Brain Structure and Function

Animal experiments reveal distinct GABAergic cell clusters within the dopaminergic midbrain regions in the rostromedial tegmental nucleus (RMTg) and retrorubral fields (RRF) that have yet to be clearly defined in humans. These neurons send prominent inhibitory projections to dopaminergic neurons in the substantia nigra and ventral tegmental area that impact motor, reward and threat processing. We have identified GABAergic RMTg and RRF cell clusters in 6{micro}m formalin-fixed paraffin-embedded transverse human midbrain sections from ten control cases obtained from the Sydney Brain Bank using immunohistochemistry for GABA and tyrosine hydroxylase. We determined the location and cell size of RMTg and RRF GABAergic neurons, further mapping these cell cluster in transverse 50{micro}m thick cresyl violet stained serial midbrain sections (every 750{micro}m) from previously published controls (Halliday et al. 1990a). GABAergic neurons were cytoarchitecturally distinct, with the largest GABAergic neurons in the RRF, followed by RMTg neurons which were larger than GABAergic neurons in the well-defined interpedunclular nucleus (Kruskal-Wallis test, p<0.0001). RMTg and RRF GABAergic neurons first appear in caudal transverse midbrain sections approximately 38mm above the obex. RMTg moves rostrally and medially from underneath the decussation of the superior cerebellar peduncle to just lateral to the interpeduncular nucleus. The RRF cluster also moves rostrally and medially to the parabrachial pigmented nucleus (PBP) just under the red nucleus. The GABAergic neurons in RMTg and RRF/PBP that modulate dopamine neuronal excitability have distinct morphologies in humans. Identifying these inhibitory neurons is key to evaluating their role in neurodegenerative diseases.

Until the discovery of white matter neurons (WMN) in the 19th century, white matter (WM) was considered to be completely devoid of neuronal cell bodies. Despite evidence consistently showing evident neuronal soma within cortical WM and their purported implication in neuropsychiatric disorders, these neurons are understudied and have not been characterized in human long-range WM tracts. Using postmortem human brain tissue, we investigated the presence, densities and proportions of excitatory/inhibitory neurons in the uncinate fasciculus (UF) and corpus callosum (CC). We also investigated the ventromedial prefrontal cortex (vmPFC) to validate our methods by comparing our results with previously reported densities of neurons in cortical WM. To identify WMN, we employed fluorescence in situ hybridization with excitatory (SLC17A7) and inhibitory (GAD1) neuronal markers and subsequently validated these neurons at the protein level with NeuN immunohistochemistry. We found that the density of WMN in the vmPFC corresponded with previous independent estimates. The UF displayed a similar, though slightly lower density of WMN compared to the vmPFC, while the CC had a far lower density of WMN than both of these regions. Due to the higher-than-expected density of WMN in the UF, we validated the findings at a second location along the UF temporal segment and confirmed the presence of substantial numbers of WMN in this tract. This research constitutes the first ever validated observation of WMN in human long-range WM tracts, laying the foundation for future research on the phenotype and function of these neurons, and how they may be affected in brain disorders.

Adolescence is a period of development which is characterised by distinct differences in decision-making strategies relative to adults. While it is broadly established that there are relative differences in the structural maturation of the prefrontal cortex (PFC) and subcortical reward nuclei, such as the amygdala and ventral striatum, heterogeneity within the PFC is often neglected. In particular very little is known about the fine-scale gray matter (GM) development of the Orbitofrontal Cortex (OFC), itself critical to a number of learning and decision-making mechanisms which show delayed development trajectories. Here we applied voxel-based morphometry to examine subregional differences in OFC grey matter in high-quality structural MRI scans of 125 subjects aged 11-35yrs from the Human Connectome Project. First, we examined fine-scale GM maturation in 5 anatomically dissociable OFC subregions and identified the best-fitting polynomial model. Next, we directly compared developmental trajectories across 3 functionally dissociable subregions, revealing a complex topological developmental profile from medial to lateral subregions. Collectively, the two complementary analyses suggest that while unequivocally the phylogenetically younger lateral OFCs showed the greatest shift in GM volume across adolescence, with maturation continuing well into young adulthood, the differences between the medial and central OFC subregions suggested a more complex pattern of maturation than a simple graded medial to lateral topological development. We argue that knowledge of these fine-scale anatomical differences in maturation could explain precise mechanistic differences in goal-directed behaviours.

