Claustrum

The claustrum (Latin, meaning "to close" or "to shut") is a thin sheet of neurons and supporting glial cells in the brain that connects to the cerebral cortex and subcortical regions including the amygdala, hippocampus and thalamus. It is located between the insular cortex laterally and the putamen medially, encased by the extreme and external capsules respectively. Blood to the claustrum is supplied by the middle cerebral artery. Other hypotheses suggest that the claustrum plays a role in salience processing, to direct attention towards the most behaviorally relevant stimuli amongst the background noise. The claustrum is difficult to study given the limited number of individuals with claustral lesions and the poor resolution of neuroimaging.

The claustrum is made up of various cell types differing in size, shape and neurochemical composition. Five cell types exist, and a majority of these cells resemble pyramidal neurons found in the cortex. Within the claustrum, there is no laminar organization of cell types as in the cortical layers, and the cell bodies can be a pyramidal, fusiform or circular. As such, the claustrum is thought to play a role in combining different information modalities, potentially to support consciousness itself. Another proposed function of the claustrum is to differentiate between relevant and irrelevant information so that the latter can be ignored.

Cortical components of consciousness include the fronto-parietal cortex, cingulate and precuneus. Due to the claustrum's widespread connectivity to these areas, it is suggested that it may play a role in both attention and consciousness. The neural networks that mediate sustained attention and consciousness send inputs to the claustrum, and one case report in humans suggests that electrical stimulation near the claustrum reversibly disrupted the patient's conscious state.

Structure

The claustrum is a small bilateral gray matter structure (comprising roughly 0.25% of the cerebral cortex) located deep to the insular cortex and extreme capsule, and superficial to the external capsule and basal ganglia. though a meeting in 2019 of experts has posited a framework by which to refer to the structures across species. However, later work has suggested the claustrum has extensive connections to cortical and subcortical regions. More specifically, electrophysiological studies show extensive connections to thalamic nuclei and the basal ganglia, while isotopological reports have linked the claustrum with the prefrontal, frontal, parietal, temporal and occipital cortices. Additional studies have also looked at the relationship of the claustrum to well-described subcortical white matter tracts. Structures such as the corona radiata, occipitofrontal fasciculus and uncinate fasciculus project to the claustrum from frontal, pericentral, parietal and occipital regions. Reciprocal connections also exist with motor, somatosensory, auditory and visual cortical regions. Even with this extensive connectivity, most projections to and from the claustrum are ipsilateral (although there are still contralateral projections), and little evidence exists to describe its afferent or efferent connections with the brainstem and spinal cord. In summary, the cortical and subcortical connectivity of the claustrum implies that it is most involved with processing sensory information, as well as the physical and emotional state of an animal.

Microanatomy

Inputs to the claustrum are organized by modality, which include prefrontal, visual, auditory and somatomotor processing areas. In the same way that the morphology of neurons in the Rexed laminae of the spinal cord is indicative of function, the visual, auditory and somatomotor regions within the claustrum share similar neurons with specific functional characteristics. For example, the portion of the claustrum that processes visual information (primarily synthesizing afferent fibers concerned with our peripheral visual field) is comprised by a majority of binocular cells that have "elongated receptive fields and no orientation selectivity".

This focus on the peripheral sensory system is not an isolated occurrence, as most sensory afferents entering the claustrum bring peripheral sensory information. Moreover, the claustrum possesses a distinct topological organization for each sensory modality as well as the dense connectivity it shares with frontal cortices. For example, there is a retinotopic organization within the visual processing area of the claustrum that mirrors that of visual association cortices and V1, in a similar (yet less complicated) manner to the retinotopic conservation within the lateral geniculate nucleus. Local interneurons themselves are connected through both chemical and electrical synapses, allowing for widespread and synchronous inhibition of local claustrum circuitry. In recent studies of the claustrum in mice cortically-projecting excitatory claustrum neurons were found to form synapses across the anteroposterior axis and were biased toward neurons that do not share projection targets, with the possible function of joining the activity of different afferent modules. Finally, many studies show that the claustrum is best distinguished structurally by its prominent plexus of parvalbumin-positive fibers formed by parvalbumin-expressing inhibitory cell types.

