The subthalamic nucleus (STN) is a small lens-shaped

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

in the

brain A brain is an 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 vision. It is the most complex organ in a ve ...

where it is, from a functional point of view, part of 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 exter ...

system. In terms of anatomy, it is the major part of the subthalamus. As suggested by its name, the subthalamic nucleus is located

ventral Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...

to 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 directions, ...

. It is also dorsal to the substantia nigra and medial to the

internal capsule The internal capsule is a white matter structure situated in the inferomedial part of each cerebral hemisphere of the brain. It carries information past the basal ganglia, separating the caudate nucleus and the thalamus from the putamen and the ...

. It was first described by Jules Bernard Luys in 1865, and the term ''corpus Luysi'' or ''Luys' body'' is still sometimes used.

Anatomy

Structure

The principal type of

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. ...

found in the subthalamic nucleus has rather long, sparsely spiny

dendrite Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the ...

s. In the more centrally located neurons, the dendritic arbors have a more ellipsoidal shape. The dimensions of these arbors (1200 μm, 600 μm, and 300 μm) are similar across many species—including rat, cat, monkey and human—which is unusual. However, the number of neurons increases with brain size as well as the external dimensions of the nucleus. The principal neurons are

glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonis ...

, which give them a particular functional position in the basal ganglia system. In humans there are also a small number (about 7.5%) of GABAergic interneurons that participate in the local circuitry; however, the dendritic arbors of subthalamic neurons shy away from the border and primarily interact with one another. The structure of the subthalamic nucleus has not been fully elucidate yet, but it is likely composed of several internal domains. The primate subthalamic nucleus is often divided in three internal anatomical-functional domains. However, this so called ''tripartite model'' has been debated because it does not fully explain the complexity of the subthalamic nucleus in brain function.

Afferent axons

The subthalamic nucleus receives its main input from the

external globus pallidus The external globus pallidus (GPe or lateral globus pallidus) combines with the internal globus pallidus (GPi) to form the globus pallidus, an anatomical subset of the basal ganglia. Globus pallidus means "pale globe" in Latin, indicating its appe ...

(GPe), not so much through the ansa lenticularis as often said but by radiating fibers crossing the medial pallidum first and the internal capsule (see figure). These afferents are GABAergic, inhibiting neurons in the subthalamic nucleus. Excitatory, glutamatergic inputs come 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% consistin ...

(particularly the motor cortex), and from the pars parafascicularis of the central complex. The subthalamic nucleus also receives

neuromodulator Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second ...

y inputs, notably dopaminergic axons from the substantia nigra pars compacta. It also receives inputs from the pedunculopontine nucleus.

Efferent targets

The axons of subthalamic nucleus neurons leave the nucleus dorsally. The efferent axons are glutamatergic (excitatory). Except for the connection to the striatum (17.3% in macaques), most of the subthalamic principal neurons are multitargets and directed to the other elements of the core of the basal ganglia. Some send axons to the substantia nigra medially and to the medial and lateral nuclei of the pallidum laterally (3-target, 21.3%). Some are 2-target with the lateral pallidum and the substantia nigra (2.7%) or the lateral pallidum and the medial (48%). Less are single target for the lateral pallidum. In the pallidum, subthalamic terminals end in bands parallel to the pallidal border. When all axons reaching this target are added, the main efference of the subthalamic nucleus is, in 82.7% of the cases, clearly the

internal globus pallidus The internal globus pallidus (GPi or medial globus pallidus; in rodents its homologue is known as the entopeduncular nucleus) and the external globus pallidus (GPe) make up the globus pallidus. The GPi is one of the output nuclei of the basal gang ...

(GPi). Some researchers have reported internal

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...

collaterals. However, there is little functional evidence for this.