A central principle in our understanding of cerebral cortical organization is that homotopic left and right areas are functionally linked to each other, and also connected with structures that share similar functions within each cerebral cortical hemisphere. Here we refer to this concept as interhemispheric functional symmetry (IHFS). While multiple studies have described the distribution and variations of IHFS in the cerebral cortex, descriptions of IHFS in the subcortex are largely absent in the neuroscientific literature. Further, the proposed anatomical basis of IHFS is centered on callosal and other commissural tracts. These commissural fibers are present in virtually all cerebral cortical areas, but almost absent in the subcortex. There is thus an important knowledge gap in our understanding of subcortical IHFS. What is the distribution and variations of subcortical IHFS, and what are the anatomical correlates and physiological implications of this important property in the subcortex? Using fMRI functional gradient analyses in a large dataset (Human Connectome Project, n=1003), here we explored IHFS in human thalamus, lenticular nucleus, cerebellar cortex, and caudate nucleus. Our detailed descriptions provide an empirical foundation upon which to build hypotheses for the anatomical and physiological basis of subcortical IHFS. Our results indicate that direct or driver cerebral cortical afferent connectivity, as opposed to indirect or modulatory cerebral cortical afferent connectivity, is associated with stronger subcortical IHFS in thalamus and lenticular nucleus. In cerebellar cortex and caudate, where there is no variability in terms of either direct vs. indirect or driver vs. modulatory cerebral cortical afferent connections, connectivity to cerebral cortical areas with stronger cerebral cortical IHFS is associated with stronger IHFS in the subcortex. These two observations support a close relationship between subcortical IHFS and connectivity between subcortex and cortex, and generate new testable hypotheses that advance our understanding of subcortical organization.

IntroductionWe present here a methodology for morphometric analysis of the substantia nigra (SN), the ventral tegmental area (VTA), the dorsal raphe nucleus (DRN) and their respective structural brain circuits. MethodsOur analyses were based on multimodal T1-weighted MRI and diffusion MRI (dMRI) segmentation and tractography in 12 human subjects drawn from the Human Connectome Project (HCP) repository. ResultsWe were able to demonstrate strong connections of the SN, VTA and DRN with several brain regions, in particular the dorsolateral prefrontal cortex (DLPFC) and the cerebellum. More specifically, we created comprehensive visualizations of the SN and VTA dopaminergic as well as the DRN serotonergic structural circuits in the human brain, which, although preliminary, demonstrate the potential of multimodal neuroimaging to investigate these circuits quantitatively in clinical conditions. Finally, we created a pilot dataset for the most frequently observed structural connections, specifically those that were present more than 92% of the time among all subjects. Discussion This pilot morphometric report examines the structural circuits of the SN, VTA and DRN, which are critically involved in several biobehaviors and clinical conditions such as addiction, stress, Parkinsons disease (PD), schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, mood disorders, COVID-19 and long COVID. Importantly, the strong structural connectivity of the DLPFC and cerebellum with the SN, VTA and DRN is expected to be a potential target of noninvasive neuromodulation treatments in neuropsychiatry. Our findings demonstrate the potential of current clinical multimodal neuroimaging to delineate the dopaminergic (DA) and serotonergic (5-HT) circuits in the human brain in clinical conditions.

