Basal ganglia disease is a group of physical problems that occur when the group of nuclei in the brain known as the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...

fail to properly suppress unwanted movements or to properly prime upper motor

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

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 Hyperkinesia refers to an increase in muscular activity that can result in excessive abnormal movements, excessive normal movements, or a combination of both. Hyperkinesia is a state of excessive restlessness which is featured in a large variet ...

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 Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in ...

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 Obsessive–compulsive disorder (OCD) is a mental and behavioral disorder in which an individual has intrusive thoughts and/or feels the need to perform certain routines repeatedly to the extent where it induces distress or impairs general ...

(OCD) and Tourette syndrome.

Basal ganglia circuits

The basal ganglia is a collective group of structures in the brain. These include the

striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives gluta ...

, (composed of the

putamen The putamen (; from Latin, meaning "nutshell") is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that compose the basal ...

and

caudate nucleus The caudate nucleus is one of the structures that make up the corpus striatum, which is a component of the basal ganglia in the human brain. While the caudate nucleus has long been associated with motor processes due to its role in Parkinson's d ...

globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rode ...

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra ap ...

, and the

subthalamic nucleus The subthalamic nucleus (STN) is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of the subthalamus. As suggested by its name, the ...

. Along with other structures, the basal ganglia are part of a

neural circuit A neural circuit is a population of neurons interconnected by synapses to carry out a specific function when activated. Neural circuits interconnect to one another to form large scale brain networks. Biological neural networks have inspired the ...

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 The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...

, and project information via the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...

to the

motor cortex The motor cortex is the region of the cerebral cortex believed to be involved in the planning, control, and execution of voluntary movements. The motor cortex is an area of the frontal lobe located in the posterior precentral gyrus immediately ...

. 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

directly to the internal segment of the

(GPi also known as GP-Medial) or the

, pars reticulata (SNr) and are then directed toward the ventral anterior nucleus (VA), and the

ventral lateral nucleus The ventral lateral nucleus (VL) is a nucleus in the ventral nuclear group of the thalamus. Inputs and outputs It receives neuronal inputs from the basal ganglia which includes the substantia nigra and the globus pallidus (via the thalamic fascic ...

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

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 Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

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 Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

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 ganglias 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 Hemiballismus or hemiballism is a basal ganglia syndrome resulting from damage to the subthalamic nucleus in the basal ganglia. Hemiballismus is a rare hyperkinetic movement disorder, that is characterized by violent involuntary limb movements, ...

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 pallidotony 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 Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

(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.

Sydenham's chorea

Sydenham's chorea is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. It is a result of an autoimmune response that occurs following infection by group A β-hemolytic streptococci (GABHS)Sydenham's Chorea Symptoms
Accessed September 24, 2009. that destroys cells in the

corpus striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...

of the

PANDAS

PANDAS is a controversial hypothesis that there exists a subset of children with rapid onset of

(OCD) or tic disorders and that these symptoms are caused by group A β-hemolytic streptococcal (GABHS) infections. The proposed link between infection and these disorders is that an initial autoimmune reaction to a GABHS infection produces antibodies that interfere with

function, causing symptom exacerbations. It has been proposed that this autoimmune response can result in a broad range of neuropsychiatric symptoms.

Dyskinetic cerebral palsy

Dyskinetic cerebral palsy is a type of

cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sens ...

primarily associated with damage to the basal ganglia in the form of

lesions A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

that occur during brain development due to

bilirubin Bilirubin (BR) ( Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from t ...

encephalopathy and hypoxic-ischemic

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

injury. Symptoms include slow, uncontrolled movements of the extremities and trunk and small, rapid, random and repetitive, uncontrolled movements known as

chorea Chorea (or choreia, occasionally) is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term ''chorea'' is derived from the grc, χορεία ("dance"; see choreia), as the quick movem ...

. Involuntary movements often increase during periods of emotional stress or excitement and disappear when the patient is sleeping or distracted.

Athymhormic syndrome

Athymhormic syndrome is a rare psychopathological and neurological

syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...

characterized by extreme passivity,

apathy Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic individual has an absence of inter ...

