Human Claustrum Research Articles

The human claustrum tracks slow waves during sleep

Slow waves are a distinguishing feature of non-rapid-eye-movement (NREM) sleep, an evolutionarily conserved process critical for brain function. Non-human studies suggest that the claustrum, a small subcortical nucleus, coordinates slow waves. We show that, in contrast to neurons from other brain regions, claustrum neurons in the human brain increase their spiking activity and track slow waves during NREM sleep, suggesting that the claustrum plays a role in coordinating human sleep architecture.

High-resolution 7T fMRI reveals the visual zone of the human claustrum

Abstract The claustrum is a thin grey matter structure located between the insular cortex and the putamen. The function of the claustrum is largely unknown with diverse hypotheses ranging from multisensory integration and consciousness to attention and cognitive control. Much research on the function of the claustrum relies on invasive techniques in animal models, as the claustrum’s uniquely thin shape makes it difficult to image non-invasively in human subjects. In the current proof-of-concept study, we used high-resolution ultra-high field (7 Tesla) functional magnetic resonance imaging (fMRI) to measure activity in the human claustrum during the processing of naturalistic stimuli. We presented short video clips as visual only, auditory only or audiovisual conditions while participants performed a central fixation task. We found distinct visual responses in both the left and the right claustrum at a consistent spatial location across participants, hemispheres and sessions. We also found deactivations in response to auditory stimulation. These deactivations were confined to the right claustrum and did not overlap with visual activity. The deactivation in response to auditory stimulation demonstrates the complexity of claustrum’s functional organization and suggests functional differentiation within the claustrum. This is the first study to demonstrate sensory-specific effects within the human claustrum. It opens the possibility for studying the claustrum’s role in higher-level aspects of sensory processing in humans.

Human Claustrum Connections: Robust In Vivo Detection by DWI-Based Tractography in Two Large Samples.

Despite substantial neuroscience research in the last decade revealing the claustrum's prominent role in mammalian forebrain organization, as evidenced by its extraordinarily widespread connectivity pattern, claustrum studies in humans are rare. This is particularly true for studies focusing on claustrum connections. Two primary reasons may account for this situation: First, the intricate anatomy of the human claustrum located between the external and extreme capsule hinders straightforward and reliable structural delineation. In addition, the few studies that used diffusion-weighted-imaging (DWI)-based tractography could not clarify whether in vivo tractography consistently and reliably identifies claustrum connections in humans across different subjects, cohorts, imaging methods, and connectivity metrics. To address these issues, we combined a recently developed deep-learning-based claustrum segmentation tool with DWI-based tractography in two large adult cohorts: 81 healthy young adults from the human connectome project and 81 further healthy young participants from the Bavarian longitudinal study. Tracts between the claustrum and 13 cortical and 9 subcortical regions were reconstructed in each subject using probabilistic tractography. Probabilistic group average maps and different connectivity metrics were generated to assess the claustrum's connectivity profile as well as consistency and replicability of tractography. We found, across individuals, cohorts, DWI-protocols, and measures, consistent and replicable cortical and subcortical ipsi- and contralateral claustrum connections. This result demonstrates robust in vivo tractography of claustrum connections in humans, providing a base for further examinations of claustrum connectivity in health and disease.

The functional connectivity of the human claustrum, according to the Human Connectome Project database.

