Topography Impacts Topology: Anatomically Central Areas Exhibit a "High-Level Connector" Profile in the Human Cortex.

Degree centrality is a widely used measure in complex networks. Within the brain, degree relates to other topological features, with high-degree nodes (i.e., hubs) exhibiting high betweenness centrality, participation coefficient, and within-module z-score. However, increasing evidence from neuroanatomical and predictive processing literature suggests that topological properties of a brain network may also be impacted by topography, that is, anatomical (spatial) distribution. More specifically, cortical limbic areas (agranular and dysgranular cortices), which occupy an anatomically central position, have been proposed to be topologically central and well suited to initiate predictions in the cerebral cortex. We estimated anatomical centrality and showed that it positively correlated with betweenness centrality, participation coefficient, and communicability, analogously to degree. In contrast to degree, however, anatomical centrality negatively correlated with within-module z-score. Our data suggest that degree centrality and anatomical centrality reflect distinct contributions to cortical organization. Whereas degree would be more related to the amount of information integration performed by an area, anatomical centrality would be more related to an area's position in the predictive hierarchy. Highly anatomically central areas may function as "high-level connectors," integrating already highly integrated information across modules. These results are consistent with a high-level, domain-general limbic workspace, integrated by highly anatomically central cortical areas.

Myeloarchitecture gradients in the human insula: Histological underpinnings and association to intrinsic functional connectivity.

Insular cortex is a core hub involved in multiple cognitive and socio-affective processes. Yet, the anatomical mechanisms that explain how it is involved in such a diverse array of functions remain incompletely understood. Here, we tested the hypothesis that changes in myeloarchitecture across the insular cortex explain how it can be involved in many different facets of cognitive function. Detailed intracortical profiling, performed across hundreds of insular locations on the basis of myelin-sensitive magnetic resonance imaging (MRI), was compressed into a lower-dimensional space uncovering principal axes of myeloarchitectonic variation. Leveraging two datasets with different high-resolution MRI contrasts, we obtained robust support for two principal dimensions of insular myeloarchitectonic differentiation in vivo, one running from ventral anterior to posterior banks and one radiating from dorsal anterior towards both ventral anterior and posterior subregions. Analyses of post mortem 3D histological data showed that the antero-posterior axis was mirrored in cytoarchitectural markers, even when controlling for sulco-gyral folding. Resting-state functional connectomics in the same individuals and ad hoc meta-analyses showed that myelin gradients in the insula relate to diverse affiliation to macroscale intrinsic functional systems, showing differential shifts in functional network embedding across each myelin-derived gradient. Collectively, our findings offer a novel approach to capture structure-function interactions of a key node of the limbic system, and suggest a multidimensional structural basis underlying the diverse functional roles of the insula.

Sex effects on structural maturation of the limbic system and outcomes on emotional regulation during adolescence.

Though adolescence is a time of emerging sex differences in emotions, sex-related differences in the anatomy of the maturing brain has been under-explored over this period. The aim of this study was to investigate whether puberty and sexual differentiation in brain maturation could explain emotional differences between girls and boys during adolescence. We adapted a dedicated longitudinal pipeline to process structural and diffusion images from 335 typically developing adolescents between 14 and 16 years. We used voxel-based and Regions of Interest approaches to explore sex and puberty effects on brain and behavioral changes during adolescence. Sexual differences in brain maturation were characterized by amygdala and hippocampal volume increase in boys and decrease in girls. These changes were mediating the sexual differences in positive emotional regulation as illustrated by positive attributes increase in boys and decrease in girls. Moreover, the differential maturation rates between the limbic system and the prefrontal cortex highlighted the delayed maturation in boys compared to girls. This is the first study to show the sex effects on the differential cortico/subcortical maturation rates and the interaction between sex and puberty in the limbic system maturation related to positive attributes, reported as being protective from emotional disorders.

Shared genetic influences on adolescent body mass index and brain structure: A voxel-based morphometry study in twins.

