Basal ganglia: functional anatomy and neuropharmacology …

Movement Disorders

Updated 03.18.2024
Released 04.04.2001
Expires For CME 03.18.2027

Basal ganglia: functional anatomy and neuropharmacology

Authors: Shailee Shah MD MS, Shameer Rafee MRCPI

See Contributor Disclosures

Editor: Robert Fekete MD

Basal ganglia: functional anatomy and neuropharmacology

In This Article

Quick Link

Introduction

Overview

The authors describe the functional anatomy of the basal ganglia, with an emphasis on extensions of the standard “rate” model that have evolved recently. They also describe basal ganglia physiology including changes observed in pathologic states, highlighting Parkinson disease. Finally, potential mechanisms of basal ganglia function and dysfunction are discussed.

Key points

	• The basal ganglia are a set of subcortical gray matter structures associated with motor, cognitive, and limbic functions. The canonical structures are the caudate nucleus, putamen, globus pallidus (interna and externa), substantia nigra (pars compacta and pars reticulata), and subthalamic nucleus.
	• These structures can be divided into afferent areas receiving information (primarily cortical), efferent nuclei sending information to the thalamus, and intrinsic nuclei that act as relays between the two.
	• Basal ganglia disorders (movement disorders) are heterogenous syndromes mechanistically involving the basal ganglia. Parkinson disease and essential tremor are examples of conditions characterized by physiological basal ganglia changes.
	• Advances in animal models and deep brain stimulation continue to improve our understanding of basal ganglia networks.
	• Despite much progress, a comprehensive model of basal ganglia function that explains its normal and pathologic function remains elusive.

Historical note and terminology

David Ferrier, in a book titled The Functions of the Brain, described the corpus striatum and other subcortical structures serving as a connection between cortical structures and the peripheral nervous system (46). The term “basal” refers to the location of this group of structures; however, “basal nuclei” would be more accurate than “basal ganglia.” Despite this, the historical terminology persists. Models for the “direct and indirect pathways” emerged in the 1990s, and our understanding of the basal ganglia pathways has built upon, expanded, and challenged this perspective. This understanding has been challenging because disorders associated with basal ganglia pathology have presented a puzzle for conventional clinicopathologic correlations. Unlike other CNS subsystems, such as the cerebellum and its connections where motor deficits are often similar regardless of the anatomic locus of pathologies, lesions of distinct basal ganglia subregions cause different clinical syndromes. The best example is the contrast between the paucity of spontaneous movement associated with parkinsonism and the excess involuntary movements associated with the chorea-athetosis-ballism spectrum. Some crude correlations based on gross pathology were possible (Table 1), but an integrated understanding of the bases for the diverse phenomena associated with basal ganglia pathology continues to emerge.

Many investigators have contributed to an improved understanding of the basal ganglia; listing everyone involved would be beyond the scope of this review. Some notable examples include Samuel Thomas von Soemmerring (1755-1830), who was the first to describe the substantia nigra. He is probably best known for his doctoral thesis on the 12 cranial nerves (127). Karl Friedrich Burdach (1776- 1847) provided a detailed anatomical description of the brain in his book (Vom Baue und Leben des Gehirns [Of Structure and Life of the Brain]). Importantly, the terminology used by Burdach in his description of the basal ganglia persists (eg, the putamen, lentiform nucleus, and globus pallidus), although not all the structures he named were discovered by him (111). The subthalamic nucleus was not noted by Burdach; it belonged to Jean Bernard Luys, whose name is sometimes lent to this structure (corpus Luysii). Luys studied the neural pathways from the subthalamic nucleus and linked it to automatic motor activity. He was also the first to describe the different functional units of the thalamus (125).

Table 1. Localization of Pathology within the Basal Ganglia

Clinical phenomenon	Localization
Chorea-athetosis-ballism Parkinson disease Dystonia	Striatum or subthalamic nucleus Substantia nigra-nigrostriatal projection Pallidum

Description

	• The basal ganglia consists of a set of closely linked substructures that form recurrent loops with the thalamus and cortex.
	• Dysfunction in these functional networks contributes to the pathophysiology of movement disorders.

Functional anatomy

The basal ganglia form a tightly connected and relatively phylogenetically conserved brain subsystem consisting of deep gray matter structures that form recurrent loops with the cortex and thalamus. These nuclei include the striatum (caudate and putamen forming the dorsal striatum, nucleus accumbens, and olfactory tubercle forming the ventral striatum), globus pallidus (external and internal segments), subthalamic nucleus, and substantia nigra (pars compacta and pars reticulata) (121). In “standard” models, the striatum is the sole input nucleus, though newer models also incorporate the hyperdirect cortical-subthalamic nucleus pathway (120).

Cortical-basal ganglia-thalamic model

(A) The “standard” model. (B) Updated model. (C) Motor thalamic circuits. Green/light gray arrows = excitatory (glutamatergic) projections; red/black circles = inhibitory (GABAergic) projections; blue/dark gray arrows = dopaminerg...

The globus pallidus externa (GPe) is essentially isolated from extra-basal ganglia structures, and the output nuclei comprise the globus pallidus interna (GPi, entopeduncular nucleus in rodents), ventral pallidum, and the substantia nigra pars reticularis (SNr). The substantia nigra pars compacta (SNc) modulates cortical-basal ganglia-thalamic circuits with dopaminergic innervation of the striatum principally but also other basal ganglia nuclei, frontal cortex, and thalamus.

Striatum. The striatum is the largest subcortical brain structure in the mammalian brain. It contains both projection (inhibitory GABAergic medium spiny neurons, 90%) and interneurons (cholinergic, 10%). Due to their volume, most information processing is accomplished by the medium spiny neurons (MSNs). They receive most of the glutamatergic excitatory input from the whole neocortical mantle and related structures, such as the hippocampal formation and the amygdala as well as thalamic intralaminar (CM/Pf) and basal ganglia-recipient relay nuclei (107). Some GABAergic striatal inputs come from the GPe (94). The striatum sends massive GABAergic efferents to GPe and the basal ganglia output nuclei.

The organization of corticostriate projections is complex. Lesion studies and functional imaging demonstrate the topographic organization of corticostriatal projections, suggesting that different striatal regions are functionally specialized depending on their cortical inputs (59). Tract tracing studies also indicate that cortical regions project to the striatum in overlapping parasagittal zones of considerable rostrocaudal extent, suggesting some interdigitation of corticostriatal projections (60). Other work suggests some convergence of corticostriatal projections from cortical regions that are functionally linked by corticocortical connections (60). A study identified six parallel subnetworks making up the cortico-basal ganglia-thalamic system (49). The thalamus acts as a “relay domain,” sending outputs back to the originating corticostriatal neurons of each subnetwork and creating a closed loop. Diffusion tensor imaging demonstrates separate but overlapping corticostriatal connections in sensorimotor (posterior putamen), associative (anterior putamen and caudate), and limbic (ventral striatum) loops (150). Resting-state fMRI functional connectivity studies also correlate with the “parallel loop model” (68). In Parkinson disease, resting-state fMRI studies suggest remapping of these networks possibly secondary to dopamine depletion, with decreased coupling in the cortico-striatal sensorimotor network and between the striatum and brainstem. There may also be increased coupling in the associative network, which could be compensatory (150). Whole-brain white matter structural connectivity studies utilizing diffusion MRI in early-stage and medication-naïve Parkinson disease patients have found increased structural connectivity between Parkinson disease-relevant brain regions, including the striatum, caudate, putamen, and supplementary motor area, and suggest reduced functional network flexibility (114).

Resting-state functional connectivity in early Parkinson disease also shows that greater motor deficits correlate with weaker coupling between the anterior putamen and midbrain, whereas cognitive decline in memory and visuospatial domains correlates with stronger coupling between the dorsal caudate and the rostral anterior cingulate cortex (97).

The striatum is composed of GABAergic medium spiny neurons and several interneuron types in 2 interdigitated compartments known as “patches” (or striosomes) and “matrix.” The striosomal compartment incorporates connections mainly from limbic areas, whereas the matrix is related to sensorimotor and associative regions (30). They represent 90% to 95% of neurons depending on the species, with lower percentages in primates (157; 146). Medium spiny neurons are characterized by the presence of multiple dendritic spines (small mushroom-shaped protuberances) that are the site of most synapses.

The “triadic” MSN synapse

Glutamatergic inputs from the cortex or thalamus synapse directly onto the head of the dendritic spine, dopaminergic projections from the SNr (VTA in ventral striatum) synapse at the neck of the spine, and cholinergic interneur...

They fire sparsely, requiring coordinated excitatory synaptic input to initiate spiking (85). Medium spiny neurons are divided into two groups of roughly equal proportions based on projection patterns (52). The monosynaptic connection from the striatum to GPi/SNr is termed the “direct” pathway, whereas “indirect” pathway medium spiny neurons (iMSNs) synapse in the GPe. Direct pathway medium spiny neurons (dMSNs) also send collaterals to the GPe. dMSNs express D1 dopamine receptors with relatively low affinity for dopamine, whereas iMSNs express higher affinity D2 dopamine receptors (52). Thus, phasic increases or decreases in striatal dopamine concentration are likely to exhibit distinct effects on dMSNs or iMSNs.

The interneurons are characterized by smooth dendrites and can be categorized into groups based on neurochemical profiling . Cholinergic interneurons are the most abundant group of interneurons (87). There are at least three subtypes of striatal GABAergic interneurons. Parvalbumin-positive fast-spiking interneurons selectively and powerfully inhibit medium spiny neurons (157), though their precise role in striatal microcircuitry remains to be determined (55). The physiology of other GABAergic interneurons (nitric-oxide synthase and calretinin-positive) is less well-studied (157).

Cholinergic interneurons probably correspond to tonically active neurons recorded in vivo; these tonically active neurons fire spontaneously at low frequencies (lower than 10 Hz) (144). Striatal cholinergic signaling may be primarily via “volume neurotransmission” because there are relatively few typical cholinergic synapses within the striatum (129). Striatal cholinergic neurons directly influence GABAergic interneuron and medium spiny neuron activity and interact with dopamine to regulate synaptic plasticity (52). Their axons arborize densely and diffusely in the striatal matrix, with sparse crossings into the patch compartment (146). Tonically active neuron firing is correlated in awake, behaving animals and may transmit coordinated signals to large striatal regions. An example is the “TAN pause,” a transient, coordinated decrease in tonically active neuron firing in response to salient behavioral events dependent on afferents from CM/Pf (101). Of relevance to Parkinson disease, the tonically active neuron pause is lost after striatal dopamine depletion (144). Cholinergic interneuron inhibition in the dorsal striatum normalizes the burst firing initiated in the SNr by dopamine depletion (similar to the effects of levodopa or subthalamic nucleus deep brain stimulation) (145). Therefore, reduction of striatal cholinergic tone by muscarinic acetylcholine receptor blockade may be expanded as a therapy for Parkinson disease (176).

