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.     

Functional aspects of the relation between the claustrum and motor cortex in the cat

In order to study the relationships between the claustrum and motor cortex neurons both of area 4 and area 6 in the cat, an experiment was performed in which the effect of claustral stimulation on pyramidal tract neurons was investigated. Single shock electrical activation of the claustrum caused an inhibition of the spontaneous activity of the neurons, or an inhibition preceded by short activation, or no effect. These evidences lead to the conclusion that the claustrum exerts a role in movement organization.     

Ontogeny and homology of the claustra in otophysan Ostariophysi (Teleostei)

We studied the ontogeny of the claustrum comparatively in representatives of all otophysan subgroups. The claustrum of cypriniforms has a cartilaginous precursor, the claustral cartilage, which subsequently ossifies perichondrally at its anterior face and develops an extensive lamina of membrane bone. The membrane bone component of the claustrum and its close association with the atrium sinus imparis, a perilymphatic space of the Weberian apparatus, are both synapomorphies of cypriniforms. The characiform claustrum is not preformed in cartilage and originates as a membrane bone ossification, a putative synapomorphy of that taxon. Among siluriforms, the claustrum is present only in more basal groups and originates as an elongate cartilage that ossifies in a characteristic ventrodorsal direction, possibly a synapomorphy of catfishes. Gymnotiforms lack the claustral cartilage and claustrum. We review all previous hypothesis of claustrum homology in light of the above findings and conclude that the most plausible hypothesis is the one originally proposed by Bloch ([1900] Jen Z Naturw 34:1-64) that claustra are homologs of the supradorsals of the first vertebra.     

Multimodal cross-talk of olfactory and gustatory information in the endopiriform nucleus in rats

The endopiriform nucleus (EPN) is a large group of multipolar cells located in the depth of the piriform cortex (PC). Although many studies have suggested that the EPN plays a role in temporal lobe epilepsy, the normal function of the EPN remains to be elucidated. By using optical imaging of coronal brain slice preparations with voltage-sensitive dye, we found signal propagation from the PC or gustatory cortex (GC) to the EPN in normal medium. In our previous research, we failed to elicit a reliable signal reproducibly in the EPN by single stimulation either to the PC or GC. In our current research, we found that a double-pulse stimulation to either the PC or GC (interpulse interval: 20-100 ms) induced robust signal propagation to the EPN through excitation in the agranular division of the insular cortex (AI), with further extension to the claustrum. Finally, double site paired-pulse stimulation to the PC and GC also evoked excitation in the AI, claustrum, and EPN. These results suggest that the EPN has dual roles: 1) further processing of modality-specific olfactory and gustatory information from the PC and GC, respectively and 2) synergistic integration of PC-derived olfactory information and GC-derived gustatory information.     

The claustrum: a historical review of its anatomy, physiology, cytochemistry and functional significance.

