hz, 1 s, 150-175 μA) of CM, often with a delay of tens of milliseconds. Striatal phasically active neurons, which likely correspond to projection neurons, responded mainly with increases in firing (13/28 cells), while tonically active neurons (likely cholinergic interneurons) often showed combinations of increases and decreases in firing (24/46 cells). In microdialysis studies, CM stimulation led to a reduction of striatal acetylcholine levels. This effect was prevented by addition of the GABA-A receptor antagonist gabazine to the microdialysis fluid. We conclude that CM stimulation frequently results in striatal response patterns with excitatory and inhibitory components. Under the conditions chosen here, the specific patterns of striatal responses to CM stimulation are likely the result of striatal processing of thalamic inputs. Through these indirect effects, local CM stimulation may engage large portions of the striatum. These effects may be relevant in the interpretation of the therapeutic effects of CM stimulation for the treatment of neurological disorders.
Electrical and pharmacological stimulation methods are commonly used to study neuronal brain circuits in vivo, but are problematic, because electrical stimulation has limited specificity, while pharmacological activation has low temporal resolution. A recently developed alternative to these methods is the use of optogenetic techniques, based on the expression of light sensitive channel proteins in neurons. While optogenetics have been applied in in vitro preparations and in in vivo studies in rodents, their use to study brain function in nonhuman primates has been limited to the cerebral cortex. Here, we characterize the effects of channelrhodopsin-2 (ChR2) transfection in subcortical areas, i.e., the putamen, the external globus pallidus (GPe) and the ventrolateral thalamus (VL) of rhesus monkeys. Lentiviral vectors containing the ChR2 sequence under control of the elongation factor 1α promoter (pLenti-EF1α -hChR2(H134R)-eYFP-WPRE, titer 109 particles/ml) were deposited in GPe, putamen and VL. Four weeks later, a probe combining a conventional electrode and an optic fiber was introduced in the previously injected brain areas. We found light-evoked responses in 31.5% and 32.7% of all recorded neurons in the striatum and thalamus, respectively, but only in 2.5% of recorded GPe neurons. As expected, most responses were time-locked increases in firing, but decreases or mixed responses were also seen, presumably via ChR2-mediated activation of local inhibitory connections. Light and electron microscopic analyses revealed robust expression of ChR2 on the plasma membrane of cell somas, dendrites, spines and terminals in the striatum and VL. This study demonstrates that optogenetic experiments targeting the striatum and basal ganglia-related thalamic nuclei can be successfully achieved in monkeys. Our results indicate important differences of the type and magnitude of responses in each structure. Experimental conditions such as the vector used, the number and rate of injections, or the light stimulation conditions have to be optimized for each structure studied.
High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a successful treatment for patients with advanced Parkinson's disease (PD). Although its exact mechanism of action is unknown, it is currently believed that the beneficial effects of the stimulation are mediated either by alleviating pathological basal ganglia output patterns of activity or by activation of the axons of passage that arise from the cerebral cortex and other sources. In this study, we show that the anatomical composition of the primate STN provides a substrate through which DBS may elicit widespread changes in brain activity via stimulation of fibers of passage. Using quantitative high-resolution electron microscopy, we found that the primate STN is traversed by numerous myelinated axons, which occupy as much as 45% of its sensorimotor territory and 36% of its associative region. In comparison, myelinated axons occupy only 27% of the surface areas of the sensorimotor and associative regions of the internal segment of the globus pallidus (GPi), another target for therapeutic DBS in PD. We also noted that myelinated axons in the STN, on average, have a larger diameter than those in GPi, which may render them more susceptible to electrical stimulation. Because axons are more excitable than other neuronal elements, our findings support the hypothesis that STN DBS, even when carried out entirely within the confines of the nucleus, mediates some of its effects by activating myelinated axons of passage.
Because of our limited knowledge of the functional role of the thalamostriatal system, this massive network is often ignored in models of the pathophysiology of brain disorders of basal ganglia origin, such as Parkinson’s disease (PD). However, over the past decade, significant advances have led to a deeper understanding of the anatomical, electrophysiological, behavioral and pathological aspects of the thalamostriatal system. The cloning of the vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2) has provided powerful tools to differentiate thalamostriatal from corticostriatal glutamatergic terminals, allowing us to carry out comparative studies of the synaptology and plasticity of these two systems in normal and pathological conditions. Findings from these studies have led to the recognition of two thalamostriatal systems, based on their differential origin from the caudal intralaminar nuclear group, the center median/parafascicular (CM/Pf) complex, or other thalamic nuclei. The recent use of optogenetic methods supports this model of the organization of the thalamostriatal systems, showing differences in functionality and glutamate receptor localization at thalamostriatal synapses from Pf and other thalamic nuclei. At the functional level, evidence largely gathered from thalamic recordings in awake monkeys strongly suggests that the thalamostriatal system from the CM/Pf is involved in regulating alertness and switching behaviors. Importantly, there is evidence that the caudal intralaminar nuclei and their axonal projections to the striatum partly degenerate in PD and that CM/Pf deep brain stimulation (DBS) may be therapeutically useful in several movement disorders.
