Mapping frontoinsular cortex from diffusion microstructure.

We developed a novel method for mapping the location, surface area, thickness, and volume of frontoinsular cortex (FI) using structural and diffusion magnetic resonance imaging. FI lies in the ventral part of anterior insular cortex and is characterized by its distinctive population von Economo neurons (VENs). Functional neuroimaging studies have revealed its involvement in affective processing, and histopathology has implicated VEN loss in behavioral-variant frontotemporal dementia and chronic alcoholism; however, structural neuroimaging of FI has been relatively limited. We delineated FI by jointly modeling cortical surface geometry and its coincident diffusion microstructure parameters. We found that neurite orientation dispersion in cortical gray matter can be used to map FI in specific individuals, and the derived measures reflect a range of behavioral factors in young adults from the Human Connectome Project (N=1052). FI volume was larger in the left hemisphere than the right (31%), and the percentage volume of FI was larger in women than men (15.3%). FI volume was associated with measures of decision-making (delay discounting, substance abuse), emotion (negative intrusive thinking and perception of hostility), and social behavior (theory of mind and working memory for faces). The common denominator is that larger FI size is related to greater self-control and social awareness.

THC Exposure is Reflected in the Microstructure of the Cerebral Cortex and Amygdala of Young Adults.

The endocannabinoid system serves a critical role in homeostatic regulation through its influence on processes underlying appetite, pain, reward, and stress, and cannabis has long been used for the related modulatory effects it provides through tetrahydrocannabinol (THC). We investigated how THC exposure relates to tissue microstructure of the cerebral cortex and subcortical nuclei using computational modeling of diffusion magnetic resonance imaging data in a large cohort of young adults from the Human Connectome Project. We report strong associations between biospecimen-defined THC exposure and microstructure parameters in discrete gray matter brain areas, including frontoinsular cortex, ventromedial prefrontal cortex, and the lateral amygdala subfields, with independent effects in behavioral measures of memory performance, negative intrusive thinking, and paternal substance abuse. These results shed new light on the relationship between THC exposure and microstructure variation in brain areas related to salience processing, emotion regulation, and decision making. The absence of effects in some other cannabinoid-receptor-rich brain areas prompts the consideration of cellular and molecular mechanisms that we discuss. Further studies are needed to characterize the nature of these effects across the lifespan and to investigate the mechanistic neurobiological factors connecting THC exposure and microstructural parameters.

Retinotopic organization of extrastriate cortex in the owl monkey--dorsal and lateral areas.

Dense retinotopy data sets were obtained by microelectrode visual receptive field mapping in dorsal and lateral visual cortex of anesthetized owl monkeys. The cortex was then physically flatmounted and stained for myelin or cytochrome oxidase. Retinotopic mapping data were digitized, interpolated to a uniform grid, analyzed using the visual field sign technique-which locally distinguishes mirror image from nonmirror image visual field representations-and correlated with the myelin or cytochrome oxidase patterns. The region between V2 (nonmirror) and MT (nonmirror) contains three areas-DLp (mirror), DLi (nonmirror), and DLa/MTc (mirror). DM (mirror) was thin anteroposteriorly, and its reduced upper field bent somewhat anteriorly away from V2. DI (nonmirror) directly adjoined V2 (nonmirror) and contained only an upper field representation that also adjoined upper field DM (mirror). Retinotopy was used to define area VPP (nonmirror), which adjoins DM anteriorly, area FSTd (mirror), which adjoins MT ventrolaterally, and TP (mirror), which adjoins MT and DLa/MTc dorsoanteriorly. There was additional retinotopic and architectonic evidence for five more subdivisions of dorsal and lateral extrastriate cortex-TA (nonmirror), MSTd (mirror), MSTv (nonmirror), FSTv (nonmirror), and PP (mirror). Our data appear quite similar to data from marmosets, though our field sign-based areal subdivisions are slightly different. The region immediately anterior to the superiorly located central lower visual field V2 varied substantially between individuals, but always contained upper fields immediately touching lower visual field V2. This region appears to vary even more between species. Though we provide a summary diagram, given within- and between-species variation, it should be regarded as a guide to parsing complex retinotopy rather than a literal representation of any individual, or as the only way to agglomerate the complex mosaic of partial upper and lower field, mirror- and nonmirror-image patches into areas.

A volumetric comparison of the insular cortex and its subregions in primates.

The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body's homeostatic state.We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent=1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent=1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee.

Distinctive neurons of the anterior cingulate and frontoinsular cortex: a historical perspective.