The claustrum is an irregular and fine sheet of grey matter in the basolateral telencephalon present in almost all mammals. The claustrum has been the object of several studies using animal models and, more recently, in human beings using neuroimaging. One of the most extended cognitive processes attributed to the claustrum is the salience process, which is also related to the insular cortex. In the same way, studies with human subjects and functional magnetic resonance imaging have reported the coactivation of the claustrum/insular cortex in the integration of sensory signals. This coactivation has been reported in the left claustrum/insular cortex or in the right claustrum/insular cortex. The asymmetry has been reported in task studies and literature related to neurological disorders such as Alzheimer's disease and schizophrenia, relating the severity of delusions with the reduction in left claustral volume. We present a functional connectivity study of the claustrum. Resting-state functional and anatomical MRI data from 100 healthy subjects were analyzed; taken from the Human Connectome Project (HCP, NIH Blueprint: The Human Connectome Project), with 2x2x2 mm3 voxel resolution. We hypothesize that 1) the claustrum is a node involved in different brain networks, 2) the functional connectivity pattern of the claustrum is different from the insular cortex's pattern, and 3) the asymmetry is present in the claustrum's functional connectivity. Our findings include at least three brain networks related to the claustrum. We found functional connectivity between the claustrum, frontoparietal network, and the default mode network as a distinctive attribute. The functional connectivity between the right claustrum with the frontoparietal network and the dorsal attention network supports the hypothesis of claustral asymmetry. These findings provide functional evidence, suggesting that the claustrum is coupled with the frontoparietal network serving together to instantiate new task states by flexibly modulating and interacting with other control and processing networks.

Aberrant claustrum structure in preterm-born neonates: an MRI study

The human claustrum is a gray matter structure in the white matter between insula and striatum. Previous analysis found altered claustrum microstructure in very preterm-born adults associated with lower cognitive performance. As the claustrum development is related to hypoxia–ischemia sensitive transient cell populations being at-risk in premature birth, we hypothesized that claustrum structure is already altered in preterm-born neonates.We studied anatomical and diffusion-weighted MRIs of 83 preterm- and 83 term-born neonates at term-equivalent age. Additionally, claustrum development was analyzed both in a spectrum of 377 term-born neonates and longitudinally in 53 preterm-born subjects. Data was provided by the developing Human Connectome Project.Claustrum development showed increasing volume, increasing fractional anisotropy (FA), and decreasing mean diffusivity (MD) around term both across term- and preterm-born neonates. Relative to term-born ones, preterm-born neonates had (i) increased absolute and relative claustrum volumes, both indicating increased cellular and/or extracellular matter and being in contrast to other subcortical gray matter regions of decreased volumes such as thalamus; (ii) lower claustrum FA and higher claustrum MD, pointing at increased extracellular matrix and impaired axonal integrity; and (iii) aberrant covariance between claustrum FA and MD, respectively, and that of distributed gray matter regions, hinting at relatively altered claustrum microstructure.Results together demonstrate specifically aberrant claustrum structure in preterm-born neonates, suggesting altered claustrum development in prematurity, potentially relevant for later cognitive performance.

Functional Aspects of the Human Claustrum – Literary Review

Functional Aspects of the Human Claustrum – Literary Review

Automated claustrum segmentation in human brain MRI using deep learning

In the last two decades, neuroscience has produced intriguing evidence for a central role of the claustrum in mammalian forebrain structure and function. However, relatively few in vivo studies of the claustrum exist in humans. A reason for this may be the delicate and sheet‐like structure of the claustrum lying between the insular cortex and the putamen, which makes it not amenable to conventional segmentation methods. Recently, Deep Learning (DL) based approaches have been successfully introduced for automated segmentation of complex, subcortical brain structures. In the following, we present a multi‐view DL‐based approach to segment the claustrum in T1‐weighted MRI scans. We trained and evaluated the proposed method in 181 individuals, using bilateral manual claustrum annotations by an expert neuroradiologist as reference standard. Cross‐validation experiments yielded median volumetric similarity, robust Hausdorff distance, and Dice score of 93.3%, 1.41 mm, and 71.8%, respectively, representing equal or superior segmentation performance compared to human intra‐rater reliability. The leave‐one‐scanner‐out evaluation showed good transferability of the algorithm to images from unseen scanners at slightly inferior performance. Furthermore, we found that DL‐based claustrum segmentation benefits from multi‐view information and requires a sample size of around 75 MRI scans in the training set. We conclude that the developed algorithm allows for robust automated claustrum segmentation and thus yields considerable potential for facilitating MRI‐based research of the human claustrum. The software and models of our method are made publicly available.

