Loneliness is linked to specific subregional alterations in hippocampus-default network covariation.

Social interaction complexity makes humans unique. But in times of social deprivation, this strength risks exposure of important vulnerabilities. Human social neuroscience studies have placed a premium on the default network (DN). In contrast, hippocampus (HC) subfields have been intensely studied in rodents and monkeys. To bridge these two literatures, we here quantified how DN subregions systematically covary with specific HC subfields in the context of subjective social isolation (i.e., loneliness). By codecomposition using structural brain scans of ∼40,000 UK Biobank participants, loneliness was specially linked to midline subregions in the uncovered DN patterns. These association cortex patterns coincided with concomitant HC patterns implicating especially CA1 and molecular layer. These patterns also showed a strong affiliation with the fornix white matter tract and the nucleus accumbens. In addition, separable signatures of structural HC-DN covariation had distinct associations with the genetic predisposition for loneliness at the population level.NEW & NOTEWORTHY The hippocampus and default network have been implicated in rich social interaction. Yet, these allocortical and neocortical neural systems have been interrogated in mostly separate literatures. Here, we conjointly investigate the hippocampus and default network at a subregion level, by capitalizing structural brain scans from ∼40,000 participants. We thus reveal unique insights on the nature of the "lonely brain" by estimating the regimes of covariation between the hippocampus and default network at population scale.

Nucleus accumbens projections: Validity and reliability of fiber reconstructions based on high-resolution diffusion-weighted MRI.

Clinical effects of deep brain stimulation are largely mediated by the activation of myelinated axons. Hence, increasing attention has been paid in the past on targeting white matter tracts in addition to gray matter. Aims of the present study were: (i) visualization of discrete afferences and efferences of the nucleus accumbens (NAc), supposed to be a major hub of neural networks relating to mental disorders, using probabilistic fiber tractography and a data driven approach, and (ii) validation of the applied methodology for standardized routine clinical applications. MR-data from 11 healthy subjects and 7 measurement sessions each were acquired on a 3T MRI-scanner. For probabilistic fiber tracking the NAc as a seed region and the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), amygdala (AMY), hippocampus (HPC), dorsomedial thalamus (dmT) and ventral tegmental area (VTA) as target regions were segmented for each subject and both hemispheres. To quantitatively assess the reliability and stability of the reconstructions, we filtered and clustered the individual fiber-tracts (NAc to target) for each session and subject and performed a point-by-point calculation of the maximum cluster distances for intra-subject comparison. The connectivity patterns formed by the obtained fibers were in good concordance with published data from tracer and/or fiber-dissection studies. Furthermore, the reliability assessment of the (NAc to target)-fiber-tracts yielded to high correlations between the obtained clustered-tracts. Using DBS with directional lead technology, the workflow elaborated in this study may guide selective electrical stimulation of NAc projections.

Corticostriatal White Matter Integrity and Dopamine D1 Receptor Availability Predict Age Differences in Prefrontal Value Signaling during Reward Learning.

Probabilistic reward learning reflects the ability to adapt choices based on probabilistic feedback. The dopaminergically innervated corticostriatal circuit in the brain plays an important role in supporting successful probabilistic reward learning. Several components of the corticostriatal circuit deteriorate with age, as it does probabilistic reward learning. We showed previously that D1 receptor availability in NAcc predicts the strength of anticipatory value signaling in vmPFC, a neural correlate of probabilistic learning that is attenuated in older participants and predicts probabilistic reward learning performance. We investigated how white matter integrity in the pathway between nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC) relates to the strength of anticipatory value signaling in vmPFC in younger and older participants. We found that in a sample of 22 old and 23 young participants, fractional anisotropy in the pathway between NAcc and vmPFC predicted the strength of value signaling in vmPFC independently from D1 receptor availability in NAcc. These findings provide tentative evidence that integrity in the dopaminergic and white matter pathways of corticostriatal circuitry supports the expression of value signaling in vmPFC which supports reward learning, however, the limited sample size calls for independent replication. These and future findings could add to the improved understanding of how corticostriatal integrity contributes to reward learning ability.

Behavioral and Neural Pathways Supporting the Development of Prosocial and Risk-Taking Behavior Across Adolescence.