The basal ganglia are comprised of the striatum, the external and internal segment of the globus pallidus (GPe and GPi, respectively), the subthalamic nucleus (STN), and the substantia nigra pars compacta and reticulata (SNc and SNr, respectively). Dopamine has long been identified as an important modulator of basal ganglia function in the striatum, and disturbances of striatal dopaminergic transmission have been implicated in diseases such as Parkinson’s disease (PD), addiction and attention deficit hyperactivity disorder. However, recent evidence suggests that dopamine may also modulate basal ganglia function at sites outside of the striatum, and that changes in dopaminergic transmission at these sites may contribute to the symptoms of PD and other neuropsychiatric disorders. This review summarizes the current knowledge of the anatomy, functional effects and behavioral consequences of the dopaminergic innervation to the GPe, GPi, STN, and SNr. Further insights into the dopaminergic modulation of basal ganglia function at extrastriatal sites may provide us with opportunities to develop new and more specific strategies for treating disorders of basal ganglia dysfunction.
The underlying etiology of parkinsonian anterocollis has been the subject of recent debate. The purpose of this study is to test the hypothesis that anterocollis in parkinsonian syndromes is associated with dystonia of the deep cervical flexors (longus colli and capitis). Eight patients with anterocollis, six in the setting of parkinsonism and two primary cervical dystonia control subjects with anterocollis underwent prospective structured clinical evaluations (interview, examination and rating scales), systematic electromyography of the cervical extensor musculature and 18F-FDG PET/CT studies of cervical muscles to examine evidence of hypermetabolism or overactivity of deep cervical flexors. Subjects with parkinsonian anterocollis were found to have hypermetabolism of the extensor and sub-occipital muscles but not in the cervical flexors (superficial or deep). EMG abnormalities were observed in all evaluated patients, but only one patient was definitely myopathic. Meanwhile, both dystonia controls exhibited hypermetabolism of cervical flexors (including the longus colli). In conclusion, we were able to demonstrate hypermetabolism of superficial and deep cervical flexors with muscle 18F-FDG PET/CT in dystonic anterocollis patients, but not in parkinsonian anterocollis patients. The hypermetabolic changes seen in parkinsonian anterocollis patients in posterior muscles may be compensatory. Alternative explanations for anterocollis include myopathy of the cervical extensors, or unbalanced rigidity of the cervical flexors, but this remains to be proven.
T-type calcium channels (Ca v 3) are key mediators of thalamic bursting activity, but also regulate single cells excitability, dendritic integration, synaptic strength and transmitter release. These functions are strongly influenced by the subcellular and subsynaptic localization of Ca v 3 channels along the somatodendritic domain of thalamic cells. In Parkinson’s disease, T-type calcium channels dysfunction in the basal ganglia-receiving thalamic nuclei likely contributes to pathological thalamic bursting activity. In this study, we analyzed the cellular, subcellular, and subsynaptic localization of the Ca v 3.1 channel in the ventral anterior (VA) and centromedian/parafascicular (CM/Pf) thalamic nuclei, the main thalamic targets of basal ganglia output, in normal and parkinsonian monkeys. All thalamic nuclei displayed strong Ca v 3.1 neuropil immunoreactivity, although the intensity of immunolabeling in CM/Pf was significantly lower than in VA. Ultrastructurally, 70–80 % of the Ca v 3.1-immunoreactive structures were dendritic shafts. Using immunogold labeling, Ca v 3.1 was commonly found perisynaptic to asymmetric and symmetric axo-dendritic synapses, suggesting a role of Ca v 3.1 in regulating excitatory and inhibitory neurotransmission. Significant labeling was also found at non-synaptic sites along the plasma membrane of thalamic neurons. There was no difference in the overall pattern and intensity of immunostaining between normal and parkinsonian monkeys, suggesting that the increased rebound bursting in the parkinsonian state is not driven by changes in Ca v 3.1 expression. Thus, T-type calcium channels are located to subserve neuronal bursting, but also regulate glutamatergic and non-glutamatergic transmission along the whole somatodendritic domain of basal ganglia-receiving neurons of the primate thalamus.
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.