BACKGROUND: Previous research has demonstrated significant relationships between obesity and brain structure. Both phenotypes are heritable, but it is not known whether they are influenced by common genetic factors. We investigated the genetic etiology of the relationship between individual variability in brain morphology and BMIz using structural MRI in adolescent twins. METHOD: The sample (n = 258) consisted of 54 monozygotic and 75 dizygotic twin pairs (mean(SD) age = 13.61(0.505), BMIz = 0.608(1.013). Brain structure (volume and density of gray and white matter) was assessed using VBM. Significant voxelwise heritability of brain structure was established using the Accelerated Permutation inference for ACE models (APACE) program, with structural heritability varying from 15 to 97%, depending on region. Bivariate heritability analyses were carried out comparing additive genetic and unique environment models with and without shared genetics on BMIz and the voxels showing significant heritability in the APACE analyses. RESULTS: BMIz was positively related to gray matter volume in the brainstem and thalamus and negatively related to gray matter volume in the bilateral uncus and medial orbitofrontal cortex, gray matter density in the cerebellum, prefrontal lobe, temporal lobe, and limbic system, and white matter density in the brainstem. Bivariate heritability analyses showed that BMIz and brain structure share ∼1/3 of their genes and that ∼95% of the phenotypic correlation between BMIz and brain structure is due to shared additive genetic influences. These regions included areas related to decision-making, motivation, liking vs. wanting, taste, interoception, reward processing/learning, caloric evaluation, and inhibition. CONCLUSION: These results suggested genetic factors are responsible for the relationship between BMIz and heritable BMIz related brain structure in areas related to eating behavior.

The "Neurological Hat Game": A fun way to learn the neurological semiology.

INTRODUCTION: In-class courses are deserted by medical students who tend to find it more beneficial to study in books and through online material. New interactive teaching methods, such as serious games increase both performance and motivation. We developed and assessed a new teaching method for neurological semiology using the "Hat Game" as a basis. METHODS: In this game, two teams of second-year medical students are playing against one another. The game is played with a deck of cards. A neurological symptom or sign is written on each card. Each team gets a predefined period of time to guess as many words as possible. One member is the clue-giver and the others are the guessers. There are three rounds: during the first round, the clue-giver uses any descriptive term he wants and as many as he wants to make his team guess the maximum number of words within the allocated time. During the second round, the clue-giver can only choose one clue-word and, during the third round, he mimes the symptom or sign. The team that has guessed the most cards wins the game. To assess the efficacy of this learning procedure, multiple choices questions (MCQs) were asked before and after the game. Exam results of second-year students on their final university Neurology exam were analyzed. A satisfaction survey was proposed to all participating students. RESULTS: Among 373 students, 121 volunteers (32.4%) were enrolled in the "Neurology Hat Game" and 112 attended the game. One hundred and seven of the 112 students completed the MCQs with a significant improvement in their responses after the game (P<0.001). The 112 students who completed the satisfaction self-administered questionnaire were very satisfied with this funny new teaching method. CONCLUSIONS: Teaching neurological semiology via the "Hat Game" is an interesting method because it is student-centered, playful and complementary to the lecturer-centered courses. A randomized controlled study would be necessary to confirm these preliminary results.

Mapping the trajectory of the amygdalothalamic tract in the human brain.

Although the thalamus is not considered primarily as a limbic structure, abundant evidence indicates the essential role of the thalamus as a modulator of limbic functions indirectly through the amygdala. The amygdala is a central component of the limbic system and serves an essential role in modulating the core processes including the memory, decision-making, and emotional reactions. The amygdalothalamic pathway is the largest direct amygdalo-diencephalic connection in the primates including the human brain. Given the crucial role of the amygdalothalamic tract (ATT) in memory function and diencephalic amnesia in stroke patients, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. To date, few diffusion-weighted studies have focused on the amygdala, yet the fine neuronal connection of the amygdala and thalamus known as the ATT has yet to be elucidated. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the ATT in the human brain. We studied 15 healthy right-handed human subjects (12 men and 3 women with age range of 24-37 years old). Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to reconstruct and measure the trajectory of the ATT. We further revealed the close relationship of the ATT with the temporopontine tract and the fornix bilaterally in 15 healthy adult human brains.

