Deep learning-based, fully automated, pediatric brain segmentation.

The purpose of this study was to demonstrate the performance of a fully automated, deep learning-based brain segmentation (DLS) method in healthy controls and in patients with neurodevelopmental disorders, SCN1A mutation, under eleven. The whole, cortical, and subcortical volumes of previously enrolled 21 participants, under 11 years of age, with a SCN1A mutation, and 42 healthy controls, were obtained using a DLS method, and compared to volumes measured by Freesurfer with manual correction. Additionally, the volumes which were calculated with the DLS method between the patients and the control group. The volumes of total brain gray and white matter using DLS method were consistent with that volume which were measured by Freesurfer with manual correction in healthy controls. Among 68 cortical parcellated volume analysis, the volumes of only 7 areas measured by DLS methods were significantly different from that measured by Freesurfer with manual correction, and the differences decreased with increasing age in the subgroup analysis. The subcortical volume measured by the DLS method was relatively smaller than that of the Freesurfer volume analysis. Further, the DLS method could perfectly detect the reduced volume identified by the Freesurfer software and manual correction in patients with SCN1A mutations, compared with healthy controls. In a pediatric population, this new, fully automated DLS method is compatible with the classic, volumetric analysis with Freesurfer software and manual correction, and it can also well detect brain morphological changes in children with a neurodevelopmental disorder.

An orexigenic subnetwork within the human hippocampus.

Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

Dissociating distinct cortical networks associated with subregions of the human medial temporal lobe using precision neuroimaging.

Tract-tracing studies in primates indicate that different subregions of the medial temporal lobe (MTL) are connected with multiple brain regions. However, no clear framework defining the distributed anatomy associated with the human MTL exists. This gap in knowledge originates in notoriously low MRI data quality in the anterior human MTL and in group-level blurring of idiosyncratic anatomy between adjacent brain regions, such as entorhinal and perirhinal cortices, and parahippocampal areas TH/TF. Using MRI, we intensively scanned four human individuals and collected whole-brain data with unprecedented MTL signal quality. Following detailed exploration of cortical networks associated with MTL subregions within each individual, we discovered three biologically meaningful networks associated with the entorhinal cortex, perirhinal cortex, and parahippocampal area TH, respectively. Our findings define the anatomical constraints within which human mnemonic functions must operate and are insightful for examining the evolutionary trajectory of the MTL connectivity across species.

A Novel Sublabial Anterior Transmaxillary Approach for Medically Refractory Mesial Temporal Lobe Epilepsy: A Comparative Anatomic Study.

BACKGROUND: Current approaches for mesial temporal lobe epilepsy may result in suboptimal seizure control and cognitive decline. An incomplete treatment of the epileptogenic zone and unnecessary violation of functional cortical and subcortical areas may contribute to suboptimal results. OBJECTIVE: To describe and test the anatomic feasibility of a novel endoscopic anterior transmaxillary (ATM) approach to the temporal lobe and to compare the described technique to other transfacial approaches. METHODS: Twenty-four cadaveric brain hemispheres fixed in formalin were used to study anterior temporal surface anatomy. Two additional hemispheres were fixed in formalin and then frozen for white matter dissections. Subsequently, bilateral dissections on 4 injected cadaveric heads were used to describe the endoscopic ATM approach and to evaluate various anterior endoscopic corridors for the temporal pole and mesial temporal lobe structures. RESULTS: The ATM approach was considered superior because of direct visualization of the temporal pole and natural alignment with the mesial temporal structures. The mean exposure corridor covered 49.1° in the sagittal plane and 66.2° in the axial plane. The ATM allowed direct access lateral to the maxillary and mandibular nerves with an anterior-posterior trajectory aligned to the longitudinal axis of the hippocampus formation, allowing for a selective amygdalohippocampectomy with preservation of the trigeminal branches and the lateral temporal neocortex. CONCLUSION: The ATM approach is anatomically feasible, providing a direct and selective approach for the temporal pole and mesial temporal lobe structures, with a substantial angle of visualization because of its direct alignment with the mesial temporal lobe structures.

[Anatomy of memory]. / Anatomie de la mémoire.

ANATOMY OF MEMORY. Memory phenomena involve neuron circuits and neurogenesis processes at the microscopic level. Nevertheless, the central role played by some key structures such as the hippocampus and the limbic lobe requires a good knowledge of their macroscopic anatomy. This article summarizes an overview of the anatomical organization of these structures and of their abundant connections.

