Basal ganglia disease is a group of physical problems that occur when the group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or to properly prime upper motor neuron circuits to initiate motor function. Research indicates that increased output of the basal ganglia inhibits thalamocortical projection neurons. Proper activation or deactivation of these neurons is an integral component for proper movement. If something causes too much basal ganglia output, then the ventral anterior (VA) and ventral lateral (VL) thalamocortical projection neurons become too inhibited, and one cannot initiate voluntary movement. These disorders are known as hypokinetic disorders. However, a disorder leading to abnormally low output of the basal ganglia leads to reduced inhibition, and thus excitation, of the thalamocortical projection neurons (VA and VL) which synapse onto the cortex. This situation leads to an inability to suppress unwanted movements. These disorders are known as hyperkinetic disorders.
Reasons for abnormal increases or decreases of basal ganglia output are not yet well understood. One possible factor could be the natural accumulation of iron in the basal ganglia, causing neurodegeneration due to its involvement in toxic, free-radical reactions. Though motor disorders are the most common associated with the basal ganglia, recent research shows that basal ganglia disorders can lead to other dysfunctions such as obsessive–compulsive disorder (OCD), Tourette syndrome and klazomania.
Basal ganglia circuits
The basal ganglia is a collective group of structures in the brain. These include the striatum, (composed of the putamen and caudate nucleus), globus pallidus, substantia nigra, and the subthalamic nucleus. Along with other structures, the basal ganglia are part of a neural circuit that is integral to voluntary motor function. It was once believed that the primary function of the basal ganglia was to integrate projections from the cerebral cortex, and project information via the thalamus to the motor cortex. Research has shown that the basal ganglia can be modeled as a group of components of parallel, re-entrant cortico-subcortical circuits, which originate in cortical areas, traverse the basal ganglia and terminate in specific areas in the frontal lobe. These areas are thought to control not only motor function but also oculomotor, prefrontal, associative, and limbic areas. Understanding these circuits has led to breakthroughs in understanding the disorders of the basal ganglia.
Direct pathway Of all the circuits, the motor circuit is the most studied due its importance to motor disorders. The direct pathway of the motor circuit is one in which projections from the cortex travel to the putamen directly to the internal segment of the globus pallidus (GPi also known as GP-Medial) or the substantia nigra, pars reticulata (SNr) and are then directed toward the ventral anterior nucleus (VA), and the ventral lateral nucleus of the thalamus (VL) and brainstem. Through this pathway the basal ganglia is able to initiate voluntary movements by disinhibiting thalamic neurons that drive upper motor neurons. This process is regulated by dopamine secreted by the striatum onto the D1 dopamine receptor on the SNc. Dopamine excites striatal neurons in the direct pathway. Proper striatal dopamine release is integral in the suppression of the basal ganglia output, which is needed for increased activity of the thalamic neurons. This activity in thalamic nuclei is an integral component of voluntary movement.
Indirect pathway
The indirect pathway of the motor circuit is thought to project from the cortex, to the putamen, and to the thalamus and brainstem indirectly by passing through the external segment of the globus pallidus (GPe) then the subthalamic nucleus (STN) before looping back to the internal segment of the globus pallidus (GPi). The indirect pathway is responsible for the termination of movement. The indirect pathway inhibits unwanted movements by simultaneous increase in excitatory input to other GPi and SNr neurons. Similar to the direct pathway, the indirect pathway is regulated by striatal dopamine. D2 dopamine receptors inhibit transmission via the indirect pathway. D2 receptors inhibit striatal neurons in the indirect, inhibitory pathway. This inhibitory effect of dopamine on the indirect pathway serves the same function as its excitatory effects in the direct pathway in that it reduces basal ganglia output, leading to the disinhibition of motor neurons.
Associated disorders
Hypokinetic disorders Hypokinetic disorders are movement disorders that are described as having reduced motor function. This is generally attributed to higher than normal basal ganglia output causing inhibition of thalamocortical motor neurons.
Parkinsonism
The muscle rigidity, tremor at rest, and slowness in initiation and execution of movement that are the cardinal motor symptoms of Parkinson's disease are attributed to a reduction in dopaminergic activity in the basal ganglia motor areas, particularly the putamen, due to gradually reduced innervation from the pars compacta of substantia nigra. Other motor deficits and common non-motor features of Parkinson's such as autonomic dysfunction, cognitive impairment, and gait/balance difficulties, are thought to result from widespread progressive pathological changes commencing in the lower brain stem and ascending to the midbrain, amygdala, thalamus and ultimately the cerebral cortex.
Hyperkinetic disorders
Hyperkinetic disorders are movement disorders characterized by increased uncontrollable motor function. They are caused by reduced basal ganglia output, which causes increased thalamocortical function which leads to the inability to stop unwanted movement.