This study tested the pathways supporting adolescent development of prosocial and rebellious behavior. Self-report and structural brain development data were obtained in a three-wave, longitudinal neuroimaging study (8-29 years, N = 210 at Wave 3). First, prosocial and rebellious behavior assessed at Wave 3 were positively correlated. Perspective taking and intention to comfort uniquely predicted prosocial behavior, whereas fun seeking (current levels and longitudinal changes) predicted both prosocial and rebellious behaviors. These changes were accompanied by developmental declines in nucleus accumbens and medial prefrontal cortex (MPFC) volumes, but only faster decline of MPFC (faster maturity) related to less rebellious behavior. These findings point toward a possible differential susceptibility marker, fun seeking, as a predictor of both prosocial and rebellious developmental outcomes.

Sex Differences in the Effect of Nucleus Accumbens Volume on Adolescent Drinking: The Mediating Role of Sensation Seeking in the NCANDA Sample.

OBJECTIVE: In adolescence, sensation seeking is associated with earlier onset of alcohol use, which is a risk factor for a variety of negative consequences later in life. Individual differences in sensation seeking are related to brain function in the nucleus accumbens (NAcc), a brain region that undergoes considerable structural development during adolescence. Therefore, the goal of this study was to determine whether NAcc volume in alcohol-naive adolescents was associated with future sensation seeking and alcohol use and whether these associations differed by sex. METHOD: High-resolution magnetic resonance imaging was used to measure NAcc volume at baseline in 514 alcohol-naive adolescents (50.2% female) from the National Consortium on Alcohol & Neurodevelopment in Adolescence study. Direct effects of NAcc volume on adolescent drinking 2 years after baseline, and indirect effects mediated through sensation seeking 1 year after baseline, were assessed. RESULTS: An indirect effect of NAcc volume on subsequent drinking through sensation seeking was significant for males, but not females. This effect was driven by a positive association between NAcc volume and sensation seeking observed in male, but not female, participants. A direct effect of NAcc volume on subsequent alcohol use was detected in females, but not males. In females, no association between NAcc volume and sensation seeking was detected, but NAcc volume was positively associated with future alcohol use. CONCLUSIONS: These findings suggest that delayed structural maturation of the NAcc may be a risk factor for alcohol use in adolescence; however, the mechanism by which the structure of the NAcc confers risk differs by sex.

Separate Contribution of Striatum Volume and Pitch Discrimination to Individual Differences in Music Reward.

Individual differences in the level of pleasure induced by music have been associated with the response of the striatum and differences in functional connectivity between the striatum and the auditory cortex. In this study, we tested whether individual differences in music reward are related to the structure of the striatum and the ability to discriminate pitch. We acquired a 3-D magnetization-prepared rapid-acquisition gradient-echo image for 32 musicians and 26 nonmusicians who completed a music-reward questionnaire and a test of pitch discrimination. The analysis of both groups together showed that sensitivity to music reward correlated negatively with the volume of both the caudate and nucleus accumbens and correlated positively with pitch-discrimination abilities. Moreover, musicianship, pitch discrimination, and caudate volume significantly predicted individual differences in music reward. These results are consistent with the proposal that individual differences in music reward depend on the interplay between auditory abilities and the reward network.

Multimodal characterization of the human nucleus accumbens.

Dysregulation of the nucleus accumbens (NAc) is implicated in numerous neuropsychiatric disorders. Treatments targeting this area directly (e.g. deep brain stimulation) demonstrate variable efficacy, perhaps owing to non-specific targeting of a functionally heterogeneous nucleus. Here we provide support for this notion, first observing disparate behavioral effects in response to direct simulation of different locations within the NAc in a human patient. These observations motivate a segmentation of the NAc into subregions, which we produce from a diffusion-tractography based analysis of 245 young, unrelated healthy subjects. We further explore the mechanism of these stimulation-induced behavioral responses by identifying the most probable subset of axons activated using a patient-specific computational model. We validate our diffusion-based segmentation using evidence from several modalities, including MRI-based measures of function and microstructure, human post-mortem immunohistochemical staining, and cross-species comparison of cortical-NAc projections that are known to be conserved. Finally, we visualize the passage of individual axon bundles through one NAc subregion in a post-mortem human sample using CLARITY 3D histology corroborated by 7T tractography. Collectively, these findings extensively characterize human NAc subregions and provide insight into their structural and functional distinctions with implications for stereotactic treatments targeting this region.

Finding influential nodes for integration in brain networks using optimal percolation theory.