Automatic Segmentation of the Dorsal Claustrum in Humans Using in vivo High-Resolution MRI.

The claustrum is a thin sheet of neurons enclosed by white matter and situated between the insula and the putamen. It is highly interconnected with sensory, frontal, and subcortical regions. The deep location of the claustrum, with its fine structure, has limited the degree to which it could be studied in vivo. Particularly in humans, identifying the claustrum using magnetic resonance imaging (MRI) is extremely challenging, even manually. Therefore, automatic segmentation of the claustrum is an invaluable step toward enabling extensive and reproducible research of the anatomy and function of the human claustrum. In this study, we developed an automatic algorithm for segmenting the human dorsal claustrum in vivo using high-resolution MRI. Using this algorithm, we segmented the dorsal claustrum bilaterally in 1068 subjects of the Human Connectome Project Young Adult dataset, a publicly available high-resolution MRI dataset. We found good agreement between the automatic and manual segmentations performed by 2 observers in 10 subjects. We demonstrate the use of the segmentation in analyzing the covariation of the dorsal claustrum with other brain regions, in terms of macro- and microstructure. We identified several covariance networks associated with the dorsal claustrum. We provide an online repository of 1068 bilateral dorsal claustrum segmentations.

In search of common developmental and evolutionary origin of the claustrum and subplate.

The human claustrum, a major hub of widespread neocortical connections, is a thin, bilateral sheet of gray matter located between the insular cortex and the striatum. The subplate is a largely transient cortical structure that contains some of the earliest generated neurons of the cerebral cortex and has important developmental functions to establish intra- and extracortical connections. In human and macaque some subplate cells undergo regulated cell death, but some remain as interstitial white matter cells. In mouse and rat brains a compact layer is formed, Layer 6b, and it remains underneath the cortex, adjacent to the white matter. Whether Layer 6b in rodents is homologous to primate subplate or interstitial white matter cells is still debated. Gene expression patterns, such as those of Nurr1/Nr4a2, have suggested that the rodent subplate and the persistent subplate cells in Layer 6b and the claustrum might have similar origins. Moreover, the birthdates of the claustrum and Layer 6b are similarly precocious in mice. These observations prompted our speculations on the common developmental and evolutionary origin of the claustrum and the subplate. Here we systematically compare the currently available data on cytoarchitecture, evolutionary origin, gene expression, cell types, birthdates, neurogenesis, lineage and migration, circuit connectivity, and cell death of the neurons that contribute to the claustrum and subplate. Based on their similarities and differences we propose a partially common early evolutionary origin of the cells that become claustrum and subplate, a likely scenario that is shared in these cell populations across all amniotes.

Electrical stimulation of the human claustrum

To probe the causal importance of the claustrum in human subjective experience, we delivered electrical pulses either unilaterally or bilaterally within the core of this structure in five neurosurgical patients implanted with intracranial electrodes. Patients reported subjective experiences in various sensory domains and exhibited reflexive movements after real but not sham stimulations. However, none of the stimulations evoked loss of consciousness or lack of subjective awareness even with strong bilateral stimulations. Our study is the first to probe the effects of electrical perturbation of human claustrum through electrodes implanted within the claustrum itself and provide novel causal information about the human claustrum.

