Divyan Bavan
Introduction
The control of movement is a core responsibility of the brain. As this is a complex process, several areas and pathways are involved. This includes the basal ganglia: a network of subcortical nuclei. Among other roles, these areas are involved in coordinating decisions regarding movement; they convert several competing inputs into a distinct plan. This mechanism behind this function has been elucidated through several studies, particularly of lesions. Specific areas of the basal ganglia can be damaged in degenerative diseases—such as Parkinson’s and Huntington’s—providing a model for understanding their roles within the wider network. With simple observation, it is obvious that these lesions impact movement. However, by understanding specifically how the basal ganglia are disrupted, it is possible to form a mechanistic explanation for these observations.
The Basal Ganglia
In a normal brain, the basal ganglia form a concrete circuit. This starts with glutamatergic input from the motor cortex to the medium spiny neurons (MSNs) of the striatum. From here, there are two pathways the signals can take: direct and indirect. While the routes and signalling is different, both pathways converge at the substantia nigra pars reticulata (SNr) and internal globus pallidus (GPi): the main output centres for the basal ganglia. In the absence of any input, these cells tonically fire and provide inhibitory input to the thalamus. Since the thalamus stimulates various motor areas, increased activity of the SNr/GPi is associated with inhibited motor activity. In contrast, inhibition of SNr/GPi leads to motor output.
Control of the SNr/GPi is mediated by the direct and indirect pathways. In the former, the striatum provides direct GABAergic input to the SNr/GPi. The result of this is disinhibition of the thalamus and activation of motor output. Thus, the direct pathway is associated with the facilitation of movement. The indirect pathway is the opposite. Instead of directly providing input to SNr/GPi, the striatum sends GABAergic signals to the external global pallidus (GPe). This area provides GABAergic input to the subthalamic nucleus (STN). Therefore, striatal input to GPe decreases the inhibition of the STN, increasing its stimulation of the SNr/GPi. This increases inhibition of the thalamus, keeping motor activity subdued. Thus, the indirect pathway is associated with the inhibition of movement.
The substantia nigra pars compacta (SNc) is unique among the basal ganglia as it provides dopaminergic input to the striatum. This input, unlike glutamate or GABA, can be stimulatory or inhibitory. This is dependent on the selective expression of dopamine receptors. For example, neurons that form the direct pathway express the D1 dopamine receptor. This receptor is stimulatory, increasing striatal inhibition of the SNr/GPi. On the other hand, the indirect pathway expresses D2 dopamine receptors. These receptors are inhibitory, decreasing striatal inhibition of GPe. This causes greater inhibition of the STN, reducing activity of SNr/GPi. Thus, dopamine facilitates movement through excitation and inhibition of the direct and indirect pathways, respectively (Young et al., 2023).
This circuit has been studied for many years. Although the explanation above is sufficient for understanding the effects of various lesions, the true network is much more interconnected. Nonetheless, even simplified versions can explain how damage to the basal ganglia affect signalling.
Parkinson’s Disease
The most famous disease affecting the basal ganglia is Parkinson’s disease (PD). This disease is synonymous with degeneration of the dopaminergic neurons in the SNc. In tissue samples from patients with PD, the lack of significant pigmentation in the SNc is evidence for this explanation. The result of this is symptoms such as a resting tremor, slowed movement, and postural instability (Zafar et al., 2023).
Unlike monogenic diseases, which are defined by changes in a specific gene, the specific cause for PD is still not understood. Current theories propose that a combination of factors begin the onset of PD, exacerbating each other as the disease progresses. One example of this is the accumulation of Lewy bodies. These aggregates of α-synuclein are characteristic of PD. In the 5-10% of hereditary PD, the genes associated with the disease are often involved in the removal of α-synuclein. These aggregates can interfere with mitochondrial function, producing reactive oxygen species that accelerate degeneration. This integrated model for the development of PD explains the progressive nature of the disease. For this reasons, motor-related symptoms only appear after many of the SNc neurons have been degenerated (Poewe et al., 2017; Zafar et al., 2023).
As discussed previously, dopaminergic input from the SNc facilitates movement. This is through excitation of the direct pathway and inhibition of the indirect pathway. In PD, the absence of dopaminergic signalling reverses these effects. Increased inhibition of the GPe leads to activation of the SNr/GPi; decreased direct signalling from the striatum has the same effect. This explains the problems with movement observed in PD (Poewe et al., 2017).
By understanding the basal ganglia and its role in movement, several treatments have been designed to mitigate the effects of PD. In the 1990s, lesion of the GPi or STN was tested as a potential treatment. The reasoning behind this treatment was that these areas inhibited the thalamus, so removing them would remove this inhibition and allow movement. As expected, this did help alleviate bradykinesia in PD patients. While this procedure appears to provide a solution, it is invasive and likely has many side effects. Instead, the current state-of-the-art for PD treatment is L-DOPA. This chemical is a metabolic precursor to dopamine. The result is partially restored dopaminergic signalling and the activation of movement. Although PD is far from being cured, our understanding of the basal ganglia has enabled treatments to come a long way (Poewe et al., 2017).
Huntington’s Disease
Unlike PD, Huntington’s disease (HD) can be linked to a single gene: HTT. This gene is mutated in HD to have over 35 CAG repeats, forming a toxic variant of the huntingtin protein. The development of HD is similar to PD, where the mutant protein forms aggregates and interferes with mitochondrial function. However, instead of affected dopaminergic neurons in the SNc, HD affects MSNs in the striatum. Unlike most neurons, MSNs cannot increase expression of chaperones and protein degradation machinery in response to misfolding and aggregation. This leaves them vulnerable to degeneration (Ajitkumar et al., 2025; Tabrizi et al., 2020).
The progression of HD is an excellent example for understanding the basal ganglia. In the early stages of HD, patients experience chorea: involuntary, random movements. This is because MSNs associated with the indirect pathway are selectively degenerated first. Due to this phenomenon, the direct pathway is much more active; movement is facilitated more often than it should be. However, as the disease progresses to Stage 3 and 4, the direct pathway MSNs also degenerate. With both types of input neurons damaged, this leaves the basal ganglia unable to perform their filtering function for movement. HD patients at this stage are very hesitant with initiating movement. Eventually, the phenotype for HD is very similar to PD, despite the different mechanism of disease (Matz and Spocter, 2022).
The stage at which HD is being treated determines the treatment plan for the patient. In stage 2 where chorea dominates, vesicular monoamine transporter 2 (VMAT2) inhibitors are often prescribed. These reduce dopaminergic input to the striatum from the SNc. Dopamine inhibits the indirect pathway and excites the direct pathway, amplifying the effects of HD. Thus, inhibiting its signalling helps reduce the symptoms associated with the disease (Ajitkumar et al., 2025).
Conclusion
By observing the consequences of lesions to the basal ganglia, it becomes apparent just how critical they are to the control of movement. This network of subcortical nuclei forms a circuit with two paths: direct and indirect. Dopamine influences both pathways, providing an overall facilitation of movement. It is here where Parkinson’s disease has its effect. PD degenerates neurons in the SNc, reducing dopaminergic signalling and amplifying the indirect pathway. This results in motor symptoms such as bradykinesia. The opposite is true for the early stages of Huntington’s disease. In this disease, MSNs of the indirect pathway are preferentially degenerated. This leads to chorea. However, later stages of the disease reverse this as the direct pathway is also degenerated. The effects of these diseases can be explained mechanistically through the signalling network formed by the basal ganglia. This has guided the design of various treatments for these diseases. Thus, it is critical to continue studying these diseases for new avenues to take.
*Works Cited*
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