, blunted affect, and a profound generalized loss of self-motivation. The syndrome is believed to be due to damage to areas of the basal ganglia or

frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove be ...

, specifically the

and

, responsible for motivation and executive functions.

Lesch–Nyhan syndrome

Lesch–Nyhan syndrome is a rare X-linked recessive disorder caused by a deficiency of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

hypoxanthine-guanine phosphoribosyltransferase Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme encoded in humans by the ''HPRT1'' gene. HGPRT is a transferase that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This r ...

(HGPRT), leading to uric acid build-up and a deficiency in dopamine production.Lesch–Nyhan syndrome.
Genetics Home Reference. Retrieved on 2007-05-24. Within the first few years of life, extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control (

dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often int ...

), writhing motions ( choreoathetosis) and arching of the spine ( opisthotonus). The resemblance to dyskinetic cerebral palsy is apparent, and as a result most individuals are initially diagnosed as having cerebral palsy. Psychological behaviours can include rejecting desired treats or travel, repaying kindness with coldness or rage, failing to answer test questions correctly despite study and a desire to succeed or provoking anger from caregivers when affection is desired.Gualtieri, C. Thomas (2002). ''Brain Injury and Mental Retardation: Psychopharmacology and Neuropsychiatry'', p. 257. Lippincott Williams & Wilkins.

/ref>

Wilson's disease

Wilson's disease is an

autosomal recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

genetic disorder caused by a mutation in the copper-transport gene '' ATP7B'', leading to excess copper build-up. About half of those affected have neurological symptoms, including

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lew ...

(most commonly cogwheel rigidity, bradykinesia or slowed movements and a lack of balance) with or without a typical hand

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...

, masked facial expressions, slurred speech,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

Fahr's disease and calcifications

Fahr's disease is a rare, genetically dominant, inherited

neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...

disorder characterized by abnormal deposits of

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

, primarily in the

. About 0.3–1.5% of people have asymptomatic basal ganglia calcifications.

Blepharospasm

Blepharospasm is any abnormal contraction or twitch of the eyelid. Blepharospasm may come from abnormal functioning of the brain's basal ganglia.

Research

Gene therapy

Many disorders of the basal ganglia are due to the dysfunction of a localized area. For this reason, gene therapy seems viable for neurodegenerative disorders. Gene therapy is performed by replacing diseased phenotypes with new genetic material. This process is still in the early stages but early results are promising. An example of this therapy might involve implanting cells genetically modified to express tyrosine hydroxylase which, in the body, could be converted to dopamine. Increasing dopamine levels in the basal ganglia could possibly offset the effects of the Parkinson's Disease.

Ablation

Lesioning is the intentional destruction of neuronal cells in a particular area used for therapeutic purposes. Though this seems dangerous, vast improvements have been achieved in patients with movement disorders. The exact process generally involves unilateral lesioning in the sensorimotor territory of the GPi. This process is called pallidotomy. It is believed that the success of pallidotomies in reducing the effects of movement disorders may result from the interruption of abnormal neuronal activity in the GPi. This ablation technique can be viewed as simply removing a faulty piece of a circuit. With the damaged piece of the circuit removed, the healthy area of the circuit can continue normal function.

Deep brain stimulation

Deep brain stimulation involves inserting, via stereotaxic surgery, electrodes into the sensorimotor area of the brain. These electrodes emit high-frequency stimulation to the implanted areas. Bilateral implantation is necessary for symmetric results as well as the ability to reduce the intensity and duration of off-periods as well increase the duration of on-periods. The most effective structures used for implantations for deep brain stimulation are the internal globus pallidus (GPi) and the subthalamic nucleus (STN). This is because it is safer and more effective to alter the influence of the basal ganglia on the thalamocortical nuclei than directly altering neural activity in upper motor neuron circuits. Deep brain stimulation is a more complicated process than other therapies such as ablation. Evidence suggests that benefits of STN deep brain stimulation is due to the activation of efferents and the modulation of discharge patterns in the GPi that are propagated throughout the thalamocorical pathways. The ability to adjust stimulation protocols lends this treatment to a variety of disorders due its ability to alter the activity of basal ganglia circuits.

References

External links

{{CNS diseases of the nervous system Brain disorders