ANATOMIE DE LA MÉMOIRE. Les phénomènes mnésiques mettent en jeu à l'échelle microscopique des circuits neuronaux et des processus de neurogenèse. Néanmoins, le rôle central joué par certaines structures clés comme l'hippocampe ou le lobe limbique impose une bonne connaissance de leur anatomie macroscopique. Cet article propose une synthèse de l'organisation anatomique de ces structures et de leurs riches connexions.

Automated hippocampal unfolding for morphometry and subfield segmentation with HippUnfold.

Like neocortical structures, the archicortical hippocampus differs in its folding patterns across individuals. Here, we present an automated and robust BIDS-App, HippUnfold, for defining and indexing individual-specific hippocampal folding in MRI, analogous to popular tools used in neocortical reconstruction. Such tailoring is critical for inter-individual alignment, with topology serving as the basis for homology. This topological framework enables qualitatively new analyses of morphological and laminar structure in the hippocampus or its subfields. It is critical for refining current neuroimaging analyses at a meso- as well as micro-scale. HippUnfold uses state-of-the-art deep learning combined with previously developed topological constraints to generate uniquely folded surfaces to fit a given subject's hippocampal conformation. It is designed to work with commonly employed sub-millimetric MRI acquisitions, with possible extension to microscopic resolution. In this paper, we describe the power of HippUnfold in feature extraction, and highlight its unique value compared to several extant hippocampal subfield analysis methods.

Developmental Hypothyroidism Influences the Development of the Entorhinal-Dentate Gyrus Pathway of Rat Offspring.

BACKGROUND: Developmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the hippocampus and neocortex. The entorhinal-dentate gyrus pathway is the main entrance of memory circuits. We investigated whether developmental hypothyroidism impaired the morphological development of the entorhinal-dentate gyrus pathway. METHODS: We examined the structure and function of the entorhinal-dentate gyrus pathway in response to developmental hypothyroidism induced using 2-mercapto-1-methylimidazole. RESULTS: 1,1´-Dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate tract tracing indicated that entorhinal axons showed delayed growth in reaching the outer molecular layer of the dentate gyrus at postnatal days 2 and 4 in hypothyroid conditions. The proportion of fibers in the outer molecular layer was significantly smaller in the hypothyroid group than in the euthyroid group at postnatal day 4. At postnatal day 10, the pathway showed a layer-specific distribution in the outer molecular layer, similar to the euthyroid group. However, the projected area of entorhinal axons was smaller in the hypothyroid group than in the euthyroid group. An electrophysiological examination showed that hypothyroidism impaired the long-term potentiation of the perforant and the cornu ammonis 3-cornu ammonis 1 pathways. Many repulsive axon guidance molecules were involved in the formation of the entorhinaldentate gyrus pathway. The hypothyroid group had higher levels of erythropoietin-producing hepatocyte ligand A3 and semaphorin 3A than the euthyroid group. CONCLUSION: We demonstrated that developmental hypothyroidism might influence the development of the entorhinal-dentate gyrus pathway, contributing to impaired long-term potentiation. These findings improve our understanding of neural mechanisms for memory function.

Multimodal gradient mapping of rodent hippocampus.

The hippocampus plays a central role in supporting our coherent and enduring sense of self and our place in the world. Understanding its functional organisation is central to understanding this complex role. Previous studies suggest function varies along a long hippocampal axis, but there is disagreement about the presence of sharp discontinuities or gradual change along that axis. Other open questions relate to the underlying drivers of this variation and the conservation of organisational principles across species. Here, we delineate the primary organisational principles underlying patterns of hippocampal functional connectivity (FC) in the mouse using gradient analysis on resting state fMRI data. We further applied gradient analysis to mouse gene co-expression data to examine the relationship between variation in genomic anatomy and functional organisation. Two principal FC gradients along a hippocampal axis were revealed. The principal gradient exhibited a sharp discontinuity that divided the hippocampus into dorsal and ventral compartments. The second, more continuous, gradient followed the long axis of the ventral compartment. Dorsal regions were more strongly connected to areas involved in spatial navigation while ventral regions were more strongly connected to areas involved in emotion, recapitulating patterns seen in humans. In contrast, gene co-expression gradients showed a more segregated and discrete organisation. Our findings suggest that hippocampal functional organisation exhibits both sharp and gradual transitions and that hippocampal genomic anatomy exerts only a subtle influence on this organisation.