Individuals with congenital sensory loss usually demonstrate altered brain morphology in areas associated with early processing of the lost sense. Here, we aimed to establish whether this also applies to individuals born without a sense of smell (congenital anosmia) by comparing cortical morphology between 33 individuals with isolated congenital anosmia and matched controls. We detected no structural alterations in the primary olfactory (piriform) cortex. However, individuals with anosmia demonstrated gray matter volume atrophy in bilateral olfactory sulci, explained by decreased cortical area, curvature, and sulcus depth. They further demonstrated increased gray matter volume and cortical thickness in the medial orbital gyri; regions closely associated with olfactory processing, sensory integration, and value-coding. Our results suggest that a lifelong absence of sensory input does not necessarily lead to morphological alterations in primary sensory cortex and extend previous findings with divergent morphological alterations in bilateral orbitofrontal cortex, indicating influences of different plastic processes.

BackgroundThe medial cerebral cortex contains several sulci of high anatomical and clinical relevance, including the cingulate, paracingulate, calcarine, parieto-occipital, callosal, Rostral, supra-rostral and subparietal sulci. These structures serve as essential neuroanatomical landmarks and surgical corridors in microneurosurgical procedures, yet they exhibit considerable morphological variability. Although numerous studies have examined these sulci, no comprehensive synthesis exists focusing exclusively on cadaveric morphological and morphometric data, which remain critical for accurate neuroanatomical understanding. MethodsThis scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology and reported following the PRISMA-ScR checklist. A comprehensive literature search identified 4,440 records, of which 60 duplicates were removed. Screening of titles and abstracts excluded 3911 records, leaving 469 for full-text review. After applying eligibility criteria, eight cadaveric studies were included. Data were extracted on sample characteristics, morphological classification, and quantitative morphometry for the medial sulci. Findings were synthesized narratively and tabulated by sulcus type. ResultsThe included studies analyzed a total of 422 hemispheres from formalin-fixed cadaveric brains. The cingulate sulcus was consistently present in all examined specimens, whereas the paracingulate sulcus displayed marked variability. The calcarine sulcus demonstrated relatively stable morphometry, with mean anterior and posterior segment lengths ranging from 2.3 to 3.5 cm, yet exhibited variable bifurcation patterns and lunate sulcus connections. The parieto-occipital sulcus was a reliable boundary between the cuneus and precuneus, with mean lengths around 4.0 cm. The subparietal sulcus was described less frequently, highlighting a gap in detailed morphometric literature. ConclusionCadaveric evidence confirms both consistent and highly variable features in the medial cerebral sulci. These variations have direct implications for surgical planning, particularly in interhemispheric approaches. The paucity of detailed morphometric descriptions for certain sulci, especially the subparietal, callosal, rostral and supra-rostral sulcus, underscores the need for further targeted anatomical research.

Cortical atlases constitute a consistent division of the human cortex into areas that have common structural as well as meaningful and distinctive functional characteristics. The most widely used atlases follow the cytoarchitectonic and myeloarchitectonic characteristics of the cortex and have been combined to the standard anatomical nomenclature of gyri and sulci. More recently, common functional features depicted by resting state functional MRI have also guided the division of the cortical brain in functional regions of interest. However, to date, there are no atlases that divide the cortex considering the common evolutionary changes experienced by the mammalian cortex. Hence, the present study proposes the division of cortical areas into five main regions of interest (ROIs) following a phylogenetic approach: 1- archicortex, 2- paleocortex, 3- peri-archicortex, 4- proisocortex, 5-neocortex, and twelve neocortical sub-ROIs: 5.1.temporopolar, 5.2.post-central, 5.3.pre-central, 5.4.pericalcarine, 5.5.superior temporal, 5.6.middle temporal, 5.7.precuneus, 5.8.insular, 5.9.inferior parietal, 5.10.caudal anterior, 5.11.posterior cingulate, and 5.12.lingual gyrus. The segmentations were done using the T1-weighted MNI-ICBM152 non-linear 6th generation symmetric average brain MRI model.