Resting state functional connectivity and cognitive task-related activation of the human claustrum

Structural and functional analyses of the human claustrum, a poorly understood telencephalic gray matter structure, are hampered by its sheet-like anatomical arrangement. Here, we first describe a functional magnetic resonance imaging (fMRI) method to reveal claustrum signal with no linear relationship with adjacent regions in human subjects. We applied this approach to resting state functional connectivity (RSFC) analysis of the claustrum at high resolution (1.5 mm isotropic voxels) using a 7T dataset (n = 20) and a separate 3T dataset for replication (n = 35). We then assessed claustrum activation during performance of a cognitive task, the multi-source interference task, at 3T (n = 33). Extensive functional connectivity was observed between claustrum and cortical regions associated with cognitive control, including anterior cingulate, prefrontal and parietal cortices. Cognitive task performance was associated with widespread activation and deactivation that overlapped with the cortical areas showing functional connectivity to the claustrum. Furthermore, during high cognitive conflict conditions of the task, the claustrum was significantly activated at the onset of the task, but not during the remainder of the difficult condition. Both of these findings suggest that the human claustrum can be functionally isolated with fMRI, and that it may play a role in cognitive control, and specifically task switching, independent of sensorimotor processing.

Comparative investigation of neuronal nitric oxide synthase immunoreactivity in rat and human claustrum

We compared the distribution, density and morphological characteristics of nitric oxide synthase-immunoreactive (NOS-ir) neurons in the rat and human claustrum. These neurons were categorized by diameter into three main types: large, medium and small. In the human claustrum, large neurons ranged from 26 to 40μm in diameter, medium neurons from 20 to 25μm and small neurons from 13 to 19μm. In the rat claustrum, large neurons ranged from 19 to 23μm in diameter, medium neurons from 15 to 18μm and small neurons from 10 to 14μm. The cell bodies of large and medium neurons varied broadly in shape – multipolar, elliptical, bipolar and irregular, consistent with a projection neuron phenotype. The small neurons were most seen as being oval or elliptical in shape, resembling an interneuron phenotype. Based on a quantitative comparison of their dendritic characteristics, the NOS-ir neurons of humans and rats displayed a statistically significant difference.

Dopamine and noradrenaline, but not serotonin, in the human claustrum are greatly reduced in patients with Parkinson's disease: possible functional implications

In the human brain, the claustrum is a small subcortical telencephalic nucleus, situated between the insular cortex and the putamen. A plethora of neuroanatomical studies have shown the existence of dense, widespread, bidirectional and bilateral monosynaptic interconnections between the claustrum and most cortical areas. A rapidly growing body of experimental evidence points to the integrative role of claustrum in complex brain functions, from motor to cognitive. Here, we examined for the first time, the behaviour of the classical monoamine neurotransmitters dopamine, noradrenaline and serotonin in the claustrum of the normal autopsied human brain and of patients who died with idiopathic Parkinson's disease (PD). We found in the normal claustrum substantial amounts of all three monoamine neurotransmitters, substantiating the existence of the respective brain stem afferents to the claustrum. In PD, the levels of dopamine and noradrenaline were greatly reduced by 93% and 81%, respectively. Serotonin levels remained unchanged. We propose that by virtue of their projections to the claustrum, the brain stem dopamine, noradrenaline and serotonin systems interact directly with the cortico-claustro-cortical information processing mechanisms, by-passing their (parallel) routes via the basal ganglia-thalamo-cortical circuits. We propose that loss of dopamine and noradrenaline in the PD claustrum is critical in the aetiology of both the motor and the non-motor symptoms of PD. This article is protected by copyright. All rights reserved.

The claustrum: Considerations regarding its anatomy, functions and a programme for research.

The claustrum is a highly conserved but enigmatic structure, with connections to the entire cortical mantle, as well as to an extended and extensive range of heterogeneous subcortical structures. Indeed, the human claustrum is thought to have the highest number of connections per millimetre cubed of any other brain region. While there have been relatively few functional investigations of the claustrum, many theoretical suggestions have been put forward, including speculation that it plays a key role in the generation of consciousness in the mammalian brain. Other claims have been more circumspect, suggesting that the claustrum has a particular role in, for example, orchestrating cortical activity, spatial information processing or decision making. Here, we selectively review certain key recent anatomical, electrophysiological and behavioural experimental advances in claustral research and present evidence that calls for a reassessment of its anatomical boundaries in the rodent. We conclude with some open questions for future research.