Global integration of information in the brain results from complex interactions of segregated brain networks. Identifying the most influential neuronal populations that efficiently bind these networks is a fundamental problem of systems neuroscience. Here, we apply optimal percolation theory and pharmacogenetic interventions in vivo to predict and subsequently target nodes that are essential for global integration of a memory network in rodents. The theory predicts that integration in the memory network is mediated by a set of low-degree nodes located in the nucleus accumbens. This result is confirmed with pharmacogenetic inactivation of the nucleus accumbens, which eliminates the formation of the memory network, while inactivations of other brain areas leave the network intact. Thus, optimal percolation theory predicts essential nodes in brain networks. This could be used to identify targets of interventions to modulate brain function.

Expression and localization of CB1R, NAPE-PLD, and FAAH in the vervet monkey nucleus accumbens.

Extensive rodent literature suggests that the endocannabinoid (eCB) system present in the nucleus accumbens (NAc) modulates dopamine (DA) release in this area. However, expression patterns of the cannabinoid receptor type 1 (CB1R), the synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), and the degradation enzyme fatty acid amide hydrolase (FAAH) in the NAc have not yet been described in non-human primates. The goal of this study is therefore to characterize the expression and localization of the eCB system within the NAc of vervet monkeys (Chlorocebus sabaeus) using Western blots and immunohistochemistry. Results show that CB1R, NAPE-PLD, and FAAH are expressed across the NAc rostrocaudal axis, both in the core and shell. CB1R, NAPE-PLD, and FAAH are localized in medium spiny neurons (MSNs) and fast-spiking GABAergic interneurons (FSIs). Dopaminergic projections and astrocytes did not express CB1R, NAPE-PLD, or FAAH. These data show that the eCB system is present in the vervet monkey NAc and supports its role in the primate brain reward circuit.

Gene expression links functional networks across cortex and striatum.

The human brain is comprised of a complex web of functional networks that link anatomically distinct regions. However, the biological mechanisms supporting network organization remain elusive, particularly across cortical and subcortical territories with vastly divergent cellular and molecular properties. Here, using human and primate brain transcriptional atlases, we demonstrate that spatial patterns of gene expression show strong correspondence with limbic and somato/motor cortico-striatal functional networks. Network-associated expression is consistent across independent human datasets and evolutionarily conserved in non-human primates. Genes preferentially expressed within the limbic network (encompassing nucleus accumbens, orbital/ventromedial prefrontal cortex, and temporal pole) relate to risk for psychiatric illness, chloride channel complexes, and markers of somatostatin neurons. Somato/motor associated genes are enriched for oligodendrocytes and markers of parvalbumin neurons. These analyses indicate that parallel cortico-striatal processing channels possess dissociable genetic signatures that recapitulate distributed functional networks, and nominate molecular mechanisms supporting cortico-striatal circuitry in health and disease.

Goal-Directed Correlates and Neurobiological Underpinnings of Adolescent Identity: A Multimethod Multisample Longitudinal Approach.

This multimethod multisample longitudinal study examined how neurological substrates associated with goal directedness and information seeking are related to adolescents' identity. Self-reported data on goal-directedness were collected across three biannual waves in Study 1. Identity was measured one wave later. Study 1 design and measurements were repeated in Study 2 and extended with structural brain data (nucleus accumbens [NAcc] and prefrontal cortex gray matter volume [PFC]), collected across three biannual waves. Study 1 included 497 adolescents (Mage T1  = 13.03 years) and Study 2 included 131 adolescents (Mage T1  = 14.69 years). Using latent growth curve models, goal directedness, NAcc, and PFC volume predicted a stronger identity one wave later. These findings provide crucial new insights in the underlying neurobiological architecture of identity.

Volumetric Associations Between Amygdala, Nucleus Accumbens, and Socially Anxious Tendencies in Healthy Women.