Sexual risk-taking and subcortical brain volume in adolescence.

Background: The developmental period of adolescence marks the initiation of new socioemotional and physical behaviors, including sexual intercourse. However, little is known about neurodevelopmental influences on adolescent sexual decision-making. Purpose: We sought to determine how subcortical brain volume correlated with condom use, and whether those associations differed by gender and pubertal development. Methods: We used FreeSurfer to extract subcortical volume among N = 169 sexually experienced youth (mean age 16.07 years; 31.95% female). We conducted multiple linear regressions to examine the relationship between frequency of condom use and subcortical volume, and whether these associations would be moderated by gender and pubertal development. Results: We found that the relationship between brain volume and condom use was better accounted for by pubertal development than by gender, and moderated the association between limbic brain volume and condom use. No significant relationships were observed in reward areas (e.g., nucleus accumbens) or prefrontal cortical control areas. Conclusions: These data highlight the potential relevance of subcortical socioemotional processing structures in adolescents' sexual decision-making.

The Face as Diversity: What Was the Medical-Scientific Value of Lombrosian Morphoanthropology?

The face as an element of diversity. The ugliness of a face or a body and deformities were considered in 1800 as symbols of atavism, regression to being primates, or expression of inferior beings. The Italian physician Cesare Lombroso was the author of the concept of morphoanthropology, according to which the human being is judged on the basis of his or her physical connotations. The ugly person, with particular marks on his or her face and body, would be brought in as a criminal. Time has dissolved the value of Lombrosian theories, and scientific research has highlighted the influence of various factors in the genesis of crime. Genetic, biological, socioenvironmental factors, regulated by neurophysiology, which adds the effect of antagonism between the prefrontal cortex and the limbic cortex, explain the tendency to commit crime.

Neurocognitive mechanisms in depression: implications for treatment.

Mood disorders collectively account for a substantial proportion of disease burden across the globe and have a devastating impact on quality of life and occupational function. Here we evaluate recent progress in understanding the neurocognitive mechanisms involved in the manifestation of mood disorders. We focus on four domains of cognitive function that are altered in patients with depression: executive control, memory, affective processing, and feedback sensitivity. These alterations implicate a distributed neural circuit composed of multiple sectors of the prefrontal cortex in interaction with subcortical regions (striatum, thalamus) and temporal lobe structures (amygdala, hippocampus). Affective processing and feedback sensitivity are highly sensitive to serotonergic manipulation and are targeted by antidepressant treatments. By drawing together cognitive, neuroanatomical, and pharmacological tiers of research, we identify treatment targets and directions for future investigation to identify people at risk, minimize relapse, and maximize long-term beneficial outcomes for those suffering from depression.

Morphine-induced locomotor sensitization produces structural plasticity in the mesocorticolimbic system dependent on CB1-R activity.

Changes in structural plasticity produced by the chronic exposure to drugs of abuse, such as alterations in dendritic spine densities, participate in the development of maladaptive learning processes leading to drug addiction. Understanding the neurobiological mechanisms involved in these aberrant changes is crucial to clarify the neurobiological substrate of addiction. Drug-induced locomotor sensitization has been widely accepted as a useful animal model to study these mechanisms related to drug addiction. We have evaluated the changes in structural plasticity in the mesocorticolimbic system involved in morphine-induced locomotor sensitization. The role of the cannabinoid receptor type 1 (CB1-R) in these neuroplastic alterations has also been studied using CB1-R-deficient (CB1-R KO) mice. Structural plasticity changes promoted by morphine are a highly dynamic phenomenon that evolves during the entire time course of the behavioral sensitization in wild-type (WT) animals. The different phases of the sensitization process were related to specific changes in connectivity between neurons revealed by modifications in dendritic spines in specific areas of the mesocorticolimbic system. Moreover, the lack of morphine-induced locomotor sensitization in CB1-R KO mice was accompanied by abnormal alterations in structural plasticity in the same mesocorticolimbic areas. These specific structural plasticity changes mediated by CB1-R activity seem necessary for the normal progression of morphine-induced locomotor sensitization and could play a critical role in the addictive process.