Several approaches in mice have been used to assess claustrum cell types, including electrophysiological, morphological, genetic, and connectomic approaches. While no clear consensus has yet been reached regarding the exact number of excitatory cell types, recent studies have suggested that cortically- and subcortically-projecting claustrum neurons are likely distinct and vary along several metrics, such as their intrinsic electrophysiological profiles, afferent projections, and neuromodulatory profiles.

Function

The claustrum has been shown to have widespread activity to numerous cortical components, all of which have been associated with having components of consciousness and sustained attention. This is because of widespread connectivity to fronto-parietal areas, cingulate cortex, and thalami. Sustained attention is from the connections to the cingulate cortex, temporal cortex, and thalamus.

Crick and Koch suggest that the claustrum has a role similar to that of a conductor within an orchestra as it attempts to co-ordinate the function of all connections. and slow-wave sleep.

Attention

The claustrum has the differential ability to select between task-relevant information and task-irrelevant information to provide directed attention. It contains the highest density of connecting white matter tracts in the cortex. This supports the notion of networking and coordination among different regions of the brain. In humans this same effect can be observed. Stimulation of the left claustrum in humans has produced "a complete arrest of volitional behavior, unresponsiveness, and amnesia without negative motor symptoms, or mere aphasia" suggesting the involvement in consciousness. As well, increased signal intensity is associated with focal dyscognitive seizures, which are seizures that elicit impairment of awareness or consciousness without convulsions. The individual becomes unaware of his or her environment, and the seizure will manifest as a blank or empty stare for a window of time.

Using an operant conditioning task combined with HFS of the claustrum resulted in significant behavioural changes of rats; this included modulated motor responses, inactivity and decreased responsiveness. Inverse correlations between grey matter volume and severity of hallucinations in the context of auditory hallucinations of schizophrenia has been supported. As well, to see the total loss of function of the claustrum, lesions to both claustrums on each hemisphere would need to occur.

A 2020 study involving artificial activation of the claustrum by optogenetic light stimulation silenced brain activity across the cortex, a phenomenon known as a "Down state," which can be seen when mice are sleeping or resting awake (quiet wakefulness).

Psilocybin

The claustrum expresses a high density of 5-HT_2A receptors, meaning it is significantly affected by serotonergic psychedelics like psilocybin. Psilocybin appears to affect the functional connectivity of the claustrum with the default mode network (DMN), and the fronto-parietal task control network (FPTC). Psilocybin was found to significantly decrease functional connectivity of the right claustrum with the default mode network, and increase right claustrum connectivity with the fronto-parietal task control network.

Parkinsonism

A team of investigators led by neuroscientists at Beth Israel Deaconess Medical Center has identified lesions in the claustrum as the likely origin of parkinsonism across different conditions. The team used a novel methodology called lesion network mapping to discover the origins of parkinsonism in 29 patients whose symptoms were not the result of Parkinson's disease but rather attributed to a brain lesion – an abnormality or injury to the brain visible on brain imaging. The mapping of the 29 lesions – which were located in different regions of the brain – revealed that connectivity to the claustrum was the single most sensitive and specific marker of lesion-induced parkinsonism.

Anxiety and stress

In mice, suppression of claustrum appears to attenuate anxiety/stress and increase chronic stress-resistance.

Other animals

In animals, through tract tracing, findings have shown that the claustrum has extensive connections throughout the cortex with sensory and motor regions along with the hippocampus. A variety of animal models have been used such as cats, rodents and monkeys.

thumb|Anatomy of a cat brain

Cats

In cats, high-frequency stimulation (HFS) of the claustrum can alter motor activity, induce autonomic changes, and precipitate an "inactivation syndrome" described as "decreased awareness". Recordings, primarily in cats and primates, show that claustral neurons respond to sensory stimuli and also respond during voluntary movements.

In terms of somatosensation, cat claustrum receives dense inputs from primary somatosensory cortex (S1), but weaker inputs from secondary somatosensory cortex (S2). The inputs from S1 overlap with inputs from primary motor cortex (at least those from the forepaw representations of both). Rodent claustrum does not receive input from S1 or S2, and is primarily driven by motor cortex.

Rodents

In rats, motor whisker areas receive input from the ipsilateral claustrum but will then project to the contralateral claustrum.