The claustrum (Cl) is a subcortical structure located in the basolateral telencephalon of the mammalian brain. It has been a subject of inquiry since the mid-nineteenth century. The Cl can be identified in a number of species, and appears as a phylogenetically related nucleus in Insectivores, Prosimians and Marsupials. Ontogenetic investigations have been the subject of much debate over the years. There are three hypotheses for claustral development. To date, the "hybrid theory" has garnered the most support. Pathological conditions specifically associated with the Cl, while few in number, are of interest from a functional perspective. Several cases of claustral agenesis have been reported. The implications of these clinical reports are discussed. Claustral neuroanatomy at the light-microscopic and electron-microscopic level is reviewed. The morphology of the claustral neuron consists of several types, which roughly corresponds to the neuron's location within distinct claustral subdivisions. The interconnectivity of the Cl with the cerebral cortex is rather complex and reflective of complex functional interrelationships. Several researchers have investigated the angioarchitecture of the Cl. It appears that vessels permeating the insula also vascularize the Cl. Literature investigating the neurotransmitters and overall chemical neuroanatomy of the Cl is extensive. These studies clearly demonstrate that the Cl is richly innervated with a wide and diverse array of neurotransmitters and neuromodulators. Lesion, stimulation and recording experiments demonstrate that the functional and physiologic capacity of the Cl is quite robust. A recurring theme of claustral function appears to be its involvement in sensorimotor integration. This may be expected of the Cl, given the degree ofheterotopic, heterosensory convergence and its interconnectivity with the key subcortical nuclei and sensory cortical areas. The Cl remains a poorly understood and under investigated nucleus. Therefore, a review of the world literature through 1986 prior to the advent of the "molecular revolution" is presented. This diverse and extensive body of knowledge is reviewed in the areas ofphylogeny, ontogeny, pathology, angioarchitecture, cytochemistry, anatomy and physiology. Theories of possible claustral function are also noted. It is hoped that this work will stimulate research scientists to further investigate the functional interrelationships of the Cl as well as to aim with far greater precision and accuracy towards a deeper understanding of its raison d'etre. The recent efforts in neurosciences by Sir Francis Crick and Christof Koch implicating the Cl in visual consciousness, is an important step in understanding just what its functions could encompass. Efforts in molecular neurosciences will be indispensable for a mechanistic understanding of these functions. Currently research efforts are underway from many perspectives. In considering the past scientific literature on the Cl, it is interesting to regard that this once obscure brain structure, may serve as a model system for the study of one of the most interesting and complex brain functions-consciousness.     

What is the function of the claustrum?

The claustrum is a thin, irregular, sheet-like neuronal structure hidden beneath the inner surface of the neocortex in the general region of the insula. Its function is enigmatic. Its anatomy is quite remarkable in that it receives input from almost all regions of cortex and projects back to almost all regions of cortex. We here briefly summarize what is known about the claustrum, speculate on its possible relationship to the processes that give rise to integrated conscious percepts, propose mechanisms that enable information to travel widely within the claustrum and discuss experiments to address these questions.     

Distribution of neurotensin-like immunoreactivity in the central nervous system of the Formosan monkey

The distribution of neurotensin-like immunoreactivity was investigated in the central nervous system of the Formosan monkey employing immunohistochemical techniques. Neurotensin-containing cells were found to be widely distributed in the forebrain. The principal densities of neurotensin-like neuronal perikarya were located in the limbic system, the basal ganglion and the cerebral cortex; particularly in the amygdala, the septum, the neostriatum, the claustrum and the insula. The stria terminalis and the preoptic area were also rich in immunostained neurotensin-like neurons. A large number of immunoreactive fibers were observed from the cerebral cortex to the spinal cord in locations such as the median eminence, the arcuate nucleus, the hippocampus, the central gray and the dorsal horn of the spinal cord. We analyzed in detail the distribution of neurotensin-like immunoreactivity in the brain of the Formosan monkey, and compared these results with those obtained in the brain of the rat, Japanese monkey and human. Some possible implications regarding differences in location of this peptide are also briefly discussed.     

Preserved Self-Awareness following Extensive Bilateral Brain Damage to the Insula, Anterior Cingulate, and Medial Prefrontal Cortices

It has been proposed that self-awareness (SA), a multifaceted phenomenon central to human consciousness, depends critically on specific brain regions, namely the insular cortex, the anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC). Such a proposal predicts that damage to these regions should disrupt or even abolish SA. We tested this prediction in a rare neurological patient with extensive bilateral brain damage encompassing the insula, ACC, mPFC, and the medial temporal lobes. In spite of severe amnesia, which partially affected his "autobiographical self", the patient's SA remained fundamentally intact. His Core SA, including basic self-recognition and sense of self-agency, was preserved. His Extended SA and Introspective SA were also largely intact, as he has a stable self-concept and intact higher-order metacognitive abilities. The results suggest that the insular cortex, ACC and mPFC are not required for most aspects of SA. Our findings are compatible with the hypothesis that SA is likely to emerge from more distributed interactions among brain networks including those in the brainstem, thalamus, and posteromedial cortices.     