The nigrostriatal projection features many terminals diverging from a relatively small number of neurons; each dopaminergic nigral neuron innervates many striatal neurons. The relative lack of specificity of nigrostriatal projections suggests that this pathway performs a diffuse “biasing” function for striatal neurons, though nigral dopamine neuron activity may not be as uniform as previously assumed (100). Dopaminergic terminals tend to synapse on the necks of medium spiny neuron spines, with cortico- and thalamo-striatal terminals on spine heads. These “triadic” synapse complexes allow tight regulation of the contributions of specific cortical and thalamic afferents to medium spiny neuron firing.

Dopamine modulates striatal output on multiple timescales via pre- and postsynaptic mechanisms. Presynaptic D2 receptors on multiple cell types regulate dopamine, acetylcholine, glutamate, and GABA release (52). Postsynaptic D1 receptor stimulation acutely enhances medium spiny neuron excitability, whereas D2 receptor activation has opposite effects (52). The differential expression of D1 and D2 receptors by medium spiny neurons (D1-dMSN; D2-iMSN) results in contrasting effects of acute changes in dopamine levels on the direct and indirect basal ganglia pathways (see below). Striatal interneurons also express multiple dopamine receptor subtypes with complex responses to dopaminergic stimulation. Inhibition of striatal cholinergic interneurons in parkinsonian mice has been shown to regulate the excitability of striatal D1 and D2 medium spiny neurons, increase the functional weight of the direct striatonigral pathway in cortical information processing, and normalize pathological basal ganglia output bursting activity to improve motor control. These effects are not seen in nonlesioned mice, demonstrating the importance of dopamine tone on the regulation of cholinergic interneuron activity in motor control (102). In addition to direct effects on striatal neuronal activity, dopamine influences synaptic plasticity at cortico- and thalamostriatal synapses of dMSNs and iMSNs in distinct ways (52). Furthermore, chronic loss of dopaminergic terminals changes striatal microanatomy. Dendritic spines and glutamatergic synapses onto iMSNs are greatly diminished (34), though dMSN excitability is diminished and iMSN excitability is enhanced to cortical stimulation (93). This may be partially explained by the strengthening of remaining corticostriatal synapses (160). Fast-spiking interneurons, which under normal circumstances have a slight preferential innervation of dMSNs compared to iMSNs, become much more strongly connected to iMSNs after dopamine loss (54).

Subthalamic nucleus (STN). The subthalamic nucleus is located ventral to the zona incerta and rostral to the substantia nigra. It has become increasingly relevant as a target for deep brain stimulation in Parkinson disease. Glutamatergic input to subthalamic nucleus comes from frontal regions, including primary, presupplementary, and supplementary motor cortex (120). Additional excitatory input comes from CM/Pf (140), which may give the subthalamic nucleus access to ascending “salience” signals from the brainstem (113). GABAergic input is primarily from the GPe (14), and sparse dopaminergic afferents come from SNc (137).

The subthalamic nucleus projects to GPe, forming a GPe-STN loop that is strengthened after dopamine depletion (44). The subthalamic nucleus also projects to the basal ganglia output nuclei, where it synapses throughout the dendritic trees of GPi and SNr neurons. STN activity has been shown to correlate with specific basal ganglia activity patterns (172). A disynaptic projection to the cerebellar cortex via the brainstem has been identified (18). Subthalamic nucleus projections diverge to innervate large regions of other basal ganglia nuclei, suggesting that it cannot encode detailed information in population activity but may broadcast information-poor timing signals. Principal subthalamic nucleus neurons are spontaneously active, with tonic in vivo firing rates in the 10 to 30 Hz range in nonhuman primates (12). They express T-type (Cav 3) calcium channels that render them prone to “rebound” bursting, and the likelihood of bursting may be modulated by subthalamic dopamine (137).

Globus pallidus, pars externa (Gpe). GPe receives GABAergic afferents from striatal iMSNs and glutamatergic input from the subthalamic nucleus and CM/Pf (140) and sends feedback GABAergic projections to the striatum and STN (66). The GPe also receives striatal projections with significant expression of adenosine type 2A receptors (87). Distinct populations of GPe neurons project to striatum and downstream nuclei (subthalamic nucleus, GPi, and SNr) (94), where they typically form large perisomatic synapses. This anatomy suggests a central role for the GPe in coordinating basal ganglia-wide activity.

In vivo recordings describe two populations of GPe neurons; one group that consistently fires at high rates with occasional pauses and another group that tends to fire sparsely with intermittent bursts (10). GPe neurons can also be classified based on their synchronization with local field potentials (LFPs) (94), but it is not known whether these two classification schemes are related to each other. In dopamine-depleted rats, the LFP-based classification identifies populations that project uniquely to striatum or subthalamic nucleus/GPi/SNr. Interpretation of rates and patterns of neuronal firing, however, is complicated in light of theoretical models that bring into question our understanding of their meaning (23), including in the context of the rate model (Montgomery 2011).

Dopaminergic projections from SNc have pre- and post-synaptic effects in GPe, though the dopaminergic innervation is much weaker than in the striatum (137). How dopamine influences pallidal activity in vivo is not well understood, though local lesions of GPe dopamine terminals recapitulate some features of parkinsonism (01). As in the striatum and subthalamic nucleus, chronic dopamine loss changes GPe anatomy and physiology. The intrinsic pacemaking ability of pallidal neurons is lost (25), intrapallidal collateral effects are strengthened (112), and subthalamopallidal connections are strengthened (44). Further complicating understanding, including in the context of the rate model, deep brain stimulation of multiple basal ganglia structures improves parkinsonian symptoms (Montgomery 2011).

The output nuclei (GPi and SNr). The GPi and SNr share structural properties with similar afferent and efferent systems. The basal ganglia output nuclei receive afferents primarily from dMSNs, GPe, and subthalamic nucleus, though afferents from CM/Pf also exist (140). Striatal afferents tend to synapse on the distal portions of dendrites, external pallidal afferents on proximal portions of dendrites, and subthalamic afferents throughout the dendritic tree (175). There is dopaminergic input to both nuclei, with a unique dendritic release mechanism in SNr (137). GPi projects primarily to relay nuclei in the thalamus, as well as CM/Pf and the pedunculopontine nucleus (02). The SNr has similar projections but also sends efferents to the superior colliculus and SNc (175). SNr neurons are consequently associated with orienting movements and saccades and regulating nigrostriatal dopaminergic neurons. These processes occur through connectivity with the superior colliculus. A detailed study showed that the SNr contains neuronal populations that target specific brainstem effectors beyond the superior colliculus. The closed-loop networks of the basal ganglia described above are linked with projections to brainstem premotor areas through relays with the thalamus, pedunculpontine formation, and reticular formation. The SNr also has an extensive range of targets in the spinal cord, regions for orofacial and vocal movements. Further, the SNr also shows electrophysiological specificity with neurons targeting different anatomical regions that have unique electrophysiological signatures (106).

Basal ganglia output neurons exhibit spontaneous activity with high firing rates during quiet wakefulness but without the pauses that characterize most GPe neurons (12). These neurons can burst at very high rates, which is enhanced after dopamine depletion (12; 147). Enhanced bursting in the dopamine-depleted state may depend on both altered afferent activity and changes intrinsic to the output nuclei (83).

Substantia nigra, pars compacta. The principal dopaminergic innervation of basal ganglia circuits comes from SNc (118). As described above, the SNc gives rise to a massive nigrostriatal projection with sparser projections to other basal ganglia nuclei, the thalamus, and an important projection to the frontal cortex. Over 70% of SNc input is GABAergic, including afferents from the rostromedial tegmental nucleus (RMTg), striatal patches, and SNr (50; 72). SNc receives glutamatergic afferents from diverse subcortical structures, including the subthalamic nucleus and pedunculopontine nucleus, as well as cholinergic inputs from pedunculopontine nucleus (118). Local somatodendritic dopamine release from SNc neurons influences both SNc and SNr (118). SNc neurons exhibit intrinsic pacemaker activity, firing below 10 Hz in vivo to maintain tonic dopamine levels in the striatum (and other targets). Phasic changes in nigrostriatal signaling are tightly regulated by upstream structures (eg, lateral habenula via RMTg) and are believed to be critical for striatum-based implicit learning processes (72; 08).

Primate tract tracing studies indicate that striatal and SNc limbic, associative, and motor subregions form primarily reciprocal connections (61). More recent imaging studies in humans also suggest a tripartite pattern of connectivity with medial SNc, lateral SNc, and ventral SN related to limbic, motor, and cognitive functional organization, respectively (174). There is, however, also an “ascending spiral” relationship in which SNc neurons project to striatal subregions adjacent to the source of their striatal afferents. This pattern is repeated in ways that, theoretically, allow limbic subregions of the SNc to influence motor and associative regions of the striatum.

Thalamic interactions with the basal ganglia. Basal ganglia afferents form large GABAergic perisomatic synapses in thalamic relay nuclei (15), which are relatively unique in that “driver” inputs to other thalamic nuclei are glutamatergic (138). These relay nuclei form recurrent loops with cortex believed to generate oscillatory brain rhythms (78). Cortex and thalamic relays send collaterals to the reticular nucleus of the thalamus, which in turn project back to thalamic relays.

Two major thalamocortical projection patterns are recognized. “Matrix” neurons tend to project diffusely to cortical layer I, whereas “core” neurons have more focused projections to layers III to IV. Basal ganglia-receiving areas consist primarily of matrix-like cells, whereas cerebellar recipient regions consist of core-like cells (27). Thalamocortical neurons express T-type (Cav 3) calcium channels that allow transitions from tonic to burst-firing modes in response to hyperpolarization (78). Modeling studies suggest that tonic firing allows the transmission of afferent signals to the cortex, whereas bursting modes may inhibit cortico-cortical communication (139). Therefore, the basal ganglia may modulate information flow in other circuits rather than transmitting information from the basal ganglia to the cortex (139).

The parafascicular nucleus receives cortical pathways and projects to the basal ganglia. The parafascicular nucleus can regulate movement initiation through projections to the subthalamic nucleus and is an important aspect in orienting movement. Stimulation of this pathway significantly restored movement in akinetic mice (6-OHDA model). This pathway could explain the therapeutic effect of deep-brain stimulation (166). CM/Pf nuclei receive dense afferents from the brainstem (eg, pedunculopontine nucleus and superior colliculus) and basal ganglia output nuclei (140), as well as cortical afferents. The pedunculopontine nucleus input is part of a major pedunculopontine nucleus-thalamic cholinergic projection. These midline intralaminar thalamic nuclei project primarily to the striatum, with synapses on medium spiny neurons, GABAergic interneurons, and cholinergic interneurons. There are weaker projections to the cortex, subthalamic nucleus, GPi, and SNr. CM/Pf degenerates in Parkinson disease and the MPTP model of parkinsonism (161), potentially contributing to the clinical and physiological features of Parkinson disease.