Corticostriatal projections form the input level of a circuitry that connects the cerebral cortex, basal ganglia, and thalamus. Three distinct, functional subcircuits exist according to the tripartite model: Sensorimotor cortices projecting mainly to the dorsolateral striatum; associative cortices projecting to the dorsomedial striatum and limbic cortices projecting to the ventral striatum. However, there is to date no atlas that allows researchers to label cortical projection areas belonging to each of these subcircuits separately. To address this research gap, the aim of this study was threefold: First, to systematically review anatomical tracing studies that focused on corticostriatal projections in non-human primates, and to classify their findings according to the tripartite model. Second, to develop an atlas of the human cerebral cortex based on this classification. Third, to test the hypothesis that labels in this atlas show structural connectivity with specific striatal subregions in humans using diffusion-based tractography in a sample of 24 healthy participants. In total, 98 studies met the inclusion criteria for our systematic review. Information about projections from the cortex to the striatum was systematically extracted by Brodmann area, and cortical areas were classified by their dominant efferent projections. Taking known homological and functional similarities and differences between non-human primate and human cortical regions into account, a new human corticostriatal projection (CSP) atlas was developed. Using human diffusion-based tractography analyses, we found that the limbic and sensorimotor atlas labels showed preferential structural connectivity with the ventral and dorsolateral striatum, respectively. However, the pattern of structural connectivity for the associative label showed the greatest degree of overlap with other labels. We provide this new atlas as a freely available tool for neuroimaging studies, where it allows for the first-time delineation of anatomically informed regions-of-interest to study functional subcircuits within the corticostriatal circuitry. This tool will enable specific investigations of subcircuits involved in the pathogenesis of neuropsychiatric illness such as schizophrenia and bipolar disorders. Highlights- Systematic review of anatomical projections from the cerebral cortex to the striatum in non-human primates. - Development of a novel cortical atlas for use in neuroimaging studies focusing on the corticostriatal brain circuitry. - Tractography in human diffusion-weighted imaging data to test if associative, limbic, and sensorimotor cortical atlas labels show preferential connectivity to regions within the striatum.

The locus coeruleus (LC) contains predominantly norepinephrine (NE) neurons that project widely throughout the brain. The LC plays a critical role in controlling behavior, particularly arousal. Historically, it was thought that the LC-NE system performed its behavioral control function by uniformly releasing NE throughout most brain regions. However, recent evidence suggests that the LCs cortical projections are organized into modules, which allows for the coordination of diverse, and sometimes opposing, functions such as fear memory formation and extinction. Nevertheless, many details remain unclear and require data from the axon collaterals of sparse neurons. We modified a viral tracing protocol using a dual-recombinase system to trace the axonal collaterals of sparse LC neurons projecting to the cingulate cortex (CgC). Our results show that even a small number of LC neurons have broad cortical projections, though the pattern is not uniform. Centered-log ratio transformation of NE fiber distribution across the cortex and hippocampus reveals a few preferential target areas (PTAs) of the labeled LC-NE neurons axonal projections. The summed NE fiber length in these defined PTs is enriched relative to the geometric mean of all other cortical and hippocampal regions where NE fibers were detected. Notably, the defined PTAs--including the rostral splenial cortex, dorsal hippocampus, somatosensory cortex, and CgC (the retrograde viral labeling injection site)--are functionally related to navigation. These results demonstrate that LC-NE neurons are organized into distinct projection modules, each comprising a small number of neurons with functionally correlated major cortical targets.

Mapping the chimpanzee brain connectome, and comparing it to humans, is key to our understanding of similarities and differences in primate evolution that occurred after the split from their common ancestor around 6 million years ago. In contrast with macaque species brain studies, less studies have specifically addressed the structural connectivity of the chim-panzee brain and its comparison with the human brain. Most comparative studies in the liter-ature focus on the anatomy of the cortex and deep nuclei to evaluate how their morphometry and asymmetry differs from that of the human brain, and some studies have emerged concern-ing the study of brain connectivity between primates. In this work, we established a new white matter atlas of the deep and superficial white matter structural connectivity in chimpanzees. In vivo anatomical and diffusion weighted magnetic resonance imaging (MRI) data were collected on a 3 Tesla magnetic resonance imaging (MRI) system in 39 chimpanzees. These datasets were subsequently processed using a dedicated fiber clustering pipeline adapted to the chimpanzee brain enabling us to create two novel deep and superficial white matter connectivity atlases representative of the chimpanzee brain. These atlases provide the scientific community with an important and novel set of reference data for understanding the commonalities and differ-ences of the structural connectivity between the human and chimpanzee brains, which will contribute to a better understanding of the hominin brain evolution.

