The zona incerta (ZI) is a horizontally elongated region of

gray matter Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distingui ...

in the subthalamus below 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, ...

. Its connections project extensively over 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 ...

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 ...

down into the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...

. Its function is unknown, though several potential functions related to "limbic–motor integration" have been proposed, such as controlling visceral activity and pain; gating sensory input and synchronizing cortical and subcortical brain rhythms. Its dysfunction may play a role in central pain syndrome. It has also been identified as a promising

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 ...

therapy target for treating

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 ...

. Its existence was first described by

Auguste Forel Auguste-Henri Forel (1 September 1848 – 27 July 1931) was a Swiss myrmecologist, neuroanatomist, psychiatrist and eugenicist, notable for his investigations into the structure of the human brain and that of ants. For example, he is considere ...

in 1877 as a "region of which nothing certain can be said". A hundred and thirty years later in 2007, Nadia Urbain and Martin Deschênes of

Université Laval Université Laval is a public research university in Quebec City, Quebec, Canada. The university was founded by royal charter issued by Queen Victoria in 1852, with roots in the founding of the Séminaire de Québec in 1663 by François de Montm ...

noted that the "zona incerta is among the least studied regions of the brain; its name does not even appear in the index of many textbooks."

Structure

This nucleus is located medially 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 ...

, ventral to the

, and is contiguous with the

thalamic reticular nucleus The thalamic reticular nucleus is part of the ventral thalamus that forms a capsule around the thalamus laterally. However, recent evidence from mice and fish question this statement and define it as a dorsal thalamic structure. It is separated fro ...

. The nucleus separates the lenticular fasciculus from the thalamic fasciculus (also known as the "field H1 of Forel") . Its cells are very heterogeneous differing widely in their shape and size. Its chemoarchitecture is also diverse containing up to 20 different types of neurochemically defined cells. It has been noted that "There are few diencephalic regions that have as much cellular and neurochemical diversity". In the rat four areas are usually identified. * a rostral sector that has densely packed spindle-shaped cells and scattered larger oval shaped cells. * a dorsal sector that has medium-sized oval-shaped cells. * a ventral sector made up of medium-sized multipolar or fusiform shaped cells that are more densely packed than the cells in the dorsal sector * a caudal sector made up of small and medium-sized somata that are either multipolar, fusiform or rounded in shape, together with a group of very large multipolar-shaped cells located medially. This is sometimes called the motor part of the zona incerta nucleus. This is the area targeted by deep brain stimulation area when the zona incerta is targeted in the treatment of Parkinson Disease. These areas lack clear cell-free borders and merge into each other. Zona incerta neurons have dendrites with a wide span 0.8 mm and their axons give off collaterals that arborized locally within the zona incerta providing a means for

lateral inhibition In neurobiology, lateral inhibition is the capacity of an excited neuron to reduce the activity of its neighbors. Lateral inhibition disables the spreading of action potentials from excited neurons to neighboring neurons in the lateral direction ...

. The ventral area of the zona incerta has been described as having "a network of GABAergic cells with widespread interconnections, so that cells in one subsector may influence the activity of cells in a different subsector". The zona incerta together with the hypothalamus is one of the two areas of the brain that produces the neuropeptide

melanin concentrating hormone Melanin-concentrating hormone (MCH), also known as pro-melanin stimulating hormone (PMCH), is a cyclic 19-amino acid orexigenic hypothalamic peptide originally isolated from the pituitary gland of teleost fish, where it controls skin pigmentation ...

. Dopaminergic ones are also more prevalent. There are in addition populations of cells producing somatostatin, angiotensin II and melanocyte stimulating hormone.

Connections

The zona incerta has connections to the

, diencephalon,

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 ...