Dopamine and noradrenaline, but not serotonin, in the human claustrum are greatly reduced in patients with Parkinson's disease: possible functional implications

In the human brain, the claustrum is a small subcortical telencephalic nucleus, situated between the insular cortex and the putamen. A plethora of neuroanatomical studies have shown the existence of dense, widespread, bidirectional and bilateral monosynaptic interconnections between the claustrum and most cortical areas. A rapidly growing body of experimental evidence points to the integrative role of claustrum in complex brain functions, from motor to cognitive. Here, we examined for the first time, the behaviour of the classical monoamine neurotransmitters dopamine, noradrenaline and serotonin in the claustrum of the normal autopsied human brain and of patients who died with idiopathic Parkinson's disease (PD). We found in the normal claustrum substantial amounts of all three monoamine neurotransmitters, substantiating the existence of the respective brain stem afferents to the claustrum. In PD, the levels of dopamine and noradrenaline were greatly reduced by 93 and 81%, respectively. Serotonin levels remained unchanged. We propose that by virtue of their projections to the claustrum, the brain stem dopamine, noradrenaline and serotonin systems interact directly with the cortico-claustro-cortical information processing mechanisms, by-passing their (parallel) routes via the basal ganglia-thalamo-cortical circuits. We suggest that loss of dopamine and noradrenaline in the PD claustrum is critical in the aetiology of both the motor and the non-motor symptoms of PD.

Topographical distribution and morphology of NADPH-diaphorase-stained neurons in the human claustrum

We studied the topographical distribution and morphological characteristics of NADPH-diaphorase-positive neurons and fibers in the human claustrum. These neurons were seen to be heterogeneously distributed throughout the claustrum. Taking into account the size and shape of stained perikarya as well as dendritic and axonal characteristics, Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd)-positive neurons were categorized by diameter into three types: large, medium and small. Large neurons ranged from 25 to 35 μm in diameter and typically displayed elliptical or multipolar cell bodies. Medium neurons ranged from 20 to 25 μm in diameter and displayed multipolar, bipolar and irregular cell bodies. Small neurons ranged from 14 to 20 μm in diameter and most often displayed oval or elliptical cell bodies. Based on dendritic characteristics, these neurons were divided into spiny and aspiny subtypes. Our findings reveal two populations of NADPHd-positive neurons in the human claustrum—one comprised of large and medium cells consistent with a projection neuron phenotype, the other represented by small cells resembling the interneuron phenotype as defined by previous Golgi impregnation studies.

Cortical and Subcortical Connections of the Human Claustrum Revealed In Vivo by Constrained Spherical Deconvolution Tractography

The claustrum is a thin layer of gray matter that is at the center of an active scientific debate. Recently, Constrained Spherical Deconvolution (CSD) tractography has proved to be an extraordinary tool allowing to track white matter fibers from cortex to cortical and subcortical targets with subvoxel resolution. The aim of this study was to evaluate claustral connectivity in the human brain. Ten normal brains were analyzed by using the High Angular Resolution Diffusion Imaging CSD-based technique. Tractography revealed 4 groups of white matter fibers connecting the claustrum with the brain cortex: Anterior, posterior, superior, and lateral. The anterior and posterior cortico-claustral tracts connected the claustrum to prefrontal cortex and visual areas. The superior tract linked the claustrum with sensory-motor areas, while the lateral pathway connected the claustrum to the auditory cortex. In addition, we demonstrated a claustral medial pathway connecting the claustrum with the basal ganglia, specifically with caudate nucleus, putamen, and globus pallidus. An interesting and exciting new finding was the demonstration of a bilateral connection between claustrum and contralateral cortical areas and a well-represented interclaustral communication with interconnection bundles interspersed within the bulk of the trunk of the corpus callosum. The physiological and pathophysiological relevance of these findings are discussed.