Human anterior cingulate and frontoinsular cortices participate in healthy social-emotional processing. These regions feature 2 related layer 5 neuronal morphotypes, the von Economo neurons and fork cells. In this paper, we review the historical accounts of these neurons and provide a German-to-English translation of von Economo's seminal paper describing the neurons which have come to bear his name. We close with a brief discussion regarding the functional and clinical relevance of these neurons and their home regions.

The von Economo neurons in apes and humans.

The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex (ACC) in great apes and humans but not other primates. We stereologically counted the VENs in FI and the limbic anterior (LA) area of ACC and found them to be more numerous in humans than in apes. In humans, VENs first appear in small numbers in the 36th week postconception are rare at birth and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than the left in FI and LA in postnatal brains; this may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, containing FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. In a preliminary diffusion tensor imaging study of the connections of FI, we found that the VEN-containing regions connect with the frontal pole as well as with other parts of frontal and insular cortex, the septum, and the amygdala. The VENs and a related cell population, the fork cells, selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing pepide, which signal satiety. The loss of VENs and fork cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. These cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals.

Biochemical specificity of von Economo neurons in hominoids.

OBJECTIVES: Von Economo neurons (VENs) are defined by their thin, elongated cell body and long dendrites projecting from apical and basal ends. These distinctive neurons are mostly present in anterior cingulate (ACC) and fronto-insular (FI) cortex, with particularly high densities in cetaceans, elephants, and hominoid primates (i.e., humans and apes). This distribution suggests that VENs contribute to specializations of neural circuits in species that share both large brain size and complex social cognition, possibly representing an adaptation to rapidly relay socially-relevant information over long distances across the brain. Recent evidence indicates that unique patterns of protein expression may also characterize VENs, particularly involving molecules that are known to regulate gut and immune function. METHODS: In this study, we used quantitative stereologic methods to examine the expression of three such proteins that are localized in VENs-activating-transcription factor 3 (ATF3), interleukin 4 receptor (IL4Rα), and neuromedin B (NMB). We quantified immunoreactivity against these proteins in different morphological classes of ACC layer V neurons of hominoids. RESULTS: Among the different neuron types analyzed (pyramidal, VEN, fork, enveloping, and other multipolar), VENs showed the greatest percentage that displayed immunostaining. Additionally, a higher proportion of VENs in humans were immunoreactive to ATF3, IL4Rα, and NMB than in other apes. No other ACC layer V neuron type displayed a significant species difference in the percentage of immunoreactive neurons. CONCLUSIONS: These findings demonstrate that phylogenetic variation exists in the protein expression profile of VENs, suggesting that humans might have evolved biochemical specializations for enhanced interoceptive sensitivity.

Frontoinsular cortical microstructure is linked to life satisfaction in young adulthood.

Life satisfaction is a component of subjective well-being that reflects a global judgement of the quality of life according to an individual's own needs and expectations. As a psychological construct, it has attracted attention due to its relationship to mental health, resilience to stress, and other factors. Neuroimaging studies have identified neurobiological correlates of life satisfaction; however, they are limited to functional connectivity and gray matter morphometry. We explored features of gray matter microstructure obtained through compartmental modeling of multi-shell diffusion MRI data, and we examined cortical microstructure in frontoinsular cortex in a cohort of 807 typical young adults scanned as part of the Human Connectome Project. Our experiments identified the orientation dispersion index (ODI), and analogously fractional anisotropy (FA), of frontoinsular cortex as a robust set of anatomically-specific lateralized diffusion MRI microstructure features that are linked to life satisfaction, independent of other demographic, socioeconomic, and behavioral factors. We further validated our findings in a secondary test-retest dataset and found high reliability of our imaging metrics and reproducibility of outcomes. In our analysis of twin and non-twin siblings, we found basic microstructure in frontoinsular cortex to be strongly genetically determined. We also found a more moderate but still very significant genetic role in determining microstructure as it relates to life satisfaction in frontoinsular cortex. Our findings suggest a potential linkage between well-being and microscopic features of frontoinsular cortex, which may reflect cellular morphology and architecture and may more broadly implicate the integrity of the homeostatic processing performed by frontoinsular cortex as an important component of an individual's judgements of life satisfaction.

The connections of the insular VEN area in great apes: A histologically-guided ex vivo diffusion tractography study.