The size of the mammalian cerebrum spans more than 5 orders of magnitude. The smallest cerebrums have a smooth (lissencephalic) cortical surface, which gets increasingly folded (gyrencephalic) with cerebral size. Further, the proportion of white-to-gray matter volume increases with the total volume. These scaling relations have unusually little variation. Even though a number of theories and models have been proposed, it remains an open question, why this is so. Here, we show that almost all variance is explained by assuming a homogeneous composition of the cortex across mammals. On the basis of this assumption we derive quantitative analytical computational models. The first model predicts the cortical surface area from the gray and white matter volume. A single free parameter, for the height of cortical columns is estimated as{lambda} = 2.9 mm (r2 = 0.996). The second model predicts the white matter volume as a function of the gray volume and the cerebral size (with parameters for intra- and extra-gyral connections lint, lext; [Formula]). The models are validated by predicting the effective cortical thickness and the folding parameter{kappa} . The results accurately predict the human intraspecific variation of the surface relations. As expected, we find a reduced{lambda} for cetaceans, and that preterm human infants do not follow the model. We also find deviations of gray and white matter volume for large cerebrums. Overall, the models thus show how the regular architecture of the cortex shapes the cerebrum. We conclude that the mammalian cerebrum scales in an isomorphic, rather than isometric, manner.

Relaxin family peptide receptor-3 (RXFP3) is a ligand-activated G-protein coupled receptor and the cognate receptor for the conserved neuropeptide relaxin-3. We recently demonstrated that chemogenetically activating an RXFP3-expressing population in the lateral hypothalamus and zona incerta (LH/ZIRXFP3) induced escape-like jumping behaviour following fear conditioning, but only in a subset of mice. Given the diverse hodology of the LH and ZI, we hypothesised that LH/ZIRXFP3 cells may consist of discrete subpopulations with unique connectivity patterns that govern different aspects of defensive behaviour. To explore this possibility, we unilaterally injected small volumes of a Cre-dependent anterograde viral tracer into four distinct sites of the LH/ZI in RXFP3-Cre mice and analysed their brain-wide efferent connectivity patterns. Each injection site group produced unique projection patterns, particularly to nuclei involved in threat and defensive behaviour. Of note were strong projections from the rostral ZI and anterior LH to the lateral habenula, and projections from the intermediate and caudal ZI to the ventrolateral periaqueductal gray. By combining retrograde tracing and RNAscope fluorescent in situ hybridisation, we identified that most LH/ZIRXFP3 projections to the lateral habenula arose from a subset of vGlut2-expressing lateral hypothalamus neurons, while most projections to the ventrolateral periaqueductal gray arose from a subset of GAD1-expressing zona incerta neurons. Taken together, our results strongly suggest that LH/ZIRXFP3 cells exhibit distinct efferent projection patterns throughout the brain depending on their topographical location within these nuclei, likely reflecting the functional diversity of these neurons.

Brain entropy (BEN) indicates the irregularity, unpredictability and complexity of brain activity. Research using regional brain entropy (rBEN) based on fMRI has established its associations with structural and functional brain networks, as well as their coupling. These relationships are influenced by the sensorimotor-association (S-A) axis and cytoarchitectural organization. Recent studies have also revealed links between functional connectome gradients and cell-type, suggesting that rBEN may have a biological basis at the cellular level. However, this possibility remains unexplored at specifically cellular level. In this study, we analyzed mean rBEN maps derived from 176 participants using HCP 7T data and correlated these with publicly available cell-type datasets. Our findings rBEN exhibited a positive correlation with oligodendrocytes (Oligo) and a negative correlation with parvalbumin-positive interneurons (PVALB) under both resting-state and movie-watching conditions at the whole-brain level. Furthermore, we observed that the S-A axis modulates the relationship between rBEN and cell-type. Specifically, L5 extratelencephalic neurons (L5 ET) showed a positive correlation with rBEN in unimodal cortex but a negative correlation in multimodal cortex and interneurons somatostatin (SST) was correlated with rBEN only in multimodal cortex. These results provide further evidence that rBEN has a biological foundation at the cellular level, with spatial heterogeneity in its associations with different cell types. Moreover, rBEN appears to capture information beyond functional connectivity network.