Huntington's disease
Huntington's disease is a hereditary disease that causes defects in behavior, cognition, and uncontrolled rapid, jerky movements. Huntington's disease stems from a defect that consists of an expanded CAG repeat in the huntingtin gene (HTT) located on the short arm p of chromosome 4. Evidence shows that the basal ganglia in patients with Huntington's disease show a decrease in activity of the mitochondrial pathway, complex II-III. Such deficiencies are often associated with basal ganglia degeneration. This degeneration of striatal neurons projecting to GPe leads to disinhibition of the indirect pathway, increased inhibition of the subthalamic nucleus, and therefore, reduced output of the basal ganglia. The neuronal degeneration eventually causes death within 10 to 20 years.
Dystonia
Dystonia is a hyperkinetic movement disorder that is characterized by involuntary movement and the slowing of intentional movement. Though there are known causes of dystonia such as metabolic, vascular, and structural abnormalities, there are still patients with dystonia with no apparent cause. Dystonia can occur as a hyperkinetic disorder or as a side effect of hypokinetic disorders such as Parkinson's disease. Until recently it was thought that dystonia was likely caused by extreme lack of function of the direct pathway between the Putamen and the GPi. Again, it was thought that this dysfunction led to a decrease in basal ganglia output to the thalamus and a resultant increased disinhibition of the thalamic projections to the premotor and motor cortex. However recent models in mice show that the dysfunction in the cerebellum may play an equal part in dystonia.
Hemiballismus
Hemiballismus is a hyperkinetic movement disorder that causes uncontrolled movement on one side of the body. It is generally caused by damage to the subthalamic nucleus (STN). Since the internal segment of the globus pallidus (GPi) is the link in the circuit between the STN and thalamic projection, destruction of localized brain cells in the GPi via a pallidotomy has proven to serve as a useful treatment for hemiballismus.
Other basal ganglia diseases The following diseases that generally involve the basal ganglia do not clearly fit into being either hypo- or hyperkinetic.
Epilepsy
The substantia nigra pars reticulata and its direct input structure, the subthalamic nucleus play a role in seizure propagation circuitry and have been described as seizure gating nuclei. Inhibition of these nuclei suppresses seizures in various experimental epilepsy models. Patients with seizures display some abnormal electrophysiological activity and structural changes like atrophy, altered blood perfusion and metabolism within their basal ganglia. Several case reports describe that deep brain stimulation of the subthalamic nucleus has been successful in reducing seizures. Other targeted treatment approaches have been limited to experimental settings and included local drug infusions and cell transplantation.
Tourette syndrome/obsessive–compulsive disorder
Tourette syndrome is a disorder that is characterized by behavioral and motor tics, OCD and attention deficit hyperactivity disorder (ADHD). For this reason, it is commonly believed that pathologies involving limbic, associative and motor circuits of the basal ganglia are likely. Since the realization that syndromes such as Tourette syndrome and OCD are caused by dysfunction of the non-motor loops of basal ganglia circuits, new treatments for these disorders, based on treatments originally designed to treat movement disorders are being developed.
Other regions of the brain including the thalamus and frontal cortex also contribute to Tourettes syndrome. Specifically dopamine, is thought to be central to the pathophysiology of Tourette syndrome. The basal ganglia are rich in dopamine receptors, and an imbalance in dopamine signaling can be correlated with the onset and severity of tics.
There are two forms of treatments: medication and therapy. The recommended form of therapy is Comprehensive behavioral intervention for tics. This is a form of behavioral therapy, which will help the patient with their tics and make them more voluntary. During this process they train individuals how to be more aware of their tics. And encourage changes in their day-to-day activities to help reduce tics. In addition to this, there are various forms of medications that can help make tics more manageable for everyday life. Medications like neuroleptics, benzamides, or atypical antipsychotics are used to decrease dopamine have been effective for the disorder. Deep brain stimulation is another solution to make tics more manageable. There is not a cure for the disorder, but the things mentioned help make tics and outbursts more manageable for an average person to live their daily life.
The key role of dopamine and Tourettes - Increasing evidence supports the TS hypothesis, particularly regarding the dopamine receptor system.; demonstrated receptor derangement or hyposensitivity in the basal ganglia dopamine pathways plays a critical role in the diathesis for Tourette syndrome. According to most theories, Tourette's syndrome is due to a chemical dysfunction of dopamine in those areas of the brain that are linked to movement control, resulting in the repetitive and uncontrolled tics seen in the syndrome (D2-like Dopamine Receptor Density in Tourette Syndrome Measured by PET, 1997). A few medical researches indicate that people with Tourette syndrome may have an increased dopamine activity level for some reason connected to either greater dopamine receptor sensitivity or irregular dopamine turnover patterns. The basal ganglia, a cerebral structure involved in controlling movement, is believed to be one of the sites vulnerable to dopamine abnormalities and is implicated in the pathogenesis of TS. It is thought that dopamine, norepinephrine, and serotonin neurotransmitters are not able to exchange messages properly between nerve cells in a person diagnosed with Tourette's.
Sydenham's chorea