Modality-specific neural effects of selective attention to taste and odor

The insular cortex is implicated in general attention and in taste perception. The effect of selective attention to taste on insular responses may therefore reflect a general effect of attention or it may be (taste) modality specific. To distinguish between these 2 possibilities, we used functional magnetic resonance imaging to evaluate brain response to tastes and odors while subjects passively sampled the stimuli or performed a detection task. We found that trying to detect a taste (attention to taste) resulted in activation of the primary taste cortex (anterior and mid-dorsal insula) but not in the primary olfactory cortex (piriform). In contrast, trying to detect an odor (attention to odor) increased activity in primary olfactory but not primary gustatory cortex. However, we did identify a region of far anterior insular cortex that responded to both taste and odor "searches." These results demonstrate modality-specific activation of primary taste cortex by attention to taste and primary olfactory cortex by attention to odor and rule out the possibility that either response reflects a general effect of attentional deployment. The findings also support the existence of a multimodal region in far anterior insular cortex that is sensitive to directed attention to taste and smell.     

Neural responses during Valsalva maneuvers in obstructive sleep apnea syndrome.

The repetitive upper airway muscle atonic episodes and cardiovascular sequelae of obstructive sleep apnea (OSA) suggest dysfunction of specific neural sites that integrate afferent airway signals with autonomic and somatic outflow. We determined neural responses to the Valsalva maneuver by using functional magnetic resonance imaging. Images were collected during a baseline and three Valsalva maneuvers in 8 drug-free OSA patients and 15 controls. Multiple cortical, midbrain, pontine, and medullary regions in both groups showed intensity changes correlated to airway pressure. In OSA subjects, the left inferior parietal cortex, superior temporal gyrus, posterior insular cortex, cerebellar cortex, fastigial nucleus, and hippocampus showed attenuated signal changes compared with controls. Enhanced responses emerged in the left lateral precentral gyrus, left anterior cingulate, and superior frontal cortex of OSA patients. The anterior cingulate, cerebellar cortex, and posterior insula exhibited altered response timing patterns between control and OSA subjects. The response patterns in OSA subjects suggest deficits in particular neural pathways that normally mediate the Valsalva maneuver and compensatory actions in other structures.     

Somatosensory evoked potentials following lesions of the claustrum

Ipsi- and contralateral cortical somatosensory evoked potentials (SEP) were recorded following median nerve stimulation in 12 patients with unilateral brain lesions and in 5 healthy subjects. Computed tomographic scans of brain were performed on admission. In all patients with lesions of the claustrum there was absence of SEP contralateral to the side of the lesion and ipsilateral to the stimulated nerve. This phenomenon did not appear in our material following lesions involving other structures e.g. thalamus or somatosensory cortex. Our observations suggest that the claustrum may influence deeply the contralateral somatosensory cortex. This may be due to the fact that a large part of the claustrum is involved in transmission of the sensory information from receptors to the somatosensory cortex.     

Shared "Core" Areas between the Pain and Other Task-Related Networks

The idea of a 'pain matrix' specifically devoted to the processing of nociceptive inputs has been challenged. Alternative views now propose that the activity of the primary and secondary somatosensory cortices (SI, SII), the insula and cingulate cortex may be related to a basic defensive system through which significant potentially dangerous events for the body's integrity are detected. By reviewing the role of the SI, SII, the cingulate and the insular cortices in the perception of nociceptive and tactile stimuli, in attentional, emotional and reward tasks, and in interoception and memory, we found that all these task-related networks overlap in the dorsal anterior cingulate cortex, the anterior insula and the dorsal medial thalamus. A thorough analysis revealed that the 'pain-related' network shares important functional similarities with both somatomotor-somatosensory networks and emotional-interoceptive ones. We suggest that these shared areas constitute the central part of an adaptive control system involved in the processing and integration of salient information coming both from external and internal sources. These areas are activated in almost all fMRI tasks and have been indicated to play a pivotal role in switching between externally directed and internally directed brain networks.     