, brainstem and

. ;Cerebral cortex Projections to the zona incerta arise across the cortical mantel from the

frontal Front may refer to: Arts, entertainment, and media Films * ''The Front'' (1943 film), a 1943 Soviet drama film * ''The Front'', 1976 film Music * The Front (band), an American rock band signed to Columbia Records and active in the 1980s and e ...

to the

occipital lobe The occipital lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The name derives from its position at the back of the head, from the Latin ''ob'', "behind", and ''caput'', "head". The occipital lobe is the vi ...

s. The heaviest projections are from cingulate cortex, frontal and parietal areas, but also projections from the medial

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46 ...

have been reported. The head area of the body seems from these areas to have the largest representation in the zona incerta. These projections preferentially go to

cortical layer 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 of ...

I neurons. There are projections from the zona incerta back to the cerebral cortex. ;Diencephalon Projections with the diencephalon are reciprocal and mainly to the

such as the intralaminar nucleus ( parafascicular nucleus and central lateral nucleus) and higher-order nuclei such as the lateral posterior nucleus. The zona incerta avoids the thalamus nuclei of the primary sensory areas such as the

ventral posterior nucleus The ventral posterior nucleus is the somato-sensory relay nucleus in thalamus of the brain. Input and output The ventral posterior nucleus receives neuronal input from the medial lemniscus, spinothalamic tracts, and trigeminothalamic tract. It p ...

of the somatosensory system and the

lateral geniculate In neuroanatomy, the lateral geniculate nucleus (LGN; also called the lateral geniculate body or lateral geniculate complex) is a structure in the thalamus and a key component of the mammalian visual pathway. It is a small, ovoid, ventral projec ...

of the visual system. Rostral zona incerta also sends inhibitory projections to paraventricular thalamus with GABAergic neurotransmission. ;Hypothalamus Projections to the hypothalamus through incertohypothalamic pathway go mainly to the paraventricular nucleus areas in the

anterior hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus i ...

lateral hypothalamus The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognit ...

, lateral

preoptic area The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular). Functions The preoptic area is responsible for ther ...

, horizontal diagonal band of Broca, and the parvocellular region of the paraventricular nucleus. ;Basal ganglia Zona incerta is connected in the basal ganglia to the substantia nigra (both

pars compacta The pars compacta (SNpc) is a portion of the ''substantia nigra'', located in the midbrain. It is formed by dopaminergic neurons and located medial to the pars reticulata. Parkinson's disease is characterized by the death of dopaminergic neuron ...

and

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 ...

) and

pedunculopontine tegmental nucleus The pedunculopontine nucleus (PPN) or pedunculopontine tegmental nucleus (PPT or PPTg) is a collection of neurons located in the upper pons in the brainstem. It lies caudal to the substantia nigra and adjacent to the superior cerebellar peduncle. ...

(but only its pars dissipata area). It also has less important connections to the entopeduncular nucleus and globus pallidus. These projections 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 ...

and excitatory rather than GABAergic and inhibitory. The zona incerta also receives input from these areas. ;Cerebellum The cerebellum sends a significant number of fibers to the zona incerta. These projections originate from various cerebellar nuclei and are glutamatergic. Given the cerebellar contributions to motor learning, timing and coordination, the interactions between the cerebellum with the zona incerta are likely to have profound influence on motor functions. ;Brainstem Zona incerta receives input from many parts of the brainstem nuclei including the

periaqueductal gray The periaqueductal gray (PAG, also known as the central gray) is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for d ...

, raphe nuclei,

, and the deep layers of the superior colliculus. It is regulated by inputs from brainstem

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cati ...

nuclei such as the Laterodorsal tegmental nucleus and pedunculopontine nucleus upon its neuron’s

muscarinic receptors Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...

. The rostral zona incerta also innervates the dorsolateral and ventrolateral compartments of the

. ;Spinal cord Zona incerta afferents terminate within the

gray matter, particularly the anterior horn, while spinal projections back to the zona incerta arise from cells located across the posterior horn and intermediate gray. ;Other Zona incerta also has connections to the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verte ...

basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal b ...