Physiology

Subthalamic nucleus

The first intracellular electrical recordings of subthalamic neurons were performed using sharp electrodes in a rat slice preparation. In these recordings three key observations were made, all three of which have dominated subsequent reports of subthalamic firing properties. The first observation was that, in the absence of current injection or synaptic stimulation, the majority of cells were spontaneously firing. The second observation is that these cells are capable of transiently firing at very high frequencies. The third observation concerns non-linear behaviors when cells are transiently depolarized after being hyperpolarized below –65mV. They are then able to engage voltage-gated calcium and sodium currents to fire bursts of action potentials. Several recent studies have focused on the autonomous pacemaking ability of subthalamic neurons. These cells are often referred to as "fast-spiking pacemakers", since they can generate spontaneous

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

s at rates of 80 to 90 Hz in primates. Oscillatory and synchronous activity is likely to be a typical pattern of discharge in subthalamic neurons recorded from patients and animal models characterized by the loss of dopaminergic cells in the substantia nigra pars compacta, which is the principal pathology that underlies

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 becom ...

Lateropallido-subthalamic system

Strong reciprocal connections link the subthalamic nucleus and the external segment of the globus pallidus. Both are fast-spiking pacemakers. Together, they are thought to constitute the "central pacemaker of the basal ganglia" with synchronous bursts. The connection of the lateral pallidum with the subthalamic nucleus is also the one in the

system where the reduction between emitter/receiving elements is likely the strongest. In terms of volume, in humans, the lateral pallidum measures 808 mm³, the subthalamic nucleus only 158 mm³. This translated in numbers of neurons represents a strong compression with loss of map precision. Some axons from the lateral pallidum go to the striatum. The activity of the medial pallidum is influenced by afferences from the lateral pallidum and from the subthalamic nucleus. The same for the

substantia nigra pars reticulata The pars reticulata (SNpr) is a portion of the substantia nigra and is located lateral to the pars compacta. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons (i.e., these neurons release GABA, which is ...

. The subthalamic nucleus sends axons to another regulator: the pedunculo-pontine complex (id). The lateropallido-subthalamic system is thought to play a key role in the generation of the patterns of activity seen in

Pathophysiology

Chronic stimulation of the STN, called

deep brain stimulation Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, through implanted electrodes, to specific targets in the brain (the brain nucleus ...

(DBS), is used to treat patients with Parkinson disease. The first to be stimulated are the terminal arborisations of afferent axons, which modify the activity of subthalamic neurons. However, it has been shown in thalamic slices from mice, that the stimulus also causes nearby astrocytes to release

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...

(ATP), a precursor to adenosine (through a catabolic process). In turn, adenosine A1 receptor activation depresses excitatory transmission in the thalamus, thus mimicking

ablation Ablation ( la, ablatio – removal) is removal or destruction of something from an object by vaporization, chipping, erosive processes or by other means. Examples of ablative materials are described below, and include spacecraft material for a ...

of the subthalamic nucleus. Unilateral destruction or disruption of the subthalamic nucleus — which can commonly occur via a small vessel stroke in patients with diabetes, hypertension, or a history of smoking – produces

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, ...

. As one of the STN's suspected functions is in impulse control, dysfunction in this region has been implicated in

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 ...

. Artificially stimulating the STN has shown some promise in correcting severe impulsive behavior and may later be used as an alternative treatment for the disorder.

Function

The function of the STN is unknown, but current theories place it as a component of the

control system that may perform action selection. It is thought to implement the so-called "hyperdirect pathway" of motor control, contrasting with the direct and indirect pathways implemented elsewhere in the basal ganglia. STN dysfunction has also been shown to increase impulsivity in individuals presented with two equally rewarding stimuli. Research has suggested that the subthalamus is an extrapyramidal center. It holds muscular responses in check, and damage may result in hemiballism (a violent flinging of the arm and leg on one side of the body). The physiological role of the STN has been for long hidden by its pathological role. But lately, the research on the physiology of the STN lead to the discovery that the STN is required to achieve intended movement, including locomotion, balance and motor coordination. It is indeed involved in stopping or interrupting on-going motor tasks. Moreover, STN excitation was generally correlated with significant reduction in locomotor activity, while in contrast, STN inhibition enhanced locomotion.

Additional images

File:Gray717.png, Coronal section of brain immediately in front of pons. Subthalamic nucleus labeled as "Nucleus of Luys".

References

{{DEFAULTSORT:Subthalamic Nucleus Subthalamus Basal ganglia