Pedunculopontine nucleus. Located at the junction of the midbrain and pons, the pedunculopontine nucleus is a phylogenetically ancient structure playing a crucial role in gait and postural control. More recently, it has also been implicated in the modulation of behavioral flexibility (109). The cuneate nucleus and pedunculopontine nucleus form the mesencephalic locomotor region (119), a functionally-electrophysiologically defined part of the mesopontine tegmentum crucial for normal gait and posture. Neurons of the pedunculopontine nucleus help regulate anticipatory postural adjustments preceding initiation of a step, as well as the step itself. Diffusion tensor imaging of Parkinson disease patients with freezing of gait shows reduced connectivity of the pedunculopontine nucleus with the cerebellum, thalamus, and regions of the frontal cortex, all of which are part of the locomotion pathway (47). Deep brain stimulation of this region of the pedunculopontine nucleus has been performed in parkinsonian patients for freezing of gait and to improve axial symptoms, with varying results (158). The pedunculopontine nucleus has connections with several components of the basal ganglia, thalamus, cerebellum, and caudal brainstem structures that regulate spinal central pattern generators. Pedunculopontine nucleus neurons are heterogeneous, mainly cholinergic, GABAergic, and glutamatergic neurotransmitters (165). Cholinergic neurons have historically defined the borders of the pedunculopontine nucleus. The axons of these cholinergic neurons are highly collateralized with connections in the midbrain, forebrain, and lower brainstem (109). The cholinergic neurons are mainly located in the subnucleus compactus of the pedunculopontine nucleus and are severely depleted in both Parkinson disease and progressive supranuclear palsy (65). The GABAergic neurons of the pedunculopontine nucleus are less extensive than the cholinergic system and are more densely populated in the rostral pedunculopontine nucleus, extending into the substantia nigra pars compacta and rostromedial tegmental nucleus (110). The innervation of the SNc is likely heterogeneous, with connections to both dopaminergic and nondopaminergic neurons (33).

Cortex. A comprehensive review of cortical anatomy and physiology is beyond the scope of this article. First, corticostriatal projections originate in all areas of the cortex (99), but corticosubthalamic projections originate in frontal areas (120). Second, the densest projection to the primary motor cortex originates from the GPi, where outputs are likely somatotopically organized (18). Third, cortical efferents can be broadly classified as intratelencephalic and pyramidal tract-like neurons (134).

Intratelencephalic neurons form slow-conducting corticocortical and corticostriatal pathways that project bilaterally (eg, from primary motor cortex) or ipsilaterally (eg, from primary somatosensory cortex) and receive minimal direct input from the basal ganglia-recipient relay thalamus (126). Pyramidal tract neurons send at most weak collaterals to the ipsilateral striatum, receive strong inputs from the basal ganglia-recipient relay thalamus, and may provide corticosubthalamic innervation (99). Thus, the “closed loop” architecture of cortico-basal ganglia-thalamic circuits may not be entirely closed (152).

Clinical applications

	• The rate model does not sufficiently explain clinical observations in movement disorders involving the basal ganglia.
	• Various movement disorders can be associated with patterned changes in oscillations and bursts in the substructures of the basal ganglia.

The rate model and electrophysiological changes in animal models of Parkinson disease

Modern understanding of basal ganglia anatomy and physiology permitted the development of a model of basal ganglia pathophysiology accounting for many clinical phenomena. Neurotoxins that selectively target monoaminergic neurons, primarily 6-OHDA and MPTP, have allowed detailed study of the physiologic consequences of striatal dopamine loss (32). These include changes in neuronal firing rates, burst activity, oscillations, and synchrony (117).

Rate changes. According to the prevailing “rate” model of basal ganglia physiology (121), striatal dopamine increases dMSN firing, decreases iMSN firing, and, ultimately, suppresses basal ganglia output to release thalamocortical circuits from tonic inhibition.

Cortical-basal ganglia-thalamic model

In parkinsonism, dMSN activity may decrease, and iMSN activity may increase, resulting in “excessive” basal ganglia inhibition of thalamocortical activity. A key feature of the rate model is the modulation of subthalamic nucleus neurons, which act as governors of neuronal activity in the basal ganglia output nuclei. In support of this model, lesions (11) or transient inactivation (154) of the “overactive” subthalamic nucleus in MPTP-treated monkeys improves parkinsonism. More persuasively, selective activation of dMSNs or iMSNs as well as bilateral activation of striatonigral neurons using optogenetic techniques dramatically alters locomotor activity in a manner consistent with the rate model (84). The standard rate model also explains the chorea-athetosis-ballism spectrum of involuntary movements and the fact that such involuntary movements occur with both striatal and subthalamic nucleus pathologies. In Huntington disease, there is disproportionate degeneration of iMSNs compared to dMSNs early in the disease course. The downstream consequence is decreased subthalamic nucleus activity and diminished basal ganglia output, disinhibiting thalamocortical activity. Destruction of the subthalamic nucleus produces similar effects, accounting for phenomenological similarity of chorea-athetosis-ballism in Huntington disease and acute subthalamic nucleus lesions.

Despite some predictive value, however, the rate model is not consistent with all observations. For example, lesioning or stimulation of the GPi produces therapeutic benefit in both hyperkinetic and hypokinetic disorders. Lesions in the thalamus and GPe should result in hypokinesis per this model; however, this has not been observed in animal studies (147). Studies have also demonstrated coactivation of both direct and indirect pathways (31; 173). These observations may support a more nuanced version of the rate model in which movement is driven by an action selection model.

Chronic dopamine depletion generally leads to changes in the firing rates of basal ganglia neurons in awake, behaving animals that match rate model predictions. In MPTP-treated monkeys, firing rates increase in subthalamic nucleus and GPi/SNr, but decrease in GPe, thalamus, and motor cortex (12; 147; 126). The cortical firing rate decrease may be specific to pyramidal tract neurons (126). In anesthetized rats, dMSNs and iMSNs decrease and increase their firing rates, respectively, after 6-OHDA lesions (93; 82). Furthermore, firing rate changes after chronic levodopa (124), dopamine agonist (17), or combined (67) treatment in MPTP-treated monkeys are consistent with the standard model. Other studies, however, are inconsistent with the rate model. Some show no or inconsistent changes in firing rates after MPTP despite clinical parkinsonism (133; 128; 89; 154). Also, subthalamic nucleus deep brain stimulation at therapeutic frequencies increases GPi firing rates in parkinsonian monkeys despite clinical improvement (62). Thus, the firing rates of basal ganglia output neurons cannot be the sole determinant of motor behavior.

Burst firing. Bursts are brief episodes of high-frequency firing against slower background activity. For many neurons, bursting is a distinct firing mode supported by specific ion channels, not simply a transient firing rate increase. Identifying firing mode transitions requires intracellular recordings, which are technically difficult in behaving animals (92). The cellular mechanisms underlying extracellularly recorded “bursts” in Parkinson disease models cannot, therefore, be established definitively and likely differ across regions.

Burst firing in GPe, subthalamic nucleus, and GPi. Several studies in the primate MPTP and rodent 6-OHDA models describe enhanced bursting in GPe, subthalamic nucleus, and GPi/SNr (12; 147; 170; 89; 96; 154). Bursting is reduced by intravenous levodopa or chronic dopamine agonist/levodopa combination therapy (67; 154), suggesting a relationship between burst-firing and clinical parkinsonism. In humans treated with apomorphine, however, subthalamic nucleus and GPi bursting increases compared to the “off” state, sometimes associated with dyskinesias (91). Therapeutic, but not subtherapeutic, GPe and subthalamic nucleus deep brain stimulation reduces GPi bursting (62; 162). Conversely, low-frequency subthalamic nucleus deep brain stimulation, which may exacerbate parkinsonism, increases GPi bursting (42). In humans, effective GPi deep brain stimulation reduced GPi burst-firing (28), though conflicting results were obtained in MPTP-treated monkeys (104). Overall, it seems that burst-firing along the indirect pathway increases after dopamine depletion and decreases with effective therapy. Emerging theories of the meaning of neuronal firing rate further complicate this understanding (23).

Thalamic bursts. There are limited data comparing thalamic activity between dopamine-depleted and intact subjects. In one study comparing thalamic activity before and after MPTP, a nonsignificant increase was found in the proportion of burst-firing neurons in the basal ganglia-recipient thalamus. Bursting was significantly increased, however, in the cerebellar-recipient thalamus (128). Others have found that clinically effective subthalamic nucleus or GPe deep brain stimulation is associated with decreased basal ganglia-recipient thalamic bursting compared to the “off” state (42; 171; 162). Results in the cerebellar recipient thalamus are less consistent (42; 171). Human studies indicate that thalamic bursting is common in Parkinson disease (115), but the studies lack healthy controls. Because these are all extracellular recordings, it is uncertain whether the bursts reflect true low-threshold spike bursts mediated by T-type Ca2+ channels or brief periods of rapid tonic firing (92). Excessive thalamic relay burst-firing is probably characteristic of Parkinson disease, though the evidence is less robust than changes in bursting behavior in the indirect pathway.

Cortical bursts. Dopamine depletion increases burst-firing in primary motor cortex as well as the percentage of time spent in bursts. As with firing rates, bursting increases among pyramidal tract neurons, but not intratelencephalic neurons (126). Because thalamic basal ganglia-recipient relay nuclei project preferentially to pyramidal tract neurons, these data suggest that cortical bursting is driven by the thalamus. On the other hand, the long duration of cortical bursts (greater than 1 second) is quite different from the brief bursts observed in the basal ganglia and thalamus.

Neuronal oscillations. “Oscillatory activity” is a nonspecific term indicating that some measure of neuronal function repeats itself periodically. This may be reflected in single-unit spiking or local field potentials.

Coordinated bursts of LFP beta oscillations cortico-basal ganglia network

Coordinated bursts of LFP beta oscillations occur throughout the rat cortico-basal ganglia network. (A) Recording sites throughout the full basal ganglia network. (B) Simultaneous LFP recordings from the sites in (A). ECoG = front...

Local field potentials are generally easier to measure than single-unit activity, are believed to represent the summation of local transmembrane currents and synaptic activity, and may reflect afferent activity.

In vivo recordings in nonhuman primates demonstrated exaggerated single-unit oscillations at tremor frequencies and harmonics, though the relationship between neuronal and mechanical oscillations is complex. Bimodal distributions (approximately 5 and 10 Hz peaks) of single unit oscillation frequencies are found in the GPi and subthalamic nucleus of tremulous MPTP-treated monkeys (12; 133; 135). Tonically active neuron firing also becomes oscillatory after MPTP lesions (132). Interestingly, higher frequency oscillations at 10 to 15 Hz may correlate best with the typical 5 Hz rest tremor of Parkinson disease (135; 154). Inactivation of the subthalamic nucleus in tremulous monkeys eliminates tremor and 8 to 20 Hz, but not 4 to 8 Hz, pallidal oscillations (169).