, the

osmoreceptor An osmoreceptor is a sensory receptor primarily found in the hypothalamus of most homeothermic organisms that detects changes in osmotic pressure. Osmoreceptors can be found in several structures, including two of the circumventricular organs – ...

s in the

subfornical organ The subfornical organ (SFO) is one of the circumventricular organs of the brain. Its name comes from its location on the ventral surface of the fornix near the interventricular foramina (foramina of Monro), which interconnect the lateral ventr ...

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...

posterior pituitary The posterior pituitary (or neurohypophysis) is the posterior lobe of the pituitary gland which is part of the endocrine system. The posterior pituitary is not glandular as is the anterior pituitary. Instead, it is largely a collection of axonal ...

and

habenula In neuroanatomy, habenula (diminutive of Latin ''habena'' meaning rein) originally denoted the stalk of the pineal gland (pineal habenula; pedunculus of pineal body), but gradually came to refer to a neighboring group of nerve cells with which the ...

. Some of these projections appear in register; the representation of the same body part in cortex and spinal cord connect to the same areas in the zona incerta. This is possibly so with the superior colliculus.

Function

;Visceral survival activities. Zona incerta controls such activities as water and food intake, sexuality and cardiovascular activity. This control is related to its effects upon the nearby posterior hypothalamus with which it shares similar connections and neurochemically defined cell types. Besides, activation of GABA neurons in rostral zona incerta evokes binge eating behavior with a preference to sweet and high-fat food. The inhibitory projection from zona incerta to paraventricular thalamus contributes to binge-like eating produced by zona incerta GABA neuron activation. Zona incerta has also been found to modulate both innate and learned defensive behaviors through its projections to the excitatory neurons of the dorsolateral and ventrolateral compartments of the

. Activation of the GABAergic neurons in the rostral zona incerta reduces sound-induced innate flight response and conditioned freezing response. The zona incerta receives pain input through the

spinothalamic tract The spinothalamic tract is a part of the anterolateral system or the ventrolateral system, a sensory pathway to the thalamus. From the ventral posterolateral nucleus in the thalamus, sensory information is relayed upward to the somatosensory co ...

and this has been shown to control the activity of the pain transmission pathway in the posterior thalamus. Electrical or chemical stimulation of the zona incerta creates limbic-related movements, such as those associated with defense orientation and copulation. ;Sensory-motor activities. At rest sensory input to the higher sensory areas of the cerebral cortex is gated through the thalamus. It has moreover been proposed that the zona incerta provides a top-down disinhibitory mechanism of this gating when there is sensory-motor activity such as the tactile use of whiskers. This has also been linked to sensory gating changes between sleep and waking. In this occurs a zona incerta mediated inhibition of thalamic nuclei such the somatosensory posterior medial thalamus. This is most strong when

input to the zona incerta is reduced as during slow-wave sleep and during anesthesia. The consequence of this has been explained upon information processing:

As a result, posterior medial thalamus neurons fail to respond to ascending sensory inputs, and function primarily in "higher-order" mode, concerned with relaying trans-cortical information. By contrast, increased cholinergic activity during wakefulness and enhanced vigilance suppresses zona incerta -mediated inhibition, thereby ungating posterior thalamus responses to ascending inputs.

The zona incerta projects to the superior colliculus and these link to the initiation of orientating eye and head movements. In monkeys for example neuronal activity in the zona incerta "pauses" before the start of a saccade and resumes at the end of a saccade. ;Synchronizing cortical and subcortical brain rhythms and integration. The GABAergic input received from the cerebral cortex has been suggested to synchronize thalamocortical and brainstem rhythms by providing a link between basal ganglia output and the cerebello-thalamo cortical loop. This allows it to synchronize oscillations generate by the basal ganglia during the preparation and execution of intended movements. One function of the loop is to carry movement instructions to the motor cortex through zona incerta output to the ventral lateral nucleus neurons in the cerebello-thalamocortical loop and to brainstem motor neurons in the medial reticular formation and midbrain extrapyramidal area. This acts to synchronize the basal ganglia areas involved in planning and execution of the movement with those in the brainstem controlling axial and proximal limb muscles with those areas in the motor cortex that control distal limb movements. ;Synthesis John Mitrofanis at the

University of Sydney The University of Sydney (USYD), also known as Sydney University, or informally Sydney Uni, is a public research university located in Sydney, Australia. Founded in 1850, it is the oldest university in Australia and is one of the country's ...

has proposed a general theory that might underlie some of the above.