Parvalbumin-immunoreactive neurons in the human claustrum

The morphology and distribution of parvalbumin-immunoreactive neurons (PV-ir) were studied in the human claustrum. PV-ir neurons were observed throughout the claustrum, with the highest numbers noted in the central (broadest) portion as compared with the dorsal and ventral aspects. Reaction product was evident in the neuronal perikarya, dendritic processes, and spines. In the majority of these labeled neurons, the cytoplasm was devoid of lipofuscin pigment. Cell bodies varied widely in both shape and size, ranging from oval and small, to multipolar and large. PV-ir neurons were classified into two groups, primarily based on dendritic morphology: spiny neurons with long and straight dendrites, and aspiny neurons with thin and curving dendritic processes. PV-ir fibers were seen throughout the neuropil, with many immuno-positive puncta noted.

Topography of Gng2- and NetrinG2-Expression Suggests an Insular Origin of the Human Claustrum

The claustrum has been described in the forebrain of all mammals studied so far. It has been suggested that the claustrum plays a role in the integration of multisensory information: however, its detailed structure and function remain enigmatic. The human claustrum is a thin, irregular, sheet of grey matter located between the inner surface of the insular cortex and the outer surface of the putamen. Recently, the G-protein gamma2 subunit (Gng2) was proposed as a specific claustrum marker in the rat, and used to better delineate its anatomical boundaries and connections. Additional claustral markers proposed in mammals include Netrin-G2 in the monkey and latexin in the cat. Here we report the expression and distribution of Gng2 and Netrin-G2 in human post-mortem samples of the claustrum and adjacent structures. Gng2 immunoreactivity was detected in the neuropil of the claustrum and of the insular cortex but not in the putamen. A faint labelling was present also in the external and extreme capsules. Double-labelling experiments indicate that Gng2 is also expressed in glial cells. Netrin-G2 labelling was seen in neuronal cell bodies throughout the claustrum and the insular cortex but not in the medially adjacent putamen. No latexin immunoreactive element was detected in the claustrum or adjacent structures. Our results confirm that both the Gng2 and the Netrin-G2 proteins show an affinity to the claustrum and related formations also in the human brain. The presence of Gng2 and Netrin-G2 immunoreactive elements in the insular cortex, but not in the putamen, suggests a possible common ontogeny of the claustrum and insula.

Comparative Anatomy of the Claustrum in Selected Species: A Morphometric Analysis

The morphology of the claustrum was studied by stereological methods in representatives of five mammalian orders (Insectivora, Rodentia, Lagomorpha, Carnivora and Primates). In each species under study, a dorsal and a ventral part of the nucleus can be distinguished. Based on differences in shape and separation from surrounding structures, five morphological types of the claustrum occur. The claustrum of Insectivora and some rodents represents the least complicated morphological type. The nucleus is very poorly separated from the surrounding structures. The human claustrum is morphologically the most complicated, although the two above-mentioned principal divisions are apparent. The ventrally situated paraamygdalar part of the human claustrum may correspond to the endopiriform nucleus or ventral part of the claustrum of other mammals, because of its morphological characteristics and connections with the limbic system. In guinea pigs, traditionally classified as members of the Rodentia, a characteristic morphological type of the claustrum is present. This observation may support arguments questioning the current position of this species in mammalian classification. Based on stereological studies, the increase of the claustral volume that occurs with increase of the hemispheric volume is significantly smaller than the increase of the isocortical volume and larger than the increase of the allocortical volume. The increase of the volume of the dorsal and ventral parts of the claustrum does not differ significantly in the species under study. Neurons of the claustrum represent differentiated morphology. The numerical density of neurons in the dorsal part of the claustrum is significantly higher than in the ventral one. Differences in the morphology and cellular structure of the two parts of the claustrum may suggest differences in function of the two parts of the nucleus, most probably concerned with transfer of information among various cortical regions. Changes in the claustrum, a cortico-related structure, that occur with increased brain volume, may suggest that its development is less dynamic than that of the isocortex.