Minimally invasive subfrontal route for the resection of medial temporal region intrinsic tumors.

BACKGROUND: The mesial temporal region (MTR) comprises important components of the limbic system, as well as vital neurovascular structures. Because of its important functional role, as much healthy brain tissue as possible must be preserved while targeting resection of MTR lesions. METHODS: A frontal minicraniotomy is used to access the MTR through a subfrontal approach. By opening the most medial part of the Sylvian fissure, the uncus-amygdala complex is exposed, and through this, the head of the hippocampus can be reached and removed as well. CONCLUSIONS: This approach is extremely suitable for MTR lesions, as it provides the advantage of sparing the most important functional structures of the temporal lobe, the temporal stem, and the limen insulae, as well as the optic radiations and the fronto-occipital connections.

White matter connections of the supplementary motor area in humans.

INTRODUCTION: The supplementary motor area (SMA) is frequently involved by brain tumours (particularly WHO grade II gliomas). Surgery in this area can be followed by the 'SMA syndrome', characterised by contralateral akinesia and mutism. Knowledge of the connections of the SMA can provide new insights on the genesis of the SMA syndrome, and a better understanding of the challenges related to operating in this region. METHODS: White matter connections of the SMA were studied with both postmortem dissection and advance diffusion imaging tractography. Postmortem dissections were performed according to the Klingler technique. 12 specimens were fixed in 10% formalin and frozen at -15°C for 2 weeks. After thawing, dissection was performed with blunt dissectors. For diffusion tractography, high-resolution diffusion imaging datasets from 10 adult healthy controls from the Human Connectome Project database were used. Whole brain tractography was performed using a spherical deconvolution approach. RESULTS: Five main connections were identified in both postmortem dissections and tractography reconstructions: (1) U-fibres running in the precentral sulcus, connecting the precentral gyrus and the SMA; (2) U-fibres running in the cingulate sulcus, connecting the SMA with the cingulate gyrus; (3) frontal 'aslant' fascicle, directly connecting the SMA with the pars opercularis of the inferior frontal gyrus; (4) medial fibres connecting the SMA with the striatum; and (5) SMA callosal fibres. Good concordance was observed between postmortem dissections and diffusion tractography. CONCLUSIONS: The SMA shows a wide range of white matter connections with motor, language and lymbic areas. Features of the SMA syndrome (akinesia and mutism) can be better understood on the basis of these findings.

Limbic justice--amygdala involvement in immediate rejection in the Ultimatum Game.

Imaging studies have revealed a putative neural account of emotional bias in decision making. However, it has been difficult in previous studies to identify the causal role of the different sub-regions involved in decision making. The Ultimatum Game (UG) is a game to study the punishment of norm-violating behavior. In a previous influential paper on UG it was suggested that frontal insular cortex has a pivotal role in the rejection response. This view has not been reconciled with a vast literature that attributes a crucial role in emotional decision making to a subcortical structure (i.e., amygdala). In this study we propose an anatomy-informed model that may join these views. We also present a design that detects the functional anatomical response to unfair proposals in a subcortical network that mediates rapid reactive responses. We used a functional MRI paradigm to study the early components of decision making and challenged our paradigm with the introduction of a pharmacological intervention to perturb the elicited behavioral and neural response. Benzodiazepine treatment decreased the rejection rate (from 37.6% to 19.0%) concomitantly with a diminished amygdala response to unfair proposals, and this in spite of an unchanged feeling of unfairness and unchanged insular response. In the control group, rejection was directly linked to an increase in amygdala activity. These results allow a functional anatomical detection of the early neural components of rejection associated with the initial reactive emotional response. Thus, the act of immediate rejection seems to be mediated by the limbic system and is not solely driven by cortical processes, as previously suggested. Our results also prompt an ethical discussion as we demonstrated that a commonly used drug influences core functions in the human brain that underlie individual autonomy and economic decision making.