Socially anxious individuals report higher social fears and feelings of distress in interpersonal interactions. Structural neuroimaging studies indicate brain morphological abnormalities in patients with social anxiety disorder (SAD), but findings are heterogeneous and partially discrepant. Studies on structural correlates of socially anxious tendencies in participants without clinical diagnoses are scarce. Using structural magnetic resonance imaging, the present study examined the relationship between social interaction anxiety and gray matter (GM) volume in 38 healthy women. The amygdala and nucleus accumbens (NAcc) were defined as a priori regions of interest. Moreover, exploratory whole-brain analyses were conducted. Higher levels of social anxiety significantly predicted increased GM volume in the right amygdala [k = 262 voxels, voxel-level threshold at p < .05 (uncorrected), with a cluster-corrected significance level of p = 0.05 calculated by Monte Carlo Simulations] and bilateral NAcc [left: k = 52 voxels, right: k = 49 voxels; at p < .05 (corrected for search volume)]. These relationships remained significant when controlling for a potential influence of trait anxiety. Additionally, socially anxious tendencies were associated with an enlarged striatum [i.e., putamen and caudate; left: k = 567 voxels, right: k = 539 voxels; at p < .001 (uncorrected)]. Our findings indicate that higher social interaction anxiety in healthy individuals is related to amygdalar and striatal volumetric increases. These brain regions are known to be involved in social perception, anxiety, and the avoidance of harm. Future studies may clarify whether the observed morphological alterations constitute a structural vulnerability factor for SAD.

Collateralization of projections from the paraventricular nucleus of the thalamus to the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala.

The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus with dense projections to the nucleus accumbens (NAc), dorsolateral region of the bed nucleus of the stria terminalis (BSTDL) and the lateral/capsular region of the central nucleus of the amygdala (CeL/CeC). Recent experimental evidence indicates that the PVT is involved in both appetitive and aversive behaviors. However, it is unknown if subgroups of neurons in the PVT innervate different subcortical targets or if the same neurons issue collaterals to multiple areas. To address this issue, we injected two different fluorescent retrograde tracers, cholera toxin subunit B conjugated to Alexa Fluor-488 or Alexa Fluor-594, into different pairs of the subcortical targets including different parts of the NAc (shell, core, dorsomedial shell, and ventromedial shell), BSTDL, and amygdala (basolateral amygdala and CeL/CeC). The results indicate a moderate to high level of collateralization of projections from neurons in the PVT to NAc, BSTDL, and CeL/CeC suggesting a potential importance of the PVT in simultaneously coordinating the activity of key regions of the brain involved in mediating emotional and motivational behaviors. We also observed a difference in the subcortical targets innervated by the anterior PVT (aPVT) and posterior PVT (pPVT) showing that more neurons in the aPVT innervate the dorsomedial part of the NAc shell, while more neurons in the pPVT innervate the ventromedial NAc shell, BSTDL, and CeL/CeC. This observation is suggestive of a potential functional difference between the aPVT and pPVT.

Facebook usage on smartphones and gray matter volume of the nucleus accumbens.

A recent study has implicated the nucleus accumbens of the ventral striatum in explaining why online-users spend time on the social network platform Facebook. Here, higher activity of the nucleus accumbens was associated with gaining reputation on social media. In the present study, we touched a related research field. We recorded the actual Facebook usage of N=62 participants on their smartphones over the course of five weeks and correlated summary measures of Facebook use with gray matter volume of the nucleus accumbens. It appeared, that in particular higher daily frequency of checking Facebook on the smartphone was robustly linked with smaller gray matter volumes of the nucleus accumbens. The present study gives additional support for the rewarding aspects of Facebook usage. Moreover, it shows the feasibility to include real life behavior variables in human neuroscientific research.

Enhanced functional connectivity and volume between cognitive and reward centers of naïve rodent brain produced by pro-dopaminergic agent KB220Z.

Dopaminergic reward dysfunction in addictive behaviors is well supported in the literature. There is evidence that alterations in synchronous neural activity between brain regions subserving reward and various cognitive functions may significantly contribute to substance-related disorders. This study presents the first evidence showing that a pro-dopaminergic nutraceutical (KB220Z) significantly enhances, above placebo, functional connectivity between reward and cognitive brain areas in the rat. These include the nucleus accumbens, anterior cingulate gyrus, anterior thalamic nuclei, hippocampus, prelimbic and infralimbic loci. Significant functional connectivity, increased brain connectivity volume recruitment (potentially neuroplasticity), and dopaminergic functionality were found across the brain reward circuitry. Increases in functional connectivity were specific to these regions and were not broadly distributed across the brain. While these initial findings have been observed in drug naïve rodents, this robust, yet selective response implies clinical relevance for addicted individuals at risk for relapse, who show reductions in functional connectivity after protracted withdrawal. Future studies will evaluate KB220Z in animal models of addiction.

Mapping the co-localization of the circadian proteins PER2 and BMAL1 with enkephalin and substance P throughout the rodent forebrain.