Language is one of the most extensively studied lateralised cognitive functions in the human brain, predominantly relying on the left hemisphere in most individuals. However, the mechanisms by which a stable white matter architecture underpins individual language functions remain unclear. Previous studies have employed structural connectivity (SC) and functional connectivity (FC) coupling for individual fingerprinting and task decoding, suggesting that variability in brain entropy may serve as a distinguishing characteristic for language lateralisation. We examined a large cohort of healthy adults (n = 285) to investigate SC-FC coupling and identify markers distinguishing different language laterality groups. Functional connectivity was measured using resting-state fMRI (rsfMRI) time-series data, while structural connectivity was determined via probabilistic fibre tractography. SC-FC coupling was investigated using the SENSAAS language atlas and defined as the Pearson correlation between non-zero elements of regional structural and functional connectivity profiles. Group differences were assessed using the PALM toolbox in FSL. Our findings revealed that increased SC-FC coupling in the left precentral sulcus was associated with typical language lateralisation, while increased coupling in the right middle temporal gyrus and left anterior insula was observed in individuals with atypical language lateralisation (pFDR < 0.05). Non-lateralised individuals exhibited increased coupling in the left anterior insula compared to lateralised (pFDR<0.05). SC-FC coupling offers a promising framework to uncover functional and anatomical differences among individuals with varying language lateralisation. This regional specificity indicates that typical, atypical, and non-lateralised profiles rely on different structural-functional alignments, likely reflecting the recruitment of alternative pathways for language processing.

Recent work has uncovered relationships between evolutionarily new small and shallow cerebral indentations, or sulci, and human behavior. Yet, this relationship remains unexplored in the lateral parietal cortex (LPC) and the lateral parieto-occipital junction (LPOJ). After defining thousands of sulci in a young adult cohort, we revised the previous LPC/LPOJ sulcal landscape to include four previously overlooked, small, shallow, and variable sulci. One of these sulci (ventral supralateral occipital sulcus, slocs-v) is present in nearly every hemisphere and is morphologically, architecturally, and functionally dissociable from neighboring sulci. A data-driven, model-based approach, relating sulcal depth to behavior, further revealed that the morphology of only a subset of LPC/LPOJ sulci, including the slocs-v, is related to performance on a spatial orientation task. Our findings build on classic neuroanatomical theories and identify new neuroanatomical targets for future "precision imaging" studies exploring the relationship among brain structure, brain function, and cognitive abilities in individual participants.

The right inferior frontal gyrus (rIFG) has most strongly, although not exclusively, been associated with response inhibition, not least based on covariations of behavioral performance measures and local grey matter characteristics. However, the white matter microstructure of the rIFG as well as its connectivity has been less in focus, especially when it comes to the consideration of potential subdivisions within this area. The present study reconstructed the structural connections of the three main subregions of the rIFG (i.e. pars opercularis, pars triangularis and pars orbitalis) using diffusion tensor imaging, and further assessed their associations with behavioral measures of inhibitory control. The results revealed a marked heterogeneity of the three subregions with respect to the pattern and extent of their connections, with the pars orbitalis showing the most widespread inter-regional connectivity, while the pars opercularis showed the least amount of connections. When relating behavioral performance measures of a stop signal task to brain structure, the data indicated a differential association of dorsal and ventral opercular connectivity with the go reaction time and the stopping accuracy, respectively.