On the relationship between emotion and cognition.

The current view of brain organization supports the notion that there is a considerable degree of functional specialization and that many regions can be conceptualized as either 'affective' or 'cognitive'. Popular examples are the amygdala in the domain of emotion and the lateral prefrontal cortex in the case of cognition. This prevalent view is problematic for a number of reasons. Here, I will argue that complex cognitive-emotional behaviours have their basis in dynamic coalitions of networks of brain areas, none of which should be conceptualized as specifically affective or cognitive. Central to cognitive-emotional interactions are brain areas with a high degree of connectivity, called hubs, which are critical for regulating the flow and integration of information between regions.

Early postnatal stress alters extracellular signal-regulated kinase signaling in the corticolimbic system modulating emotional circuitry in adult rats.

The present study elucidated whether early life stress alters the extracellular signal-regulated kinase (ERK) pathway that underlies fear retrieval and fear extinction based on a contextual fear conditioning paradigm, using a juvenile stress model. Levels of phospho-ERK (pERK), the active form of ERK, increased after fear retrieval in the hippocampal CA1 region but not in the medial prefrontal cortex (mPFC). ERK activation in the CA1 following fear retrieval was not observed in adult rats who received aversive footshock (FS) stimuli during the second postnatal period (2wFS), which exhibited low levels of freezing. In fear extinction, pERK levels in the CA1 were increased by repeated extinction trials, but they were not altered after extinction retrieval. In contrast, pERK levels in the mPFC did not change during extinction training, but were enhanced after extinction retrieval. These findings were compatible in part with electrophysiological data showing that synaptic transmission in the CA1 field and mPFC was enhanced during extinction training and extinction retrieval, respectively. ERK activation in the CA1 and mPFC associated with extinction processes did not occur in rats that received FS stimuli during the third postnatal period (3wFS), which exhibited sustained freezing behavior. The repressed ERK signaling and extinction deficit observed in the 3wFS group were ameliorated by treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine. These findings suggest that early postnatal stress induced the downregulation of ERK signaling in distinct brain regions through region-specific regulation, which may lead to increased behavioral abnormalities or emotional vulnerabilities in adulthood.

Functional anatomy of the basal ganglia: limbic aspects.

INTRODUCTION: The basal ganglia (BG) have been implicated in different processes that control action such as the control of movement parameters but also in processing cognitive and emotional information from the environment. Here, we review existing anatomical data on the interaction between the BG and the limbic system that support implication of the BG in limbic functions. STATE OF THE ART: The BG form a system that is fairly different from the limbic system, but have strong ties, both anatomical and functional, to the latter. Different models have been proposed. In the parallel model, five segregated circuits from the frontal cortex are individualized and terminate in different regions of the BG and thalamus, before projecting back to their cortical area of origin. Based on the extrafrontal cortical projections, another model has been proposed. It subdivides the cortico-striatal projection into three functional territories: limbic, associative and sensorimotor. In a third spiral model, propagation is possible between limbic information processed by the most medial striatal neurons to motor information processed by the most lateral neurons. PERSPECTIVES: Three main levels of interaction between the BG system and the limbic system are considered. (1) The BG receive direct afferences from several structures associated with the limbic system. Limbic cortical areas project to the striatum, of which the internal architecture is particularly complex, with significant cross-species differences: a compartmental striosome/matrix subdivision described mainly in primates, and a core/shell topographic subdivision of the nucleus accumbens more sharply marked in rodents. (2) Projections from the amygdala form a patchy dorso-ventral progressive gradient in the nucleus accumbens and ventral caudate. (3) Both shell and striosomes receive limbic information from cortical and subcortical limbic structures and project to the dopaminergic neurons of the substantia nigra pars compacta, which in turn modulates their activity. (4) There is a significant overlap between the ventral portions of the BG, nucleus accumbens and ventral pallidum, and the ventral subcortical structures of the limbic system, extended amygdala and nucleus basalis. CONCLUSION: Important interactions exist between the limbic system and the BG system but questions remain about the role that this information plays in the functional organisation of this system. Is limbic information processed separately in the BG, or is it integrated to motor and cognitive information? Do pathological conditions such as obsessive-compulsive disorders or Tourette syndrome result from abnormal afferent limbic input to the BG or abnormal processing within the BG?