Neuronal oscillations are correlated also with bradykinesia and rigidity (70). MPTP-treated monkeys lacking the typical rest tremor of Parkinson disease exhibit low-frequency oscillations in single unit activity similar to those with tremor (108; 67). Chronic levodopa, combined levodopa/dopamine agonist treatment, and therapeutic deep brain stimulation increase spontaneous movement and suppress these low-frequency oscillations (108; 67; 171; 53). Higher frequency “beta” (approximately 15 to 30 Hz) oscillations are correlated with rigidity and bradykinesia in humans and rodent models of Parkinson disease (86; 76; 45). Single unit and local field potential beta oscillations were recorded from the subthalamic nucleus and GPi of humans with Parkinson disease, and beta power reductions were correlated with clinical improvement (22; 168; 86). Enhanced beta frequency oscillations are observed in the cortex, striatum, globus pallidus, subthalamic nucleus, and SNr of dopamine-depleted rodents (95; 20). However, acute dopamine depletion using reserpine in rodent models showed enhanced beta oscillations without involvement of the primary motor cortex (07). The enhanced beta oscillations are suggested to reflect a basal ganglia network-wide abnormality that causes some features of parkinsonism (90). Beta oscillations are directly associated with acute and chronic regulations of dopaminergic tone. However, power and coherence between single units and LFPs did not show a similar relationship. This suggests that beta frequencies specifically are an accurate marker of changes in dopaminergic tone (74). One study compared the proportion of beta oscillatory neurons in the subthalamic nucleus, GPi, and ventrolateral thalamus of patients with Parkinson disease. A significantly higher proportion of beta oscillatory neuronal activity was noted in both subthalamic nucleus and GPi, suggesting abnormal synchronization of these neurons in the pathologic state (43). Subthalamic nucleus LFPs have been used as a physiological marker to distinguish between tremor-dominant and postural-instability-gait-difficulty subtypes of Parkinson disease (156). It has been noted that enhanced neuronal oscillations emerge after motor deficits in the dopamine-deficient state (89; 96; 36), arguing against a causal role for “pathologic” oscillations in the genesis of bradykinesia and rigidity. In humans, abnormal oscillatory activity in basal ganglia thalamocortical loops has been studied using depth recordings during deep brain stimulation, and advances toward closed-loop devices allow for local field potential recordings directly through implanted leads (131). More recent recordings incorporating signals from the surface of the cortex using electrocorticography have provided improved capacity to better understand the phase-amplitude coupling of cortical-subcortical structures and abnormal synchrony of activity in Parkinson disease (130).

Levodopa-induced dyskinesias are also associated with characteristic neuronal oscillations. The subthalamic nucleus and GPi/SNr of dyskinetic humans and rats show elevated local field potential power at low frequencies (5 to 10 Hz) contralateral to the dyskinetic hemibody (48; 04; 167). As rats became dyskinetic, a striatal shift from beta to high gamma (approximately 70 to 100 Hz) oscillations was observed (63). A similar beta-to-high gamma shift is observed in the subthalamic nucleus and GPi of levodopa-treated humans, though no mention was made of whether the patients experienced dyskinesias (22). High gamma oscillations are also observed in nondyskinetic healthy rats treated with apomorphine or amphetamine (13).

Synchronization. “Synchrony” describes 2 or more events that occur nearly simultaneously and may refer to single unit spikes, local field potential (LFP) phase across recording sites, or consistent relationships between single unit spikes and LFP phase. The LFP itself represents coordinated transmembrane potential fluctuations and is, thus, a measure of local synchrony. The Parkinson disease literature often refers to “burst synchrony” or “oscillatory synchrony” as if these concepts are inseparable. However, not all bursts occur in an oscillatory pattern, tonically (non-burst) firing neurons may fire synchronously, and not all synchronized activity is periodic (26). For example, GPe neurons exhibit more nonoscillatory synchrony than GPi neurons after MPTP (67).

Under normal physiologic conditions in awake animals, basal ganglia and motor cortical neurons rarely fire synchronously (06). After dopamine depletion, however, single unit oscillations in the GPi, GPe, and subthalamic nucleus become highly synchronized with each other (108; 67; 95; 96; 135; 43). Tonically active neuron and GPi oscillations are also synchronized in dopamine-depleted primates (132). Deep brain stimulation and chronic combined levodopa/dopamine agonist treatment tend to reduce interneuronal synchrony (108; 67). Despite the strong evidence for a role of single-unit synchrony in the pathophysiology of Parkinson disease, however, at least one study found that synchrony develops after motor deficits (89). On the other hand, in the basal ganglia-recipient thalamus, synchrony increased before clinical parkinsonism became evident (128).

Related to synchrony is the loss of specificity of basal ganglia neurons for passive and active movement (21). The proportion of neurons with firing rate changes during movement is larger in MPTP-treated monkeys compared to controls (88), and an increased proportion of basal ganglia and thalamic neurons encode for movement about multiple joints (16; 128). Collectively, these data suggest that information transfer into and out of the basal ganglia may be compromised in the dopamine-depleted basal ganglia.

LFP oscillations throughout cortico-basal ganglia-thalamic circuits also synchronize after dopamine depletion (40). The exaggerated beta oscillations of the dopamine-deficient state are highly coherent across the cortex and basal ganglia (96; 20). Single-unit activity is also strongly entrained in “pathologic” LFPs (57; 168; 96; 20).

Relating physiology to clinical symptoms

Anatomical changes have already been shown to have utility in tracking Parkinson disease progression and specific Parkinson disease subtypes. Patients with freezing of gait-predominant Parkinson disease showed greater cortical and subcortical atrophy compared with non-freezing of gait Parkinson disease whereas non-freezing of patients with gait Parkinson disease had greater basal ganglia and sensorimotor atrophy (141). How physiological changes in cortico-basal ganglia-thalamic circuits described above translate into the motor features of movement disorders remains a central question. Much of this literature is dominated by discussions of Parkinson disease pathophysiology due to the greater availability of deep brain recordings in Parkinson disease patients. We discuss the relationship of the available data to the pathophysiology of Parkinson disease and key areas for future investigation.

Dysfunction of basal ganglia connectivity in prodromal and early Parkinson disease. Resting-state fMRI shows aberrant connectivity within the basal ganglia network (bilateral caudate, putamen, and globus pallidus) and frontal lobes in patients with early Parkinson disease (153). The dysfunction in connectivity has similarities with that seen in patients with REM behavioral disorder (RBD), a prodromal symptom of Parkinson disease that tends to occur 10 to 15 years prior to the onset of motor symptoms (136). Reduced dopaminergic transmission in REM behavioral disorder compared to more significant dopaminergic deficiency in early Parkinson disease may account for differences in connectivity between the 2 groups (136). Patients with prodromal Parkinson disease in the form of REM behavior disorder or hyposmia have also been shown to have reduced striato-thalamo-pallidal intra- and interhemispheric connectivity without alteration between other cortical and subcortical structures at this stage of the disease (35). Diffusion MRI studies in the early stage have also suggested decreased flexibility between functional networks implicated in Parkinson disease (114).

The relationship of dopamine depletion to Parkinson disease. The 6-OHDA and MPTP models are quite good at modeling the physiologic and behavioral effects of dopamine loss. Nonetheless, there are caveats. First, the toxins act quickly, creating rapid dopamine loss that is clearly different from the slow progression of Parkinson disease. Second, MPTP and 6-OHDA selectively kill monoaminergic neurons but do not recapitulate the progressive degeneration of all neuronal types (eg, cholinergic) affected by Parkinson disease (19). Third, they do not recapitulate the currently presumed causative pathologic lesion thought to underlie the development of Parkinson disease, that being abnormal synuclein present diffusely throughout the nervous system (37). Lastly, Parkinson disease involves pathophysiology of multiple neurotransmitter systems beyond dopamine (79).

The origins of “pathologic” physiology. Because of the looped nature of cortical-basal ganglia-thalamic circuits, it is difficult to distinguish cause from effect among the many changes observed in the dopamine-depleted state. Starting with the striatum, it is possible to suggest a sequence of events that could lead to electrophysiological and clinical parkinsonism.

Consistent with the “rate” model, iMSN firing rates in anesthetized rats increase after dopamine depletion (93). Because striatopallidal synapses exhibit short-term facilitation, rapid iMSN firing may drive pause-and-burst activity in GPe (80). This is an attractive hypothesis, as it explains how selectively driving iMSNs can cause akinesia and excessive basal ganglia bursting (84). In essence, information may be translated from a rate code in the striatum to a pattern code in GPe. Microanatomic changes in the striatum and GPe also likely contribute to the excessive synchrony and loss of somatotopy observed in the parkinsonian state (54; 112).

The GPe-STN network has been proposed to generate pathologic rhythms (14).

Cortical-basal ganglia-thalamic model

Bursting GPe neurons may hyperpolarize subthalamic nucleus neurons, which fire rebound bursts that stimulate GPe neurons in recurrent cycles. The dopamine-denervated subthalamic nucleus may also be intrinsically more “bursty” (14). In support of the importance of a GPe-STN oscillator in the generation of pathologic rhythms, local pharmacologic manipulations and lesions of the GPe and subthalamic nucleus decrease oscillations and bursting at the basal ganglia output (169; 154). Modeling studies indicate that the GPe-STN oscillator may be capable of generating beta rhythms (71), though it may not be able to do so in isolation (148). Aberrant cortical activity could also drive pathologic subthalamic nucleus activity via the hyperdirect pathway, as suggested by reduced oscillatory activity after local blockade of glutamate receptors in the subthalamic nucleus (154). Recordings from patients with Parkinson disease provide more information on this network-high frequency (21 to 30 Hz) coherence between the supplementary motor area and subthalamic nucleus correlated with the hyperdirect pathway. Cortico-subthalamic nucleus coherence and cortico-subthalamic nucleus tract density correlated spectrally to upper beta frequencies, implying a strong functional relationship within the hyperdirect pathway from the cortex to subthalamic nucleus. Importantly, this pathway did not relay via the striatum. Deep-brain stimulation may be effective, at least in part, by suppressing this hyperdirect pathway (123). The GPe-STN circuit is well-positioned to transmit pathological patterns to the basal ganglia output nuclei.

The rate model predicts that excessive basal ganglia output should suppress thalamic firing, which does not seem to be the case (128). Instead, pallidal output may influence the fine timing of thalamic spikes driven by cortical inputs (58) and gate cortico-cortical communication by regulating transitions between burst (“closed” gate) and tonic (“open” gate) firing modes (139). Whether excessive/bursty GPi activity forces bursting in thalamocortical neurons in unknown.

Given the role of thalamocortical circuits in generating oscillatory synchrony in sensory pathways (78), it is likely that these circuits play a role in the generation of pathologic rhythms in Parkinson disease. This may occur at a network level in the reciprocal loops between the cortex and thalamus or within local cortical circuits (24).

Thalamocortical bursts evoke long-lasting, spatially distributed activity (09), suggesting that synchronized thalamocortical bursts could drive an intracortical beta resonance.

Plastic changes in cortical-basal ganglia-thalamic circuits clearly play a role in the circuit-level physiology of Parkinson disease (34; 54; 160; 08; 44; 112). Beta oscillations and synchrony emerge with chronic, but not acute, decreases in dopamine signaling (89; 96; 36). Further, motor deficits develop progressively after dopamine loss/receptor blockade (08), presumably due to altered regulation of cortico- and thalamo-striatal synaptic plasticity and the microanatomic changes described above.

Research has focused on basal ganglia-thalamocortical loops, but the basal ganglia also influence motor output via direct connections to brainstem nuclei, including the pedunculopontine nucleus and superior colliculus (02; 175). The pedunculopontine nucleus gives the basal ganglia access to important brainstem motor centers and creates yet another cortical-basal ganglia-thalamic loop. Deep brain stimulation of the pedunculopontine nucleus can increase thalamic perfusion, even when performed unilaterally (151). The pedunculopontine nucleus has been difficult to study in animal models, however, because it comprises multiple cell types and lacks clear borders (02).