Contributions of Subsurface Cortical Modulations to Discrimination of Executed and Imagined Grasp Forces through Stereoelectroencephalography

Stereoelectroencephalographic (SEEG) depth electrodes have the potential to record neural activity from deep brain structures not easily reached with other intracranial recording technologies. SEEG electrodes were placed through deep cortical structures including central sulcus and insular cortex. In order to observe changes in frequency band modulation, participants performed force matching trials at three distinct force levels using two different grasp configurations: a power grasp and a lateral pinch. Signals from these deeper structures were found to contain information useful for distinguishing force from rest trials as well as different force levels in some participants. High frequency components along with alpha and beta bands recorded from electrodes located near the primary motor cortex wall of central sulcus and electrodes passing through sensory cortex were found to be the most useful for classification of force versus rest although one participant did have significant modulation in the insular cortex. This study electrophysiologically corroborates with previous imaging studies that show force-related modulation occurs inside of central sulcus and insular cortex. The results of this work suggest that depth electrodes could be useful tools for investigating the functions of deeper brain structures as well as showing that central sulcus and insular cortex may contain neural signals that could be used for control of a grasp force BMI.     

Spatio-temporal analysis of cortical activity evoked by gustatory stimulation in humans.

Gustatory activated regions in the cerebral cortex have not been identified precisely in humans. In this study we recorded the magnetic fields from the brain in response to two tastants, 1 M NaCl and 3 mM saccharin. We estimated the location of areas activated sequentially after the onset of stimulation with magnetic source imaging. We investigated the primary gustatory area (area G) precisely, and found it at the transition between the parietal operculum and the insular cortex. The central sulcus was activated less frequently than area G but with almost the same latency in cases of NaCl stimulation. Following area G, we found activation in several cortical regions, e.g. both the frontal operculum and the anterior part of the insula, the hippocampus, the parahippocampal gyrus and the superior temporal sulcus.     

Hemispheric dominance of cortical activity evoked by focal electrogustatory stimuli.

Functional magnetic resonance imaging was used to observe cortical hemodynamic responses to electric taste stimuli applied separately to the right and left sides of the tongue tip. In 11 right-handed normal adults activation occurred primarily in the insular cortex, superior temporal lobe, inferior frontal lobe, including premotor regions, and in inferior parts of the postcentral gyrus. Unexpectedly, the location and laterality of activation were largely identical regardless of the side of the tongue stimulated. Activation in the superior insula, the presumed location of primary gustatory cortex, was predominantly, but not exclusively, in the right hemisphere, whereas central (more inferior) insular activations were more evenly bilateral. Right hemispheric dominance of activation also occurred in premotor regions (Brodmann areas 6 and 44), whereas left hemispheric dominance occurred only in the superior temporal cortex (Brodmann areas 22/42). The electric taste-evoked hemodynamic response pattern was more consistent with activation of the gustatory system than activation of somatosensory systems. The results suggest that the sites for cortical processing of electric taste information are dependent on hemispheric specialization.     

Subjecting elite athletes to inspiratory breathing load reveals behavioral and neural signatures of optimal performers in extreme environments

Background

It is unclear whether and how elite athletes process physiological or psychological challenges differently than healthy comparison subjects. In general, individuals optimize exercise level as it relates to differences between expected and experienced exertion, which can be conceptualized as a body prediction error. The process of computing a body prediction error involves the insular cortex, which is important for interoception, i.e. the sense of the physiological condition of the body. Thus, optimal performance may be related to efficient minimization of the body prediction error. We examined the hypothesis that elite athletes, compared to control subjects, show attenuated insular cortex activation during an aversive interoceptive challenge.

Methodology/Principal Findings

Elite adventure racers (n = 10) and healthy volunteers (n = 11) performed a continuous performance task with varying degrees of a non-hypercapnic breathing load while undergoing functional magnetic resonance imaging. The results indicate that (1) non-hypercapnic inspiratory breathing load is an aversive experience associated with a profound activation of a distributed set of brain areas including bilateral insula, dorsolateral prefrontal cortex and anterior cingulated; (2) adventure racers relative to comparison subjects show greater accuracy on the continuous performance task during the aversive interoceptive condition; and (3) adventure racers show an attenuated right insula cortex response during and following the aversive interoceptive condition of non-hypercapnic inspiratory breathing load.