The zona incerta is in a position to form a primal synaptic interface of the diencephalon, linking diverse sensory channels to appropriate visceral, arousal, attention and posture-locomotion responses. The different sensory inputs, whether exteroreceptive (somatic) or interoreceptive (visceral), influence these activities by driving zona incerta cells with different projection patterns and functions; each of these cells may be located in different sectors of the zone… In essence, it is suggested that the zona incerta has the pathways to integrate both exteroreceptive (e.g. somatosensory) and interoreceptive (e.g. thirst) sensory challenges, so that visceral activity, arousal, attention and/or posture locomotion are altered and/or generated. The zona incerta could form a neural niche in the thalamus from where these responses are "recruited" immediately, as to give an instant response.

Clinical significance

Parkinson's disease

might disrupt the zona incerta as it is hyperactive in parkinsonian experimental animals. In humans with Parkinson's disease, surgical lesion of the zona incerta alleviates their parkinsonian motor symptoms.

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 ...

of the subthalamic nucleus in those with Parkinson's disease has identified the zona incerta as a promising target area for effective therapy. Unlike deep bilateral stimulation of the ventral lateral nucleus such stimulation of the zona incerta improves all aspects of tremor including both the distal and proximal parts of limbs and the body more generally. This also occurs without

dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...

and disequilibrium as this stimulation does not interrupt

proprioceptive Proprioception ( ), also referred to as kinaesthesia (or kinesthesia), is the sense of self-movement, force, and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by proprioceptors, mechanosensory neurons ...

sensation and the processing of the

fine motor skill Fine motor skill (or dexterity) is the coordination of small muscles in movement with the eyes, hands and fingers. The complex levels of manual dexterity that humans exhibit can be related to the nervous system. Fine motor skills aid in the growt ...

movements of

vocal cord In humans, vocal cords, also known as vocal folds or voice reeds, are folds of throat tissues that are key in creating sounds through vocalization. The size of vocal cords affects the pitch of voice. Open when breathing and vibrating for speec ...

s. Researchers observed that "The ventral lateral nucleus has long been established as an effective surgical target for controlling distal limb tremor, including Parkinson Disease tremor. However, because it receives predominantly cerebellar afferents and no direct basal ganglia afferents, the reason why it is effective in controlling Parkinson Disease tremor has remained a paradox. The conduction of abnormal oscillations generated in the basal ganglia in Parkinson Disease to the ventral lateral nucleus via zona incerta would therefore explain this paradox and also explain why we observed such a potent anti-tremor effect from stimulating zona incerta in our patients with Parkinson Disease" The study further noted that deep brain stimulation upon the zona incerta "is effective in suppressing all components of tremor affecting both the distal and proximal part of the body. These results, if replicated in larger randomised controlled studies, have important implications for our current surgical management of patients with tremor and point to a more promising target area than the ventral lateral nucleus of the thalamus."

Central pain syndrome

Central pain syndrome is pain initiated or caused by injury or dysfunction in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. Recent research suggests that the development and maintenance of such pain could link to abnormal inhibitory regulation by the zona incerta of the posterior thalamus. It has been suggested that there exists

a significant suppression of both spontaneous and evoked activity in inhibitory neurons in zona incerta and abnormally high spontaneous and evoked activity of neurons in posterior thalamus in animals with central pain syndrome. The positive association between behavioral and neurophysiological thresholds in rats with central pain syndrome is consistent with a causal role for suppressed incerto-thalamic inputs in central pain syndrome.

References

External links

*
Sectional Atlas: Posterior Diencephalon at Habenula Nucleus
{{DEFAULTSORT:Zona Incerta Brainstem Subthalamus