The relationship between “pathologic” physiology and clinical parkinsonism. Determining how network-level changes relate to clinical parkinsonism remains an elusive goal. No doubt, many physiologic changes have direct causal links with distinct motor abnormalities, but it is equally likely that some do not.

Parkinsonian tremor is an excellent illustration of this problem (69). Parkinson disease patients with tremor demonstrate increased functional connectivity between the GPi, putamen, and cerebello-thalamic circuit, indicative of increased oscillatory activity in these networks (70). Deep brain stimulation of the cerebello-thalamo-cortical network reduces tremor in Parkinson disease (29). The cerebellar recipient thalamus is a likely tremor generator,but is not directly connected to the basal ganglia.

Cortical-basal ganglia-thalamic model

It is not obvious how striatal dopamine loss is translated into tremor or why DRT, anticholinergics, and STN/GPi deep brain stimulation effectively suppress tremors. Indeed, striatal dopamine deficiency does not correlate with the presence or severity of tremor (142). Subthalamo-cerebellar connections link the basal ganglia and cerebellum but do not readily explain the efficacy of GPi deep brain stimulation. Alternatively, the basal ganglia-recipient thalamus may influence the cerebellar recipient thalamus through recurrent thalamocortical connections (69).

Beta oscillations are consistently correlated with bradykinesia and rigidity (but not tremor). Transient cortical and basal ganglia beta oscillations also occur in healthy subjects and appear to represent a subset of oscillatory basal ganglia states characterized by transitions between combinations of theta (approximately 8 Hz), beta, low gamma (approximately 50 Hz), and high gamma (approximately 80 Hz) oscillations (13; 159). These beta “bursts” are associated with resistance to altering current motor plans (76; 90).

Coordinated bursts of LFP beta oscillations cortico-basal ganglia network

Local field potentials are generally easier to measure than single-unit activity and may reflect afferent activity. Pathologically persistent beta activity may, therefore, prevent initiation of new actions (13; 105; 90). From a mechanistic standpoint, behavioral inertia could be related to excessive entrainment of single neurons throughout the motor system to stable beta frequency states (96; 13; 20; 90). In patients with Parkinson disease, exaggerated coupling between the phase of beta oscillations in the basal ganglia and the amplitude of broadband activity in the primary motor cortex results in excessive beta phase locking of cortical motor neurons, manifesting clinically as bradykinesia and rigidity (38). This hypothesis implies that beta oscillations cause bradykinesia and rigidity by enhancing neuronal synchrony, which reduces the information that can be transmitted by neuronal ensembles (05). In Parkinson disease, this may be reflected in imprecise movements or rigidity as small groups of muscles cannot be activated independently. Deep brain stimulation of the subthalamic nucleus in parkinsonian patients reduces phase-amplitude interactions with a subsequent reduction in bradykinesia and rigidity (39). A similar effect has been demonstrated with pallidal deep brain stimulation as well (164).

The physiology of other movement disorders has also been studied, though not in as much detail. For example, dystonia shares many physiologic features with Parkinson disease. In recordings from human subjects, both disorders exhibit enhanced neuronal oscillations, synchrony, and burst-firing in the subthalamic nucleus (143) and GPi (149; 155; 21). Thus, none of these changes in and of themselves can drive parkinsonism. In dystonia, however, firing rates are lower (149; 155) as are peak oscillation frequencies (149; 167). After several studies demonstrating clinically significant improvement, deep brain stimulation of the GPi for chronic, medically intractable dystonia was approved by the FDA in 2003 (41). The presumed mechanism is “normalization” of neuronal patterns, which prevents pathologic bursting and oscillatory activity within the network. This results in improved sensorimotor information processing and reduction of disease symptoms (73). Reduction of cortical synchronization by subthalamic deep brain stimulation has been seen in studies of isolated dystonia and Parkinson disease as well (130).

Levodopa-induced dyskinesias share electrophysiological features with dystonia. In both cases, low frequency (approximately 4 to 10 Hz) LFP and single-unit oscillations are prominent at the basal ganglia output, and firing rates are relatively low (124; 48; 04; 67; 03). Burst-firing may also be increased during dyskinesias, though results are inconsistent (17; 91). It has also been shown that levodopa-induced dyskinesia murine models (6-OHDA) showed that the dyskinetic state is largely mediated through the direct basal ganglia pathway and via suppression of the indirect pathway (163). Teasing out the physiology of dyskinesias is difficult, however, as only a handful of studies have compared the “on” and “on with dyskinesias” states (04; 67).

A final major problem for understanding basal ganglia physiology and the pathophysiology of movement disorders is linking what we know of basal ganglia physiology, the nature of movement disorders, and normal functions of the basal ganglia. Considerable animal experimental data and human clinical studies indicate that a major function of the basal ganglia is the acquisition of habitual action patterns via reward-based learning mechanisms mediated at least in part by striatal dopamine. Phasic dopamine signaling may act as a “reward prediction error” signal, indicating the difference between expected (predicted) and actual behavioral outcomes (56). Some interesting experimental work suggests that bradykinesia following striatal dopamine loss is the consequence of the misperception of the value of motor acts (103; 173).

The constellation of motor abnormalities and neuropsychiatric dysfunction seen in Tourette syndrome highlights the interaction of the basal ganglia and associative loops. Motor and vocal tics may manifest due to deficient GABAergic synaptic inhibition in corticobasal ganglia connections involving the sensorimotor, premotor, possibly supplementary motor, and striatopallidothalamic networks (51). Common comorbid neuropsychiatric diseases such as attention deficit disorder or obsessive-compulsive disorder may be related to deficient GABAergic synaptic inhibition in the cortex and striatum. The influence of emotion on tics is apparent and highlights the role of the limbic system and amygdala on the corticobasal ganglia network (122). Deep brain stimulation of various targets in the motor and limbic pathways (most commonly the centromedian thalamic nucleus, GPi, and nucleus accumbens) for Tourette syndrome is increasingly successful and may regulate abnormal neuronal activity in these networks (75; 77; 98). The promising results of deep brain stimulation targeting the bilateral STN or nucleus accumbens for obsessive-compulsive disorder demonstrate the overlap between motor and limbic pathways in the corticostriatothalamocortical network (64; 81).

Concluding remarks

Driven by the advent of deep-brain stimulation, functional and structural neuroimaging, and the availability of animal models of dopamine deficits, new data have been collected regarding the physiology of the basal ganglia. Although these findings have spawned numerous theories regarding the pathophysiology of Parkinson disease and other movement disorders, the only consensus is that the “standard” model is incomplete. Now that the clinical and electrophysiological phenomenology of Parkinson disease are well-described, the next steps will be to test hypotheses linking neuropathology with physiological changes and physiological changes with clinical symptoms and therapeutic response. This will require a range of models, taking advantage of cell-type specific manipulations available in rodents (eg, optogenetics) and the close homology between humans and non-human primates. Many important questions remain whose answers may not only directly impact patient care but also elucidate the normal functions of the basal ganglia. It remains to be seen which lines of inquiry will provide the critical insights that allow the rational manipulation of neural circuits to achieve the ultimate goal of transforming “pathological” neural activity into patterns compatible with normal motor, cognitive, and emotional function.

Table 2. Selected Areas for Future Research

Systems physiology
	• The relationship between neuropathology (eg, dopamine loss) and changes in network physiology • The role of microanatomic changes after dopamine loss in generating changes in network physiology • The relationship between changes in firing rates, bursting, oscillations, and synchrony • The relationship between bradykinesia, tremor, and rigidity and changes in network activity • The roles of the “patch” and “matrix” components of striatum • The role of the “motor” thalamus • Relationship between metabolism and blood flow with basal ganglia function • Evaluating the roles of neuronal or systems oscillation and synchrony in relation to basal ganglia function and parkinsonism
Tremor
	• The variable response of tremor to dopamine replacement • Specific mechanism underlying tremor • Mechanisms of tremor responsiveness to anticholinergics • The efficacy of STN/GPi/VIM deep brain stimulation for non-dopa-responsive tremor
Deep brain stimulation
	• The clinical similarity between deep brain stimulation and focal lesions • The differential effects of subthalamic nucleus deep brain stimulation and GPi deep brain stimulation provoking and improving dyskinesias, respectively • The correlation between dopa-responsive symptoms and deep brain stimulation-responsive symptoms (except for tremor) • Computational models of the effects of deep brain stimulation on the basal ganglia network • Deep brain stimulation of both GPi and STN in refractory dystonia
	• The role of closed-loop or adaptive deep brain stimulation in understanding the basal ganglia electrophysiology of pathologic states
Dyskinesias
	• The physiology of being “on” versus “on with dyskinesias” • The physiological differences between “diphasic” and “peak-dose” dyskinesias

