Basal ganglia disease - AbsoluteAstronomy.com

Basal ganglia disease refers to a group of physical dysfunctions that occur when the group of nuclei in the brain known as the basal ganglia

Basal ganglia

The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...

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

Neuron

A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

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 thalamocortical projection neurons become too inhibited and one cannot initiate voluntary movement. These disorders are known as hypokinetic disorder

Hypokinesia

Hypokinesia refers to decreased bodily movement. It is associated with basal ganglia diseases , mental health disorders and prolonged inactivity due to illness, amongst other diseases.Hypokinesia describes a spectrum of disorders:...

s. However, a disorder leading to abnormally low output of the basal ganglia leads to relatively no inhibition of the thalamocortical projection neurons. This situation leads to an inability to suppress unwanted movements. These disorders are known as hyperkinetic disorders. Currently, reasons for abnormal increases or decreases of basal ganglia output are poorly 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) and Tourette syndrome

Tourette syndrome

Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...

Basal Ganglia Circuits

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

Striatum

The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...

, (composed of the putamen

Putamen

The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...

and caudate nucleus

Caudate nucleus

The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...

), globus pallidus

Globus pallidus

The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...

, substantia nigra

Substantia nigra

The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...

, and the subthalamic nucleus

Subthalamic nucleus

The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. Anatomically, it is the major part of subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also...

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

Cerebral cortex

The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

, and project information via the thalamus

Thalamus

The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...

to the motor cortex

Motor cortex

Motor cortex is a term that describes regions of the cerebral cortex involved in the planning, control, and execution of voluntary motor functions.-Anatomy of the motor cortex :The motor cortex can be divided into four main parts:...

. New research shows that the basal ganglia can be modeled as a group of components of parallel, reentrant 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

Limbic system

The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...

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

Putamen

directly to the internal segment of the globus pallidus

Globus pallidus

(GPi) or the substantia nigra

Substantia nigra

, pars reticulata

Pars reticulata

-Anatomy:Neurons in the pars reticulata are much less densely packed than those in the pars compacta . They are smaller and thinner than the dopaminergic neurons and conversely identical and morphologically similar to the pallidal neurons...

(SNr) and are then directed toward the ventral anterior nucleus

Ventral anterior nucleus

-Inputs and outputs:The ventral anterior nucleus receives neuronal inputs from the basal ganglia which includes the substantia nigra and the globus pallidus. It also has inputs from the cerebellum. It sends out neuronal input to the supplementary motor cortex and to primary motor...

(VA), and the ventral lateral nucleus

Ventral lateral nucleus

-Inputs and outputs:It receives neuronal inputs from the basal ganglia which includes the substantia nigra and the globus pallidus . It also has inputs from the cerebellum ....

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

Striatum

and 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 acitivity 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) and the subthalamic nucleus (STN). 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 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.

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 most noted hypokinetic disorder is Parkinson’s Disease. Parkinsonism is a disorder characterized by muscular rigidity, and bradykinesia (tremors at rest). This disorder is due to a lack of dopamine in the basal ganglia. This lack of dopamine causes neuronal discharge abnormalities within the motor circuit. This is apparent through abnormalities within cortical activation patterns during movement tasks. A lack of dopamine in the non-motor areas of the brain also leads to depression because dopamine in the pleasure center of the brain is responsible for the feeling of happiness. Current research shows that dopamine depletion is responsible for increased inhibition of GPe, disinhibition of STN, and subsequent increased excitation of GPi and SNr. This increased output of the basal ganglia leads to increased inhibition of the thalamocortical neurons.

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 lead 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 a gene located on 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 STN, and therefore, reduced output of the basal ganglia. The neuronal degeneration eventually causes death within 10 to 20 years.

Dystonia

Dystonia is 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 lead 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 pallidotony has proven to serve as a useful treatment for Hemiballismus.

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

Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...

(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.

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.

Lesioning/ablation

Lesionsing is a term that signifies the destruction of neuronal cells in a particular area. 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

Pallidotomy

Pallidotomy is a procedure where a tiny electrical probe is placed in the globus pallidus , which is then heated to 80 degrees celsius for 60 seconds, to destroy a small area of brain cells...

. 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 Stimualtion

Deep brain stimulation involves inserting, via stereotaxic surgery

Stereotactic surgery

Stereotactic surgery or stereotaxy is a minimally invasive form of surgical intervention which makes use of a three-dimensional coordinates system to locate small targets inside the body and to perform on them some action such as ablation, biopsy, lesion, injection, stimulation, implantation,...

, 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 subthalmic 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

Upper motor neuron

Upper motor neurons are motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway, that is, any motor neurons that are not directly responsible for stimulating the target muscle...

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 do its ability to alter the activity of basal ganglia circuits.