Hyperactivity of the basolateral amygdaloid nuclear complex (BLA) is a hallmark of anxiety-related disorders in humans. Excitation of BLA projection neurons (PN) is fine-tuned by inhibitory interneurons (INs). Monoaminergic afferents to the BLA modulate PN and IN activity. In the present study, BLA-INs immunoreactive(ir) for parvalbumin (PV) or neuropeptide Y (NPY) and their interrelations with serotonergic and catecholaminergic afferents were analyzed in wildtype (WT) and serotonin transporter knockout (5-HTT KO) mice, a model for anxiety- and stress-related disorders. In WT mice, PV- and NPY-ir INs fall into morphological subgroups which possess perisomatic appositions by serotonergic and tyrosine hydroxylase-ir afferents. Dual immunolabeling shows no colocalization of PV and NPY. NPY/somatostatin(SOM) dual labeling documents colocalization of the peptides in some neurons, and single labeling for NPY or SOM in others. These features appear largely preserved in 5-HTT KO mice. However, quantification of PV- and NPY-ir neurons documents a reduction in number and density of NPY-ir neurons throughout the rostrocaudal extent of the amygdala in 5-HTT KO mice. PV-ir neurons remain unchanged. Quantitative PCR shows increased expression of Npy receptor 2, Som receptor 4, and corticotropin releasing factor receptor 1 in the BLA of 5-HTT KO mice. mRNA for the three peptides is unchanged, indicating that it may be NPY propeptide translation which is reduced in 5-HTT KO mice. Taken together, the results document an effect of life-long serotonin imbalance on the BLA NPY-system, which may contribute to previously observed morphological alterations in BLA PNs and increased anxiety-like behavior in 5-HTT KO mice.

Characterization of the structural integrity of cortex in adults who have undergone resection for epilepsy treatment has, in some cases, revealed persistent or even accelerated cortical atrophy but, in others, the converse is evident, and atrophy decelerates or even reverses. Whether this variability applies to a pediatric population, for whom postoperative plasticity may be greater than in adulthood, remains to be determined. Furthermore, understanding the morphometrics of this patient population is important, as cognitive gains have been associated with the anatomical status of preserved cortex post-resection. Here, we used high-resolution structural T1 magnetic resonance imaging data to compare the (1) gross anatomy, (2) cortical thickness, volume, and surface area for 34 cortical regions, and (3) volume for nine subcortical regions of 32 pediatric post-surgical cases and 51 healthy controls. Patients with either a preserved right hemisphere (RH) or left hemisphere (LH) had lower total white matter volume and select subcortical structures volumes, relative to controls; lateral ventricle size of both preserved RH and LH patients was also significantly larger than that of controls. However, relative to controls, only patients with a preserved RH had significantly lower total gray matter volume and lower thickness, volume, and surface area in multiple cortical regions, primarily in frontal and temporal cortex. The differences in preserved RH cortex of LH resection patients may relate to transfer of language function from the resected LH. Our findings lay the foundation for future studies probing associations of the morphometric differences in pediatric epilepsy surgery patients with neuropsychological outcomes.

Decades of histological research in non-human primates have revealed a dense web of short-range connections underpinning prefrontal cortex (PFC) function. However, translating this anatomical ground-truth to the living human brain has been a major challenge, leaving our understanding of the PFCs intrinsic wiring incomplete. These short-range fibers are difficult to resolve with non-invasive methods like diffusion tractography, which are often hampered by false positives. Here, we provide the first systematic in-vivo visualization of these pathways in the human brain. By informing high-resolution probabilistic tractography with established tract-tracing findings, we mapped 91 histologically-defined short-range connections within and between five major PFC subdivisions in 1,003 individuals (547 F, 456 M). Our anatomically-informed approach successfully reconstructed these intricate connections with high precision (>80%) and accuracy (>70%) relative to histological findings. The resulting tracts not only captured broad organizational principles but also replicated fine-grained patterns previously only seen in invasive studies. Furthermore, these connections showed high test-retest reliability within individuals alongside significant variability between them, highlighting a stable yet unique anatomical fingerprint. Ultimately, this study shows how linking histology to tractography provides a powerful framework to advance our understanding of the human connectome and opens avenues to investigate local circuitry that underpins cognition and disease.