We mapped the connections of the insular von Economo neuron (VEN) area in ex vivo brains of a bonobo, an orangutan and two gorillas with high angular resolution diffusion MRI imaging acquired in 36 h imaging sessions for each brain. The apes died of natural causes without neurological disorders. The localization of the insular VEN area was based on cresyl violet-stained histological sections from each brain that were coregistered with structural and diffusion images from the same individuals. Diffusion MRI tractography showed that the insular VEN area is connected with olfactory, gustatory, visual and other sensory systems, as well as systems for the mediation of appetite, reward, aversion and motivation. The insular VEN area in apes is most strongly connected with frontopolar cortex, which could support their capacity to choose voluntarily among alternative courses of action particularly in exploring for food resources. The frontopolar cortex may also support their capacity to take note of potential resources for harvesting in the future (prospective memory). All of these faculties may support insight and volitional choice when contemplating courses of action as opposed to rule-based decision-making.

The effect of gaze angle and fixation distance on the responses of neurons in V1, V2, and V4.

What we see depends on where we look. This paper characterizes the modulatory effects of point of regard in three-dimensional space on responsiveness of visual cortical neurons in areas V1, V2, and V4. Such modulatory effects are both common, affecting 85% of cells, and strong, frequently producing changes of mean firing rate by a factor of 10. The prevalence of neurons in area V4 showing a preference for near distances may be indicative of the involvement of this area in close scrutiny during object recognition. We propose that eye-position signals can be exploited by visual cortex as classical conditioning stimuli, enabling the perceptual learning of systematic relationships between point of regard and the structure of the visual environment.

Selective reduction of Von Economo neuron number in agenesis of the corpus callosum.

Von Economo neurons (VENs) are large spindle-shaped neurons localized to anterior cingulate cortex (ACC) and fronto-insular cortex (FI). VENs appear late in development in humans, are a recent phylogenetic specialization, and are selectively destroyed in frontotemporal dementia, a disease which profoundly disrupts social functioning and self-awareness. Agenesis of the corpus callosum (AgCC) is a congenital disorder that can have significant effects on social and emotional behaviors, including alexithymia, difficulty intuiting the emotional states of others, and deficits in self- and social-awareness that can impair humor, comprehension of non-literal or affective language, and social judgment. To test the hypothesis that VEN number is selectively reduced in AgCC, we used stereology to obtain unbiased estimates of total neuron number and VEN number in postmortem brain specimens of four normal adult controls, two adults with isolated callosal dysgenesis, and one adult whose corpus callosum and ACC were severely atrophied due to a non-fatal cerebral arterial infarction. The partial agenesis case had approximately half as many VENs as did the four normal controls, both in ACC and FI. In the complete agenesis case the VENs were almost entirely absent. The percentage of neurons in FI that are VENs was reduced in callosal agenesis, but was actually slightly above normal in the stroke patient. These results indicate that the VEN population is selectively reduced in AgCC, but that the VENs do not depend on having an intact corpus callosum. We conclude that in agenesis of the corpus callosum the reduction in the number of VENs is not the direct result of the failure of this structure to develop, but may instead be another consequence of the genetic disruption that caused the agenesis. The reduction of the VEN population could help to explain some of the social and emotional deficits that are seen in this disorder.

Intuition and autism: a possible role for Von Economo neurons.

Von Economo neurons (VENs) are a recently evolved cell type which may be involved in the fast intuitive assessment of complex situations. As such, they could be part of the circuitry supporting human social networks. We propose that the VENs relay an output of fronto-insular and anterior cingulate cortex to the parts of frontal and temporal cortex associated with theory-of-mind, where fast intuitions are melded with slower, deliberative judgments. The VENs emerge mainly after birth and increase in number until age 4 yrs. We propose that in autism spectrum disorders the VENs fail to develop normally, and that this failure might be partially responsible for the associated social disabilities that result from faulty intuition.

Medial Prefrontal and Anterior Insular Connectivity in Early Schizophrenia and Major Depressive Disorder: A Resting Functional MRI Evaluation of Large-Scale Brain Network Models.

Anomalies in the medial prefrontal cortex, anterior insulae, and large-scale brain networks associated with them have been proposed to underlie the pathophysiology of schizophrenia and major depressive disorder (MDD). In this study, we examined the connectivity of the medial prefrontal cortices and anterior insulae in 24 healthy controls, 24 patients with schizophrenia, and 24 patients with MDD early in illness with seed-based resting state functional magnetic resonance imaging analysis using Statistical Probability Mapping. As hypothesized, reduced connectivity was found between the medial prefrontal cortex and the dorsal anterior cingulate cortex and other nodes associated with directed effort in patients with schizophrenia compared to controls while patients with MDD had reduced connectivity between the medial prefrontal cortex and ventral prefrontal emotional encoding regions compared to controls. Reduced connectivity was found between the anterior insulae and the medial prefrontal cortex in schizophrenia compared to controls, but contrary to some models emotion processing regions failed to demonstrate increased connectivity with the medial prefrontal cortex in MDD compared to controls. Although, not statistically significant after correction for multiple comparisons, patients with schizophrenia tended to demonstrate decreased connectivity between basal ganglia-thalamocortical regions and the medial prefrontal cortex compared to patients with MDD, which might be expected as these regions effect action. Results were interpreted to support anomalies in nodes associated with directed effort in schizophrenia and nodes associated with emotional encoding network in MDD compared to healthy controls.