FKBP51 modulates hippocampal size and function in post-translational regulation of Parkin.

FK506-binding protein 51 (encoded by Fkpb51, also known as Fkbp5) has been associated with stress-related mental illness. To investigate its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assisted morphological analysis revealed that male Fkbp51 knock-out (KO) mice possess more elongated dentate gyrus (DG) but shorter hippocampal height in coronal sections when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls and pharmacological manipulation experiments suggest that this may occur through the regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support a role for FKBP51 in the regulation of microtubule-associated protein expression. Furthermore, Fkbp51 KO hippocampi exhibited decreases in ßIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory mechanism of Parkin by FKBP51 and the significance of their interaction on disease onset. KO has more flattened hippocampus using AI-assisted measurement Both pyramidal cell layer (PCL) of CA and granular cell layer (GCL) of DG distinguishable as two layers: deep cell layer and superficial layer. Distinct MAP2 expression between deep and superficial layer between KO and WT, Higher Parkin expression in KO brain Mechanism of FKBP51 inhibition resulting in Parkin, MAP2, Tau, and Tubulin expression differences between KO and WT mice, and resulting neurite outgrowth differences.

Suppression of non-selected solutions as a possible brain mechanism for ambiguity resolution in the word fragment task completion task.

Brain systems dealing with multiple meanings of ambiguous stimuli are relatively well studied, while the processing of non-selected meanings is less investigated in the neurophysiological literature and provokes controversy between existing theories. It is debated whether these meanings are actively suppressed and, if yes, whether suppression characterizes any task that involves alternative solutions or only those tasks that emphasize semantic processing or the existence of alternatives. The current functional MRI event-related study used a modified version of the word fragment completion task to reveal brain mechanisms involved in implicit processing of the non-selected solutions of ambiguous fragments. The stimuli were pairs of fragmented adjectives and nouns. Noun fragments could have one or two solutions (resulting in two words with unrelated meanings). Adjective fragments had one solution and created contexts strongly suggesting one solution for ambiguous noun fragments. All fragmented nouns were presented twice during the experiment (with two different adjectives). We revealed that ambiguity resolution was associated with a reduced BOLD signal within several regions related to language processing, including the anterior hippocampi and amygdala and posterior lateral temporal cortex. Obtained findings were interpreted as resulting from brain activity inhibition, which underlies a hypothesized mechanism of suppression of non-selected solutions.

Influence of exclusive breastfeeding on hippocampal structure, satiety responsiveness, and weight status.

Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7-11-year-olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age- and sex-adjusted body mass index (%BMIp85 ), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children's Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMIp85 and its indirect effect through satiety responsiveness. %BMIp85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMIp85 . However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.

Two opposing hippocampus to prefrontal cortex pathways for the control of approach and avoidance behaviour.

The decision to either approach or avoid a potentially threatening environment is thought to rely upon the coordinated activity of heterogeneous neural populations in the hippocampus and prefrontal cortex (PFC). However, how this circuitry is organized to flexibly promote both approach or avoidance at different times has remained elusive. Here, we show that the hippocampal projection to PFC is composed of two parallel circuits located in the superficial or deep pyramidal layers of the CA1/subiculum border. These circuits have unique upstream and downstream connectivity, and are differentially active during approach and avoidance behaviour. The superficial population is preferentially connected to widespread PFC inhibitory interneurons, and its activation promotes exploration; while the deep circuit is connected to PFC pyramidal neurons and fast spiking interneurons, and its activation promotes avoidance. Together this provides a mechanism for regulation of behaviour during approach avoidance conflict: through two specialized, parallel circuits that allow bidirectional hippocampal control of PFC.

A comparative study of pre-alpha islands in the entorhinal cortex from selected primates and in lissencephaly.