Despite rhythmic expression of clock genes being found throughout the central nervous system, very little is known about their function outside of the suprachiasmatic nucleus. Determining the pattern of clock gene expression across neuronal subpopulations is a key step in understanding their regulation and how they may influence the functions of various brain structures. Using immunofluorescence and confocal microscopy, we quantified the co-expression of the clock proteins BMAL1 and PER2 with two neuropeptides, Substance P (SubP) and Enkephalin (Enk), expressed in distinct neuronal populations throughout the forebrain. Regions examined included the limbic forebrain (dorsal striatum, nucleus accumbens, amygdala, stria terminalis), thalamus medial habenula of the thalamus, paraventricular nucleus and arcuate nucleus of the hypothalamus and the olfactory bulb. In most regions examined, BMAL1 was homogeneously expressed in nearly all neurons (~90%), and PER2 was expressed in a slightly lower proportion of cells. There was no specific correlation to SubP- or Enk- expressing subpopulations. The olfactory bulb was unique in that PER2 and BMAL1 were expressed in a much smaller percentage of cells, and Enk was rarely found in the same cells that expressed the clock proteins (SubP was undetectable). These results indicate that clock genes are not unique to specific cell types, and further studies will be required to determine the factors that contribute to the regulation of clock gene expression throughout the brain.

The telencephalon of the Göttingen minipig, cytoarchitecture and cortical surface anatomy.

During the last 20 years pigs have become increasingly popular in large animal translational neuroscience research as an economical and ethical feasible substitute to non-human primates. The anatomy of the pig telencephalon is, however, not well known. We present, accordingly, a detailed description of the surface anatomy and cytoarchitecture of the Göttingen minipig telencephalon based on macrophotos and consecutive high-power microphotographs of 15 µm thick paraffin embedded Nissl-stained coronal sections. In 1-year-old specimens the formalin perfused brain measures approximately 55 × 47 × 36 mm (length, width, height) and weighs around 69 g. The telencephalic part of the Göttingen minipig cerebrum covers a large surface area, which can be divided into a neocortical gyrencephalic part located dorsal to the rhinal fissure, and a ventral subrhinal part dominated by olfactory, amygdaloid, septal, and hippocampal structures. This part of the telencephalon is named the subrhinal lobe, and based on cytoarchitectural and sulcal anatomy, can be discerned from the remaining dorsally located neocortical perirhinal/insular, pericallosal, frontal, parietal, temporal, and occipital lobes. The inner subcortical structure of the minipig telencephalon is dominated by a prominent ventricular system and large basal ganglia, wherein the putamen and the caudate nucleus posterior and dorsally are separated into two entities by the internal capsule, whereas both structures ventrally fuse into a large accumbens nucleus. The presented anatomical data is accompanied by surface renderings and high-power macrophotographs illustrating the telencephalic sulcal pattern, and the localization of the identified lobes and cytoarchitectonic areas. Additionally, 24 representative Nissl-stained telencephalic coronal sections are presented as supplementary material in atlas form on http://www.cense.dk/minipig_atlas/index.html and referred to as S1-S24 throughout the manuscript.

Heritability of the shape of subcortical brain structures in the general population.

The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. In 3,686 unrelated individuals aged between 45 and 98 years, brain magnetic resonance imaging and genotyping was performed. The maximal heritability of shape varies from 32.7 to 53.3% across the subcortical structures. Genetic contributions to shape extend beyond influences on intracranial volume and the gross volume of the respective structure. The regional variance in heritability was related to the reliability of the measurements, but could not be accounted for by technical factors only. These findings could be replicated in an independent sample of 1,040 twins. Differences in genetic contributions within a single region reveal the value of refined brain maps to appreciate the genetic complexity of brain structures.

Neural changes in the primate brain correlated with the evolution of complex motor skills.

Complex motor skills of eventual benefit can be learned after considerable trial and error. What do structural brain changes that accompany such effortful long-term learning tell us about the mechanisms for developing innovative behavior? Using MRI, we monitored brain structure before, during and after four marmosets learnt to use a rake, over a long period of 10-13 months. Throughout learning, improvements in dexterity and visuo-motor co-ordination correlated with increased volume in the lateral extrastriate cortex. During late learning, when the most complex behavior was maintained by sustained motivation to acquire the skill, the volume of the nucleus accumbens increased. These findings reflect the motivational state required to learn, and show accelerated function in higher visual cortex that is consistent with neurocognitive divergence across a spectrum of primate species.