Anatomical analysis of an aye-aye brain (Daubentonia madagascariensis, primates: Prosimii) combining histology, structural magnetic resonance imaging, and diffusion-tensor imaging.

This report presents initial results of a multimodal analysis of tissue volume and microstructure in the brain of an aye-aye (Daubentonia madagascariensis). The left hemisphere of an aye-aye brain was scanned using T2-weighted structural magnetic resonance imaging (MRI) and diffusion-tensor imaging (DTI) prior to histological processing and staining for Nissl substance and myelinated fibers. The objectives of the experiment were to estimate the volume of gross brain regions for comparison with published data on other prosimians and to validate DTI data on fiber anisotropy with histological measurements of fiber spread. Measurements of brain structure volumes in the specimen are consistent with those reported in the literature: the aye-aye has a very large brain for its body size, a reduced volume of visual structures (V1 and LGN), and an increased volume of the olfactory lobe. This trade-off between visual and olfactory reliance is likely a reflection of the nocturnal extractive foraging behavior practiced by Daubentonia. Additionally, frontal cortex volume is large in the aye-aye, a feature that may also be related to its complex foraging behavior and sensorimotor demands. Analysis of DTI data in the anterior cingulum bundle demonstrates a strong correlation between fiber spread as measured from histological sections and fiber spread as measured from DTI. These results represent the first quantitative comparison of DTI data and fiber-stained histology in the brain.

Brain of the African elephant (Loxodonta africana): neuroanatomy from magnetic resonance images.

We acquired magnetic resonance images of the brain of an adult African elephant, Loxodonta africana, in the axial and parasagittal planes and produced anatomically labeled images. We quantified the volume of the whole brain (3,886.7 cm3) and of the neocortical and cerebellar gray and white matter. The white matter-to-gray matter ratio in the elephant neocortex and cerebellum is in keeping with that expected for a brain of this size. The ratio of neocortical gray matter volume to corpus callosum cross-sectional area is similar in the elephant and human brains (108 and 93.7, respectively), emphasizing the difference between terrestrial mammals and cetaceans, which have a very small corpus callosum relative to the volume of neocortical gray matter (ratio of 181-287 in our sample). Finally, the elephant has an unusually large and convoluted hippocampus compared to primates and especially to cetaceans. This may be related to the extremely long social and chemical memory of elephants.

Three-dimensional structure and evolution of primate primary visual cortex.

In this study, three-dimensional reconstructions of primate primary visual cortex (V1) were used to address questions about its evolution. The three-dimensional shape of V1 in anthropoids is significantly longer and narrower than in strepsirrhines. This difference is an effect of clade and is not due to differences in activity pattern or V1 size. New measurements of V1 volume were also provided in order to reassess V1 size differences between strepsirrhines and anthropoids. It was found that for a given lateral geniculate nucleus (LGN) volume, anthropoids have a significantly larger V1 than strepsirrhines do. This is important since LGN is the principal source of V1's input. Finally, independent contrasts analysis was used to examine the scaling of V1 relative to LGN, the rest of cortex, and the rest of the brain. It was confirmed that V1 scales with positive allometry relative to LGN. A number of possible explanations for scaling are discussed. V1 scaling may have to do with the tendency of large brains to be more compartmentalized than small brains, or V1 scaling might reflect the geometry of information representation.

High-resolution computed tomography study of the cranium of a fossil anthropoid primate, Parapithecus grangeri: new insights into the evolutionary history of primate sensory systems.

Extant anthropoids have large brains, small olfactory bulbs, and high-acuity vision compared with other primates. The relative timing of the evolution of these characteristics may have important implications for brain evolution. Here computed tomography is used to examine the cranium of a fossil anthropoid, Parapithecus grangeri. It is found that P. grangeri had a relatively small brain compared with living primates. In addition, it had an olfactory bulb in the middle of the range for living primates. Methods for relating optic foramen area and other cranial measurements to acuity are discussed. Multiple regression is used to estimate retinal ganglion cell number in P. grangeri. Given currently available comparative data, P. grangeri seems to have had retinal ganglion cell counts intermediate for living primates, overlapping with the upper end of the range for strepsirrhines and possibly with the lower end for anthropoids.