Media

References

01: Abedi PM, Delaville C, De Deurwaerdère P, Benjelloun W, Benazzouz A. Intrapallidal administration of 6-hydroxydopamine mimics in large part the electrophysiological and behavioral consequences of major dopamine depletion in the rat. Neuroscience 2013;236:289-97. PMID 23376117
02: Alam M, Schwabe K, Krauss JK. The pedunculopontine nucleus area: critical evaluation of interspecies differences relevant for its use as a target for deep brain stimulation. Brain 2011;134(Pt 1):11-23. PMID 21147837
03: Alegre M, López-Azcárate J, Alonso-Frech F, et al. Subthalamic activity during diphasic dyskinesias in Parkinson’s disease. Mov Disord 2012;27(9):1178-81. PMID 22744752
04: Alonso-Frech F, Zamarbide I, Alegre M, et al. Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson's disease. Brain 2006;129(Pt 7):1748-57. PMID 16684788
05: Averbeck BB, Latham PE, Pouget A. Neural correlations, population coding and computation. Nat Rev Neurosci 2006;7(5):358-66. PMID 16760916
06: Bar-Gad I, Heimer G, Ritov Y, Bergman H. Functional correlations between neighboring neurons in the primate globus pallidus are weak or nonexistent. J Neurosci 2003;23(10):4012-6. PMID 12764086
07: Beck MH, Haumesser JK, Kuhn J, Altschuler J, Kuhn AA, van Riesen C. Short- and long-term dopamine depletion causes enhanced beta oscillations in the cortico-basal ganglia loop of parkinsonian rats. Exp Neurol 2016;286:124-36. PMID 27743915
08: Beeler JA, Frank MJ, McDaid J, et al. A role for dopamine-mediated learning in the pathophysiology and treatment of Parkinson's disease. Cell Rep 2012;2(6):1747-61. PMID 23246005
09: Beierlein M, Fall CP, Rinzel J, Yuste R. Thalamocortical bursts trigger recurrent activity in neocortical networks: layer 4 as a frequency-dependent gate. J Neurosci 2002;22(22):9885-94. PMID 12427845
10: Benhamou L, Bronfeld M, Bar-Gad I, Cohen D. Globus pallidus external segment neuron classification in freely moving rats: a comparison to primates. PLoS One 2012;7(9):e45421. PMID 23028997
11: Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249(4975):1436-8. PMID 2402638
12: Bergman H, Wichmann T, Karmon B, DeLong MR. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 1994;72(2):507-20. PMID 7983515
13: Berke JD. Fast oscillations in cortical-striatal networks switch frequency following rewarding events and stimulant drugs. Eur J Neurosci 2009;30(5):848-59. PMID 19659455
14: Bevan MD, Atherton JF, Baufreton J. Cellular principles underlying normal and pathological activity in the subthalamic nucleus. Curr Opin Neurobiol 2006;16(6):621-8. PMID 17084618
15: Bodor AL, Giber K, Rovó Z, Ulbert I, Acsády L. Structural correlates of efficient GABAergic transmission in the basal ganglia-thalamus pathway. J Neurosci 2008;28(12):3090-102. PMID 18354012
16: Boraud T, Bezard E, Bioulac B, Gross CE. Ratio of inhibited-to-activated pallidal neurons decreases dramatically during passive limb movement in the MPTP-treated monkey. J Neurophysiol 2000;83(3):1760-3. PMID 10712496
17: Boraud T, Bezard E, Bioulac B, Gross CE. Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey. Brain 2001;124(Pt 3):546-57. PMID 11222455
18: Bostan AC, Dum RP, Strick PL. Functional anatomy of basal ganglia circuits with the cerebral cortex and the cerebellum. Prog Neurol Surg 2018;33:50-61. PMID 29332073
19: Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24(2):197-211. PMID 12498954
20: Brazhnik E, Cruz AV, Avila I, et al. State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats. J Neurosci 2012;32(23):7869-80. PMID 22674263
21: Bronfeld M, Bar-Gad I. Loss of specificity in basal ganglia related movement disorders. Front Syst Neurosci 2011;5:38. PMID 21687797
22: Brown P, Oliviero A, Mazzone P, Insola A, Tonali P, Di Lazzaro V. Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease. J Neurosci 2001;21(3):1033-8. PMID 11157088
23: Buzsaki G, Peyrache A, Kubie J. Emergence of cognition from action. Cold Spring Harb Symp Quant Biol 2014;79:41-50. PMID 25752314
24: Castro-Alamancos MA. The motor cortex: a network tuned to 7-14 Hz. Front Neural Circuits 2013;7:21. PMID 23439785
25: Chan CS, Glajch KE, Gertler TS, et al. HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease. Nat Neurosci 2011a;14(1):85-92. PMID 21076425
26: Chan V, Starr PA, Turner RS. Bursts and oscillations as independent properties of neural activity in the parkinsonian globus pallidus internus. Neurobiol Dis 2011b;41(1):2-10. PMID 20727974
27: Clasca F, Rubio-Garrido P, Jabaudon D. Unveiling the diversity of thalamocortical neuron subtypes. Eur J Neurosci 2012;35(10):1524-32. PMID 22606998
28: Cleary DR, Raslan AM, Rubin JE, et al. Deep brain stimulation entrains local neuronal firing in human globus pallidus internus. J Neurophysiol 2013;109(4):978-87. PMID 23197451
29: Coenen VA, Allert N, Paus S, Kronenburger M, Urbach H, Madler B. Modulation of the cerebello-thalamo-cortical network in thalamic deep brain stimulation for tremor: a diffusion tensor imaging study. Neurosurgery 2014;75(6):657-69;discussion 669-70. PMID 25161000
30: Crittenden JR, Graybiel AM. Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments. Front Neuroanat 2011;5:59. PMID 21941467
31: Cui G, Jun SB, Jin X, et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 2013;494(7436):238-42. PMID 23354054
32: Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron 2003;39(6):889-909. PMID 12971891
33: Dautan D, Hacioğlu Bay H, Bolam JP, Gerdjikov TV, Mena-Segovia J. Extrinsic sources of cholinergic innervation of the striatal complex: a whole-brain mapping analysis. Front Neuroanat 2016;10:1. PMID 26834571
34: Day M, Wang Z, Ding J, et al. Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 2006;9(2):251-9. PMID 16415865
35: Dayan E, Browner N. Alterations in striato-thalamo-pallidal intrinsic functional connectivity as a prodrome of Parkinson’s disease. Neuroimage Clin 2017;16:313-8. PMID 28856094
36: Degos B, Deniau JM, Chavez M, Maurice N. Chronic but not acute dopaminergic transmission interruption promotes a progressive increase in cortical beta frequency synchronization: relationships to vigilance state and akinesia. Cereb Cortex 2009;19(7):1616-30. PMID 18996909
37: Dehay B, Bourdenx M, Gorry P, et al. Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. Lancet Neurol 2015;14(8):855-66. PMID 26050140
38: de Hemptinne C, Ryapolova-Webb ES, Air EL, et al. Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease. Proc Natl Acad Sci USA 2013;110(12):4780-5. PMID 23471992
39: de Hemptinne C, Swann NC, Ostrem JL, et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease. Nat Neurosci 2015;18(5):779-86.** PMID 25867121
40: Dejean C, Nadjar A, Le Moine C, Bioulac B, Gross CE, Boraud T. Evolution of the dynamic properties of the cortex-basal ganglia network after dopaminergic depletion in rats. Neurobiol Dis 2012;46(2):402-13. PMID 22353564
41: Diamond A, Shahed J, Azher S, Dat-Vuong K, Jankovic J. Globus pallidus deep brain stimulation in dystonia. Mov Disord 2006;21(5):692-5. PMID 16342255
42: Dorval AD, Russo GS, Hashimoto T, Xu W, Grill WM, Vitek JL. Deep brain stimulation reduces neuronal entropy in the MPTP-primate model of Parkinson's disease. J Neurophysiol 2008;100(5):2807-18. PMID 18784271
43: Du G, Zhuang P, Zhang Y, Li J, Li Y. Neuronal firing rate and oscillatory patterns in the basal ganglia nuclei differ from those of the ventrolateral thalamus in patients with Parkinson disease. Neurosci Lett 2018;683:1-6. PMID 29913198
44: Fan KY, Baufreton J, Surmeier DJ, Chan CS, Bevan MD. Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons. J Neurosci 2012;32(40):13718-28. PMID 23035084
45: Feng H, Zhuang P, Hallett M, Zhang Y, Li J, Li Y. Characteristics of subthalamic oscillatory activity in parkinsonian akinetic-rigid type and mixed type. Int J Neurosci 2016;126(9):819-28. PMID 26268485
46: Ferrier D. The Functions of the Brain. London: Smith, Elder, & Co, 1876.
47: Fling BW, Cohen RG, Mancini M, Nutt JG, Fair DA, Horak FB. Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait. Brain 2013;136(Pt 8):2405-18. PMID 23824487
48: Foffani G, Ardolino G, Meda B, et al. Altered subthalamo-pallidal synchronisation in parkinsonian dyskinesias. J Neurol Neurosurg Psychiatry 2005;76(3):426-8. PMID 15716541
49: Foster NN, Barry J, Korobkova L, et al. The mouse cortico-basal ganglia-thalamic network. Nature 2021;598(7879):188-94. PMID 34616074
50: Fujiyama F, Sohn J, Nakano T, et al. Exclusive and common targets of neostriatofugal projections of rat striosome neurons: a single neuron-tracing study using a viral vector. Eur J Neurosci 2011;33(4):668-77. PMID 21314848
51: Ganos C, Roessner V, Munchau A. The functional anatomy of Gilles de la Tourette syndrome. Neurosci Biobehav Rev 2013;37(6):1050-62. PMID 23237884
52: Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 2011;34:441-66. PMID 21469956
53: Gilmour TP, Lieu CA, Nolt MJ, Piallat B, Deogaonkar M, Subramanian T. The effects of chronic levodopa treatments on the neuronal firing properties of the subthalamic nucleus and substantia nigra reticulata in hemiparkinsonian rhesus monkeys. Exp Neurol 2011;228(1):53-8. PMID 21146527
54: Gittis AH, Hang GB, Ladow ES, et al. Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine. Neuron 2011a;71(5):858-68. PMID 21903079
55: Gittis AH, Leventhal DK, Fensterheim BA, Pettibone JR, Berke JD, Kreitzer AC. Selective inhibition of striatal fast-spiking interneurons causes dyskinesias. J Neurosci 2011b;31(44):15727-31. PMID 22049415
56: Glimcher PW. Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis. Proc Natl Acad Sci U S A 2011;108 Suppl 3:15647-54. PMID 21389268
57: Goldberg JA, Rokni U, Boraud T, Vaadia E, Bergman H. Spike synchronization in the cortex/basal-ganglia networks of Parkinsonian primates reflects global dynamics of the local field potentials. J Neurosci 2004;24(26):6003-10. PMID 15229247
58: Goldberg JH, Fee MS. A cortical motor nucleus drives the basal ganglia-recipient thalamus in singing birds. Nat Neurosci 2012;15(4):620-7. PMID 22327474
59: Haber SN. The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat 2003;26(4):317-30. PMID 14729134
60: Haber SN. Corticostriatal circuitry. Dialogues Clin Neurosci 2016;18(1):7-21. PMID 27069376
61: Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci 2000;20(6):2369-82. PMID 10704511
62: Hahn PJ, Russo GS, Hashimoto T, et al. Pallidal burst activity during therapeutic deep brain stimulation. Exp Neurol 2008;211(1):243-51. PMID 18355810
63: Halje P, Tamtè M, Richter U, Mohammed M, Cenci MA, Petersson P. Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations. J Neurosci 2012;32(47):16541-51. PMID 23175810
64: Hamani C, Pililsis J, Rughani AI, et al. Deep brain stimulation for obsessive-compulsive disorder: systematic review and evidence-based guideline sponsored by the American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons and endorsed by the CNS and American Association of Neurological Surgeons. Neurosurgery 2014;75(4):327-33;quiz 333. PMID 25050579
65: Hazrati LN, Wong JC, Hamani C, et al. Clinicopathological study in progressive supranuclear palsy with pedunculopontine stimulation. Mov Disord 2012;27(10):1304-7. PMID 22865554
66: Hegeman DJ, Hong ES, Hernandez VM, Chan CS. The external globus pallidus: progress and perspectives. Eur J Neurosci 2016;43(10):1239-65. PMID 26841063
67: Heimer G, Rivlin-Etzion M, Bar-Gad I, Goldberg JA, Haber SN, Bergman H. Dopamine replacement therapy does not restore the full spectrum of normal pallidal activity in the 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine primate model of Parkinsonism. J Neurosci 2006;26(31):8101-14. PMID 16885224
68: Helmich RC, Derikx LC, Bakker M, Scheeringa R, Bloem BR, Toni I. Spatial remapping of cortico-striatal connectivity in Parkinson's disease. Cereb Cortex 2010;20(5):1175-86. PMID 19710357
69: Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits. Brain 2012;135(Pt 11):3206-26. PMID 22382359
70: Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol 2011;69(2):269-81. PMID 21387372
71: Holgado AJ, Terry JR, Bogacz R. Conditions for the generation of beta oscillations in the subthalamic nucleus-globus pallidus network. J Neurosci 2010;30(37):12340-52. PMID 20844130
72: Hong S, Jhou TC, Smith M, Saleem KS, Hikosaka O. Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J Neurosci 2011;31(32):11457-71. PMID 21832176
73: Hu W, Stead M. Deep brain stimulation for dystonia. Transl Neurodegener 2014;3(1):2. PMID 24444300
74: Iskhakova L, Rappel P, Deffains M, et al. Modulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations. Nat Commun 2021;12(1):7026. PMID 34857767
75: Israelashvili M, Loewenstern Y, Bar-Gad I. Abnormal neuronal activity in Tourette syndrome and its modulation using deep brain stimulation. J NeurophysioI 2015;114(1):6-20. PMID 25925326
76: Jenkinson N, Brown P. New insights into the relationship between dopamine, beta oscillations and motor function. Trends Neurosci 2011;34(12):611-8. PMID 22018805
77: Jo HJ, McCairn KW, Gibson WS, et al. Global network modulation during thalamic stimulation of Tourette syndrome. Neuroimage Clin 2018;18:502-9. PMID 29560306
78: Jones EG. Synchrony in the interconnected circuitry of the thalamus and cerebral cortex. Ann N Y Acad Sci 2009;1157:10-23. PMID 19351352
79: Kalia LV, Brotchie JM, Fox SH. Novel nondopaminergic targets for motor features of Parkinson's disease: review of recent trials. Mov Disord 2013;28(2):131-44. PMID 23225267
80: Kim J, Kita H. Short-term plasticity shapes activity pattern-dependent striato-pallidal synaptic transmission. J Neurophysiol 2013;109(4):932-9. PMID 23197459
81: Kim W, Pouratian N. Deep brain stimulation for Tourette syndrome. Neurosurg Clin N Am 2014;25(1):117-35. PMID 24262904
82: Kita H, Kita T. Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia. J Neurosci 2011;31(28):10311-22. PMID 21753008
83: Kliem MA, Maidment NT, Ackerson LC, Chen S, Smith Y, Wichmann T. Activation of nigral and pallidal dopamine D1-like receptors modulates basal ganglia outflow in monkeys. J Neurophysiol 2007;98(3):1489-500. PMID 17634344
84: Kravitz AV, Freeze BS, Parker PR, et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 2010;466(7306):622-6. PMID 20613723
85: Kreitzer AC. Physiology and pharmacology of striatal neurons. Annu Rev Neurosci 2009;32:127-47. PMID 19400717
86: Kuhn AA, Tsui A, Aziz T, et al. Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity. Exp Neurol 2009;215(2):380-7. PMID 19070616
87: Lanciego JL, Luquin N, Obeso JA. Functional neuroanatomy of the basal ganglia. Cold Spring Harb Perspect Med 2012;2(12):a009621. PMID 23071379
88: Leblois A, Meissner W, Bezard E, Bioulac B, Gross CE, Boraud T. Temporal and spatial alterations in GPi neuronal encoding might contribute to slow down movement in Parkinsonian monkeys. Eur J Neurosci 2006;24(4):1201-8. PMID 16930445
89: Leblois A, Meissner W, Bioulac B, Gross CE, Hansel D, Boraud T. Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism. Eur J Neurosci 2007;26(6):1701-13. PMID 17880401
90: Leventhal DK, Gage GJ, Schmidt R, Pettibone JR, Case AC, Berke JD. Basal ganglia beta oscillations accompany cue utilization. Neuron 2012;73(3):523-36. PMID 22325204
91: Levy R, Dostrovsky JO, Lang AE, Sime E, Hutchison WD, Lozano AM. Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease. J Neurophysiol 2001;86(1):249-60. PMID 11431506