Variability in nucleus accumbens activity mediates age-related suboptimal financial risk taking.

As human life expectancy continues to rise, financial decisions of aging investors may have an increasing impact on the global economy. In this study, we examined age differences in financial decisions across the adult life span by combining functional neuroimaging with a dynamic financial investment task. During the task, older adults made more suboptimal choices than younger adults when choosing risky assets. This age-related effect was mediated by a neural measure of temporal variability in nucleus accumbens activity. These findings reveal a novel neural mechanism by which aging may disrupt rational financial choice.

Low frequency fluctuations reveal integrated and segregated processing among the cerebral hemispheres.

Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting-state functional connectivity (RSFC) remains relatively uncharacterized. In the present study, we examine non-homotopic regions, characterizing heterotopic RSFC and comparing it to intrahemispheric RSFC, to examine the impact of hemispheric separation on the integration and segregation of processing in the brain. Resting-state fMRI scans were acquired from 59 healthy participants to examine inter-regional correlations in spontaneous low frequency fluctuations in BOLD signal. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions (56 per hemisphere) distributed throughout the entire cerebrum. We compared RSFC for pairings of non-homologous regions located in different hemispheres (heterotopic connectivity) to RSFC for the same pairings when located within hemisphere (intrahemispheric connectivity). For positive connections, connectivity strength was greater within each hemisphere, consistent with integrated intrahemispheric processing. However, for negative connections, RSFC strength was greater between the hemispheres, consistent with segregated interhemispheric processing. These patterns were particularly notable for connections involving frontal and heteromodal regions. The distribution of positive and negative connectivity was nearly identical within and between the hemispheres, though we demonstrated detailed regional variation in distribution. We discuss implications for leading models of interhemispheric interaction. The future application of our analyses may provide important insight into impaired interhemispheric processing in clinical and aging populations.

Regional heterogeneity in limbic maturational changes: evidence from integrating cortical thickness, volumetric and diffusion tensor imaging measures.

Magnetic resonance imaging (MRI) studies of structural brain development have suggested that the limbic system is relatively preserved in comparison to other brain regions with healthy aging. The goal of this study was to systematically investigate age-related changes of the limbic system using measures of cortical thickness, volumetric and diffusion characteristics. We also investigated if the "relative preservation" concept is consistent across the individual sub-regions of the limbic system. T1 weighted structural MRI and Diffusion Tensor Imaging data from 476 healthy participants from the Brain Resource International Database was used for this study. Age-related changes in grey matter (GM)/white matter (WM) volume, cortical thickness, diffusional characteristics for the pericortical WM and for the fiber tracts associated with the limbic regions were quantified. A regional variability in the aging patterns across the limbic system was present. Four important patterns of age-related changes were highlighted for the limbic sub-regions: 1. early maturation of GM with late loss in the hippocampus and amygdala; 2. an extreme pattern of GM preservation in the entorhinal cortex; 3. a flat pattern of reduced GM loss in the anterior cingulate and the parahippocampus and; 4. accelerated GM loss in the isthmus and posterior cingulate. The GM volumetric data and cortical thickness measures proved to be internally consistent, while the diffusional measures provided complementary data that seem consistent with the GM trends identified. This heterogeneity can be hypothesized to be associated with age-related changes of cognitive function specialized for that region and direct connections to the other brain regions sub-serving these functions.