Conclusions/Significance

These findings support the hypothesis that elite athletes during an aversive interoceptive condition show better performance and an attenuated insular cortex activation during the aversive experience. Interestingly, differential modulation of the right insular cortex has been found previously in elite military personnel and appears to be emerging as an important brain system for optimal performance in extreme environments.     

Comparative analysis of the subventricular zone in rat, ferret and macaque: evidence for an outer subventricular zone in rodents

The mammalian cerebral cortex arises from precursor cells that reside in a proliferative region surrounding the lateral ventricles of the developing brain. Recent work has shown that precursor cells in the subventricular zone (SVZ) provide a major contribution to prenatal cortical neurogenesis, and that the SVZ is significantly thicker in gyrencephalic mammals such as primates than it is in lissencephalic mammals including rodents. Identifying characteristics that are shared by or that distinguish cortical precursor cells across mammalian species will shed light on factors that regulate cortical neurogenesis and may point toward mechanisms that underlie the evolutionary expansion of the neocortex in gyrencephalic mammals. We immunostained sections of the developing cerebral cortex from lissencephalic rats, and from gyrencephalic ferrets and macaques to compare the distribution of precursor cell types in each species. We also performed time-lapse imaging of precursor cells in the developing rat neocortex. We show that the distribution of Pax6+ and Tbr2+ precursor cells is similar in lissencephalic rat and gyrencephalic ferret, and different in the gyrencephalic cortex of macaque. We show that mitotic Pax6+ translocating radial glial cells (tRG) are present in the cerebral cortex of each species during and after neurogenesis, demonstrating that the function of Pax6+ tRG cells is not restricted to neurogenesis. Furthermore, we show that Olig2 expression distinguishes two distinct subtypes of Pax6+ tRG cells. Finally we present a novel method for discriminating the inner and outer SVZ across mammalian species and show that the key cytoarchitectural features and cell types that define the outer SVZ in developing primates are present in the developing rat neocortex. Our data demonstrate that the developing rat cerebral cortex possesses an outer subventricular zone during late stages of cortical neurogenesis and that the developing rodent cortex shares important features with that of primates.     

Unilateral paramedian-sagittal brain cut extending from the level of the anterior commissure to the midlevel of the third ventricle above the amygdala affects gonadal function in male rat: a lateralized effect

The aim of the present investigations was to study involvement of fiber systems to and from the insular cortex above the amygdala in the neural control of the hypophysio-testicular axis in male rats. Animals were subjected to a unilateral paramedian-sagittal brain cut above the amygdala, extending from the level of the anterior commissure to the midlevel of the third ventricle and causing among others partial deafferentation of the insular cortex. Right-sided cut induced a significant rise in basal testosterone secretion in vitro of both testes as compared to intact or sham-operated controls without affecting serum testosterone level. By contrast, left-sided cut slightly suppressed testicular steroidogenesis and significantly decreased serum testosterone concentration. In animals underwent sham or actual cut on either side, serum luteinizing hormone levels were similar, but significantly lower than those in intact controls. No change was observed in serum FSH concentration of any experimental group. The results indicate that afferent and efferent connections of the partially deafferented cortical regions including among others the insular cortex are involved in the control of testosterone secretion. The data further suggest functional laterality of the interrupted structures.     

Von Economo neurons in the anterior insula of the macaque monkey

The anterior insular cortex (AIC) and its unique spindle-shaped von Economo neuron (VEN) emerged within the last decade as having a potentially major role in self-awareness and social cognition in humans. Invasive examination of the VEN has been precluded so far by the assumption that this neuron occurs among primates exclusively in humans and great apes. Here, we demonstrate the presence of the VEN in the agranular anterior insula of the macaque monkey. The morphology, size, laminar distribution, and proportional distribution of the monkey VEN suggest that it is at least a primal anatomical homolog of the human VEN. This finding sheds new light on the phylogeny of the VEN and AIC. Most importantly, it offers new and much-needed opportunities to investigate the primal connections and physiology of a neuron that could be crucial for human self-awareness, social cognition, and related neuropsychiatric disorders.