92: Llinás RR, Steriade M. Bursting of thalamic neurons and states of vigilance. J Neurophysiol 2006;95(6):3297-308. PMID 16554502
93: Mallet N, Ballion B, Le Moine C, Gonon F. Cortical inputs and GABA interneurons imbalance projection neurons in the striatum of parkinsonian rats. J Neurosci 2006;26(14):3875-84. PMID 16597742
94: Mallet N, Micklem BR, Henny P, et al. Dichotomous organization of the external globus pallidus. Neuron 2012;74(6):1075-86. PMID 22726837
95: Mallet N, Pogosyan A, Márton LF, Bolam JP, Brown P, Magill PJ. Parkinsonian beta oscillations in the external globus pallidus and their relationship with subthalamic nucleus activity. J Neurosci 2008a;28(52):14245-58. PMID 19109506
96: Mallet N, Pogosyan A, Sharott A, et al. Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. J Neurosci 2008b;28(18):4795-806. PMID 18448656
97: Manza P, Zhang S, Li CS, Leung HC. Resting-state functional connectivity of the striatum in early-stage Parkinson's disease: cognitive decline and motor symptomatology. Hum Brain Mapp 2016;37(2):648-62. PMID 26566885
98: Martinez-Ramirez D, Jimenez-Shahed J, Leckman JF, et al. Efficacy and safety of deep brain stimulation in Tourette Syndrome: the international Tourette Syndrome deep brain stimulation public database and registry. JAMA Neurol 2018;75(3):353-9. PMID 29340590
99: Mathai A, Smith Y. The corticostriatal and corticosubthalamic pathways: two entries, one target. So what. Front Syst Neurosci 2011;5:64. PMID 21866224
100: Matsumoto M, Hikosaka O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 2009;459(7248):837-41. PMID 19448610
101: Matsumoto N, Minamimoto T, Graybiel AM, Kimura M. Neurons in the thalamic CM-Pf complex supply striatal neurons with information about behaviorally significant sensory events. J Neurophysiol 2001;85(2):960-76. PMID 11160526
102: Maurice N, Liberge M, Jaouen F, et al. Striatal cholinergic interneurons control motor behavior and basal ganglia function in experimental parkinsonism. Cell Rep 2015;13(4):657-66. PMID 26489458
103: Mazzoni P, Hristova A, Krakauer JW. Why don't we move faster. Parkinson's disease, movement vigor, and implicit motivation. J Neurosci 2007;27(27):7105-16. PMID 17611263
104: McCairn KW, Turner RS. Deep brain stimulation of the globus pallidus internus in the parkinsonian primate: local entrainment and suppression of low-frequency oscillations. J Neurophysiol 2009;101(4):1941-60. PMID 19164104
105: McCarthy MM, Moore-Kochlacs C, Gu X, Boyden ES, Han X, Kopell N. Striatal origin of the pathologic beta oscillations in Parkinson's disease. Proc Natl Acad Sci U S A 2011;108(28):11620-5. PMID 21697509
106: McElvain LE, Chen Y, Moore JD, et al. Specific populations of basal ganglia output neurons target distinct brain stem areas while collateralizing throughout the diencephalon. Neuron 2021;109(10):1721-38.e4. PMID 33823137
107: McGeorge AJ, Faull RL. The organization of the projection from the cerebral cortex to the striatum in the rat. Neuroscience 1989;29(3):503-37. PMID 2472578
108: Meissner W, Leblois A, Hansel D, et al. Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations. Brain 2005;128(Pt 10):2372-82. PMID 16123144
109: Mena-Segovia J, Bolam JP. Rethinking the penduculopontine nucleus: from cellular organization to function. Neuron 2017;94(1):7-18. PMID 28384477
110: Mena-Segovia J, Micklem BR, Nair-Roberts RG, Ungless MA, Bolam JP. GABAergic neuron distribution in the pedunculopontine nucleus defines functional subterritories. J Comp Neurol 2009;515(4):397-408. PMID 19459217
111: Meyer A. Karl Friedrich Burdach and his place in the history of neuroanatomy. J Neurol Neurosurg Psychiatry 1970;33(5):553-61. PMID 4922393
112: Miguelez C, Morin S, Martinez A, et al. Altered pallido-pallidal synaptic transmission leads to aberrant firing of globus pallidus neurons in a rat model of Parkinson's disease. J Physiol 2012;590(Pt 22):5861-75. PMID 22890706
113: Minamimoto T, Hori Y, Kimura M. Roles of the thalamic CM-PF complex-Basal ganglia circuit in externally driven rebias of action. Brain Res Bull 2009;78(2-3):75-9. PMID 18793702
114: Mishra VR, Sreenivasan KR, Yang Z, et al. Unique white matter structural connectivity in early-stage drug-naive Parkinson disease. Neurology 2020;94(8):e774-84. PMID 31882528
115: Molnar GF, Pilliar A, Lozano AM, Dostrovsky JO. Differences in neuronal firing rates in pallidal and cerebellar receiving areas of thalamus in patients with Parkinson's disease, essential tremor, and pain. J Neurophysiol 2005;93(6):3094-101. PMID 15703231
116: Montgomery E Jr. Cortically evoked responses of human pallidal neurons. Mov Disord 2011;26(14):2583; author reply 2583-4. PMID 21994043
117: Montgomery EB Jr. Starting from scratch-basal ganglia pathophysiology. Mov Disord 2020;35(1):196-7. PMID 31965628
118: Morikawa H, Paladini CA. Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms. Neuroscience 2011;198:95-111. PMID 21872647
119: Morita H, Hass CJ, Moro E, Sudhyadhom A, Kumar R, Okun MS. Pedunculopontine nucleus stimulation: where are we now and what needs to be done to move the field forward? Front Neurol 2014;5:243. PMID 25538673
120: Nambu A, Tokuno H, Takada M. Functional significance of the cortico-subthalamo-pallidal 'hyperdirect' pathway. Neurosci Res 2002;43(2):111-7. PMID 12067746
121: Nelson AB, Kreitzer AC. Reassessing models of basal ganglia function and dysfunction. Annu Rev Neurosci 2014;37:117-35. PMID 25032493
122: Obeso JA, Rodriguez-Oroz MC, Stamelou M, Bhatia KP, Burn DJ. The expanding universe of disorders of the basal ganglia. Lancet 2014;384(9942):523-31.** PMID 24954674
123: Oswal A, Cao C, Yeh CH, et al. Neural signatures of hyperdirect pathway activity in Parkinson's disease. Nat Commun 2021;12(1):5185. PMID 34465771
124: Papa SM, Desimone R, Fiorani M, Oldfield EH. Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesias. Ann Neurol 1999;46(5):732-8. PMID 10553990
125: Parent A, Parent M, Leroux-Hugon V. Jules Bernard Luys: a singular figure of 19th century neurology. Can J Neurol Sci 2002;29(3):282-8. PMID 12195620
126: Pasquereau B, Turner RS. Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons. Cereb Cortex 2011;21(6):1362-78. PMID 21045003
127: Pearce JM. Samuel Thomas Soemmerring (1755-1830): The Naming of Cranial Nerves. Eur Neurol 2017;77(5-6):303-6. PMID 28456809
128: Pessiglione M, Guehl D, Rolland AS, et al. Thalamic neuronal activity in dopamine-depleted primates: evidence for a loss of functional segregation within basal ganglia circuits. J Neurosci 2005;25(6):1523-31. PMID 15703406
129: Pisani A, Bernardi G, Ding J, Surmeier DJ. Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci 2007;30(10):545-53. PMID 17904652
130: Qasim SE, de Hemptinne C, Swann NC, Miocinovic S, Ostrem JL, Starr PA. Electrocorticography reveals beta desynchronization in the basal ganglia-cortical loop during rest tremor in Parkinson's disease. Neurobiol Dis 2016;86:177-86. PMID 26639855
131: Ramirez-Zamora A, Giordano J, Gunduz A, et al. Proceedings of the seventh annual deep brain stimulation think tank: advances in neurophysiology, adaptive DBS, virtual reality, neuroethics and technology. Front Hum Neurosci 2020;14:54. PMID 32292333
132: Raz A, Frechter-Mazar V, Feingold A, Abeles M, Vaadia E, Bergman H. Activity of pallidal and striatal tonically active neurons is correlated in MPTP-treated monkeys but not in normal monkeys. J Neurosci 2001;21(3):RC128. PMID 11157099
133: Raz A, Vaadia E, Bergman H. Firing patterns and correlations of spontaneous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine vervet model of parkinsonism. J Neurosci 2000;20(22):8559-71. PMID 11069964
134: Reiner A, Hart NM, Lei W, Deng Y. Corticostriatal projection neurons - dichotomous types and dichotomous functions. Front Neuroanat 2010;4:142. PMID 21088706
135: Rivlin-Etzion M, Elias S, Heimer G, Bergman H. Computational physiology of the basal ganglia in Parkinson's disease. Prog Brain Res 2010;183:259-73. PMID 20696324
136: Rolinski M, Griffanti L, Piccini P, et al. Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson's disease. Brain 2016;139(Pt 8):2224-34. PMID 27297241
137: Rommelfanger KS, Wichmann T. Extrastriatal dopaminergic circuits of the basal ganglia. Front Neuroanat 2010;4:139. PMID 21103009
138: Rovo Z, Ulbert I, Acsády L. Drivers of the primate thalamus. J Neurosci 2012;32(49):17894-908. PMID 23223308
139: Rubin JE, McIntyre CC, Turner RS, Wichmann T. Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects. Eur J Neurosci 2012;36(2):2213-28. PMID 22805066
140: Sadikot AF, Rymar VV. The primate centromedian-parafascicular complex: anatomical organization with a note on neuromodulation. Brain Res Bull 2009;78(2-3):122-30. PMID 18957319
141: Sarasso E, Basaia S, Cividini C, et al. MRI biomarkers of freezing of gait development in Parkinson's disease. NPJ Parkinsons Dis 2022;8(1):158. PMID 36379944
142: Scherfler C, Schwarz J, Antonini A, et al. Role of DAT-SPECT in the diagnostic work up of parkinsonism. Mov Disord 2007;22(9):1229-38. PMID 17486648
143: Schrock LE, Ostrem JL, Turner RS, Shimamoto SA, Starr PA. The subthalamic nucleus in primary dystonia: single-unit discharge characteristics. J Neurophysiol 2009;102(6):3740-52. PMID 19846625
144: Schulz JM, Reynolds JN. Pause and rebound: sensory control of cholinergic signaling in the striatum. Trends Neurosci 2013;36(1):41-50. PMID 23073210
145: Sgambato-Faure V. Control of the direct pathway by cholinergic interneurons is involved in parkinsonian motor symptoms. Mov Disord 2016;32(3):393. PMID 27804149
146: Shariatgorji M, Nilsson A, Goodwin RJ, et al. Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections. Neuron 2014;84(4):697-707. PMID 25453841
147: Soares J, Kliem MA, Betarbet R, Greenamyre JT, Yamamoto B, Wichmann T. Role of external pallidal segment in primate parkinsonism: comparison of the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment. J Neurosci 2004;24(29):6417-26. PMID 15269251
148: Stanford IM, Loucif KC, Wilson CL, Cash D, Lacey MG. Limitations of the Isolated GP-STN Network. In: Bolam JP, Ingham CA, Magill PJ, editors. The Basal Ganglia VIII. New York, NY: Springer Science, 2005:65-73.
149: Starr PA, Rau GM, Davis V, et al. Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque. J Neurophysiol 2005;93(6):3165-76. PMID 15703229
150: Stoessl AJ, Lehericy S, Strafella AP. Imaging insights into basal ganglia function, Parkinson's disease and dystonia. Lancet 2014;384(9942):532-44. PMID 24954673
151: Strafella AP, Lozano AM, Ballanger B, Poon YY, Lang AE, Moro E. rCBF changes associated with PPN stimulation in a patient with Parkinson's disease: a PET study. Mov Disord 2008;23(7):1051-4. PMID 18412282
152: Sutton AC, Yu W, Calos ME, et al. Elevated potassium provides an ionic mechanism for deep brain stimulation in the hemiparkinsonian rat. Eur J Neurosci 2013;37(2):231-41. PMID 23121286
153: Szewczyk-Krolikowski K, Menke RA, Rolinski M, et al. Functional connectivity in the basal ganglia network differentiates PD patients from controls. Neurology 2014;83(3):208-14. PMID 24920856
154: Tachibana Y, Iwamuro H, Kita H, Takada M, Nambu A. Subthalamo-pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia. Eur J Neurosci 2011;34(9):1470-84. PMID 22034978
155: Tang JK, Moro E, Mahant N, et al. Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson's disease. J Neurophysiol 2007;98(2):720-9. PMID 17537900
156: Telkes I, Viswanathan A, Jimenez-Shahed J, et al. Local field potentials of subthalamic nucleus contain electrophysiological footprints of motor subtypes of Parkinson's disease. Proc Natl Acad Sci U S A 2018;115(36):E8567-76. PMID 30131429
157: Tepper JM, Tecuapetla F, Koós T, Ibáñez-Sandoval O. Heterogeneity and diversity of striatal GABAergic interneurons. Front Neuroanat 2010;4:150. PMID 21228905
158: Thevathasan W, Debu B, Aziz T, et al. Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: a clinical review. Mov Disord 2018;33(1):10-20. PMID 28960543
159: van der Meer MA, Redish AD. Low and high gamma oscillations in rat ventral striatum have distinct relationships to behavior, reward, and spiking activity on a learned spatial decision task. Front Integr Neurosci 2009;3:9. PMID 19562092
160: Villalba RM, Smith Y. Differential structural plasticity of corticostriatal and thalamostriatal axo-spinous synapses in MPTP-treated Parkinsonian monkeys. J Comp Neurol 2011;519(5):989-1005. PMID 21280048
161: Villalba RM, Wichmann T, Smith Y. Neuronal loss in the caudal intralaminar thalamic nuclei in a primate model of Parkinson's disease. Brain Struct Funct 2014;219(1):381-94. PMID 23508713
162: Vitek JL, Zhang J, Hashimoto T, Russo GS, Baker KB. External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network. Exp Neurol 2012;233(1):581-6. PMID 22001773
163: Wahyu ID, Chiken S, Hasegawa T, et al. Abnormal cortico-basal ganglia neurotransmission in a mouse model of l-DOPA-induced dyskinesia. J Neurosci 2021;41(12):2668-83. PMID 33563724
164: Wang DD, de Hemptinne C, Miocinovic S, et al. Pallidal deep-brain stimulation disrupts pallidal beta oscillations and coherence with primary motor cortex in Parkinson's disease. J Neurosci 2018;38(19):4556-68. PMID 29661966
165: Wang HL, Morales M. Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat. Eur J Neurosci 2009;29(2):340-58. PMID 19200238
166: Watson GD, Hughes RN, Petter EA, et al. Thalamic projections to the subthalamic nucleus contribute to movement initiation and rescue of parkinsonian symptoms. Sci Adv 2021;7(6):eabe9192. PMID 33547085
167: Weinberger M, Hutchison WD, Alavi M, et al. Oscillatory activity in the globus pallidus internus: comparison between Parkinson's disease and dystonia. Clin Neurophysiol 2012;123(2):358-68. PMID 21843964
168: Weinberger M, Mahant N, Hutchison WD, et al. Beta oscillatory activity in the subthalamic nucleus and its relation to dopaminergic response in Parkinson's disease. J Neurophysiol 2006;96(6):3248-56. PMID 17005611
169: Wichmann T, Bergman H, DeLong MR. The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophysiol 1994;72(2):521-30. PMID 7983516
170: Wichmann T, Soares J. Neuronal firing before and after burst discharges in the monkey basal ganglia is predictably patterned in the normal state and altered in parkinsonism. J Neurophysiol 2006;95(4):2120-33. PMID 16371459
171: Xu W, Russo GS, Hashimoto T, Zhang J, Vitek JL. Subthalamic nucleus stimulation modulates thalamic neuronal activity. J Neurosci 2008;28(46):11916-24. PMID 19005057
172: Yasoshima Y, Kai N, Yoshida S, et al. Subthalamic neurons coordinate basal ganglia function through differential neural pathways. J Neurosci 2005;25(34):7743-53. PMID 16120775
173: Yin HY. The basal ganglia in action. Neuroscientist 2017;23(3):299-313. PMID 27306757
174: Zhang Y, Larcher KM, Misic B, Dagher A. Anatomical and functional organization of the human substantia nigra and its connections. ELife 2017;6:e26653. PMID 28826495
175: Zhou FM, Lee CR. Intrinsic and integrative properties of substantia nigra pars reticulata neurons. Neuroscience 2011;198:69-94. PMID 21839148
176: Ztaou S, Amalric M. Contribution of cholinergic interneurons to striatal pathophysiology in Parkinson’s disease. Neurochem Int 2019;126:1-10. PMID 30825602