Xanthogranuloma of the choroid plexus in the fat-tailed dwarf lemur (Cheirogaleus medius).

This report documents the death of two fat-tailed dwarf lemurs (Cheirogaleus medius) maintained over 6 years each in our laboratory. Postmortem studies revealed xanthogranuloma of the choroid plexus, a mass replete with stored lipids, including cholesterol crystals. Six months prior to their deaths, both animals developed a peculiar head tilt and signs suggestive of neurological dysfunction. At autopsy, each had masses projecting into the lateral and IVth ventricles and an associated obstructive hydrocephalus. Cryostat sections of the brains of both lemurs showed histological features consistent with xanthogranuloma of the choroid plexus, a histologically benign and usually asymptomatic lesion found in up to 7% of human autopsies. This case is of special interest because of the unique feeding strategies in the fat-tailed dwarf lemur. Since C. medius remains in torpor for 6 months out of the year during the time of food scarcity in the forests of Madagascar, the animal must accumulate large reserves of fat during its active period. In the laboratory, however, dwarf lemurs do not normally go into torpor, and the accumulated fat is not used. The finding of this tumor, therefore, suggests that the combination of a captive high-fat diet and the unusual fat-storage mechanisms utilized by C. medius contributed to the buildup of lipids and might be etiologically related to the development of those lesions. © 1996 Wiley-Liss, Inc.

A framework for interpreting functional networks in schizophrenia.

Some promising genetic correlates of schizophrenia have emerged in recent years but none explain more than a small fraction of cases. The challenge of our time is to characterize the neuronal networks underlying schizophrenia and other neuropsychiatric illnesses. Early models of schizophrenia have been limited by the ability to readily evaluate large-scale networks in living patients. With the development of resting state and advanced structural magnetic resonance imaging, it has become possible to do this. While we are at an early stage, a number of models of intrinsic brain networks have been developed to account for schizophrenia and other neuropsychiatric disorders. This paper reviews the recent voxel-based morphometry (VBM), diffusion tensor imaging (DTI), and resting functional magnetic resonance imaging literature in light of the proposed networks underlying these disorders. It is suggested that there is support for recently proposed models that suggest a pivotal role for the salience network. However, the interactions of this network with the default mode network and executive control networks are not sufficient to explain schizophrenic symptoms or distinguish them from other neuropsychiatric disorders. Alternatively, it is proposed that schizophrenia arises from a uniquely human brain network associated with directed effort including the dorsal anterior and posterior cingulate cortex (PCC), auditory cortex, and hippocampus while mood disorders arise from a different brain network associated with emotional encoding including the ventral anterior cingulate cortex (ACC), orbital frontal cortex, and amygdala. Both interact with the dorsolateral prefrontal cortex and a representation network including the frontal and temporal poles and the fronto-insular cortex, allowing the representation of the thoughts, feelings, and actions of self and others across time.

The Claustrum and Insula in Microcebus murinus: A High Resolution Diffusion Imaging Study.

The claustrum and the insula are closely juxtaposed in the brain of the prosimian primate, the gray mouse lemur (Microcebus murinus). Whether the claustrum has closer affinities with the cortex or the striatum has been debated for many decades. Our observation of histological sections from primate brains and genomic data in the mouse suggest former. Given this, the present study compares the connections of the two structures in Microcebus using high angular resolution diffusion imaging (HARDI, with 72 directions), with a very small voxel size (90 micra), and probabilistic fiber tractography. High angular and spatial resolution diffusion imaging is non-destructive, requires no surgical interventions, and the connection of each and every voxel can be mapped, whereas in conventional tract tracer studies only a few specific injection sites can be assayed. Our data indicate that despite the high genetic and spatial affinities between the two structures, their connectivity patterns are very different. The claustrum connects with many cortical areas and the olfactory bulb; its strongest probabilistic connections are with the entorhinal cortex, suggesting that the claustrum may have a role in spatial memory and navigation. By contrast, the insula connects with many subcortical areas, including the brainstem and thalamic structures involved in taste and visceral feelings. Overall, the connections of the Microcebus claustrum and insula are similar to those of the rodents, cat, macaque, and human, validating our results. The insula in the Microcebus connects with the dorsolateral frontal cortex in contrast to the mouse insula, which has stronger connections with the ventromedial frontal lobe, yet this is consistent with the dorsolateral expansion of the frontal cortex in primates. In addition to revealing the connectivity patterns of the Microcebus brain, our study demonstrates that HARDI, at high resolutions, can be a valuable tool for mapping fiber pathways for multiple sites in fixed brains in rare and difficult-to-obtain species.