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Shailee Shah MD MS

Dr. Shah of Vanderbilt University Medical Center has no relevant financial relationship to disclose.
See Profile
Shameer Rafee MRCPI

Dr. Rafee of University College Dublin received speaker's honorariums from Ipsen and Merz and travel grants from Abbvie and Ipsen.
See Profile

Editor

Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
See Profile

Former Authors

Ryan R Walsh MD PhD
Sana Aslam DO
Philip A Hanna MD, Olukayode Onasanya MD, Jonathan W Mink, Damien J Ellens MD, Daniel K Leventhal MD PhD, Roger L Albin MD, and Brent Bluett DO

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Basal ganglia: functional anatomy and neuropharmacology

Also Relevant

Basal ganglia hemorrhage
Corticobasal degeneration
Deep brain stimulation in movement disorders
Rostral brainstem and thalamic infarctions
Parkinson disease

Clinical Categories

Movement Disorders

Basal ganglia: functional anatomy and neuropharmacology …

Basal ganglia: functional anatomy and neuropharmacology

Introduction

Overview

Key points

Historical note and terminology

Table 1. Localization of Pathology within the Basal Ganglia

Description

Functional anatomy

Clinical applications

The rate model and electrophysiological changes in animal models of Parkinson disease

Relating physiology to clinical symptoms

Concluding remarks

Table 2. Selected Areas for Future Research

Media

References

Contributors

Authors

Editor

Former Authors

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

Basal ganglia: functional anatomy and neuropharmacology

Introduction

Overview

Key points

Historical note and terminology

Table 1. Localization of Pathology within the Basal Ganglia

Description

Functional anatomy

Clinical applications

The rate model and electrophysiological changes in animal models of Parkinson disease

Relating physiology to clinical symptoms

Concluding remarks

Table 2. Selected Areas for Future Research

Media

References

Contributors

Authors

Editor

Former Authors

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

This is an article preview.
Start a Free Account
to access the full version.