The entorhinal cortex (EC) is the main interface between the sensory association areas of the neocortex and the hippocampus. It is crucial for the evaluation and processing of sensory data for long-term memory consolidation and shows damage in many brain diseases, for example, neurodegenerative diseases, such as Alzheimer's disease and developmental disorders. The pre-alpha layer of the EC in humans (layer II) displays a remarkable distribution of neurons in islands. These cellular islands give rise to a portion of the perforant path-the major reciprocal data stream for neocortical information into the hippocampal formation. However, the functional relevance of the morphological appearance of the pre-alpha layer in cellular islands and the precise timing of their initial appearance during primate evolution are largely unknown. Here, we conducted a comparative study of the EC from 38 nonhuman primates and Homo sapiens and found a strong relationship between gyrification index (GI) and the presence of the pre-alpha cellular islands. The formation of cellular islands also correlated with brain and body weight as well as neopallial volume. In the two human lissencephalic cases, the cellular islands in the pre-alpha layer were lacking. These findings emphasize the relationship between cortical folding and island formation in the EC from an evolutionary perspective and suggest a role in the pathomechanism of developmental brain disorders.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

FreeSurfer-based segmentation of hippocampal subfields: A review of methods and applications, with a novel quality control procedure for ENIGMA studies and other collaborative efforts.

Structural hippocampal abnormalities are common in many neurological and psychiatric disorders, and variation in hippocampal measures is related to cognitive performance and other complex phenotypes such as stress sensitivity. Hippocampal subregions are increasingly studied, as automated algorithms have become available for mapping and volume quantification. In the context of the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium, several Disease Working Groups are using the FreeSurfer software to analyze hippocampal subregion (subfield) volumes in patients with neurological and psychiatric conditions along with data from matched controls. In this overview, we explain the algorithm's principles, summarize measurement reliability studies, and demonstrate two additional aspects (subfield autocorrelation and volume/reliability correlation) with illustrative data. We then explain the rationale for a standardized hippocampal subfield segmentation quality control (QC) procedure for improved pipeline harmonization. To guide researchers to make optimal use of the algorithm, we discuss how global size and age effects can be modeled, how QC steps can be incorporated and how subfields may be aggregated into composite volumes. This discussion is based on a synopsis of 162 published neuroimaging studies (01/2013-12/2019) that applied the FreeSurfer hippocampal subfield segmentation in a broad range of domains including cognition and healthy aging, brain development and neurodegeneration, affective disorders, psychosis, stress regulation, neurotoxicity, epilepsy, inflammatory disease, childhood adversity and posttraumatic stress disorder, and candidate and whole genome (epi-)genetics. Finally, we highlight points where FreeSurfer-based hippocampal subfield studies may be optimized.

White Fiber Correlates of Amygdalohippocampectomy Through the Middle Temporal Gyrus Approach.

OBJECTIVE: The white fiber and gross anatomy relevant for performing amygdalohippocampectomy through the middle temporal gyrus approach for mesial temporal sclerosis has been depicted by white fiber dissection. METHODS: Three previously frozen and formalin fixed cerebral hemispheres were studied. The Klingler method of fiber dissection was used to study the anatomy. The primary tools used were hand-made wooden spatulas, forceps, and microscissors. The anatomy of the amygdala and hippocampus and the landmarks for performing the disconnection during epilepsy surgery are presented. The white fibers at risk during the middle temporal gyrus approach were studied. RESULTS: The white fiber tracts at risk during the middle temporal gyrus approach for epilepsy surgery are the fibers of the inferior frontooccipital fasciculus, temporal extension of the anterior commissure, Meyer loop of the optic radiation, and uncinate fasciculus. On the basis of our anatomic dissections, we present a novel entry point into the temporal horn, potentially minimizing injury to the fibers of the sagittal stratum. We also propose novel landmarks to perform the amygdala disconnection in mesial temporal sclerosis. CONCLUSIONS: The middle temporal gyrus is a commonly used approach to perform temporal lobectomy and amygdalohippocampectomy for patients with mesial temporal sclerosis. The anatomy relevant to the approach as presented will aid while performing epilepsy surgery.

Theta rhythmicity governs human behavior and hippocampal signals during memory-dependent tasks.

Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding and recall of cue-object associative memories. We find no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz). Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but significantly more for remembered than forgotten trials, providing a potential mechanistic underpinning for the theta oscillations found in behavioral responses.

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.

Changes in white matter microstructure and MRI-derived cerebral blood flow after 1-week of exercise training.

Exercise is beneficial for brain health, inducing neuroplasticity and vascular plasticity in the hippocampus, which is possibly mediated by brain-derived neurotrophic factor (BDNF) levels. Here we investigated the short-term effects of exercise, to determine if a 1-week intervention is sufficient to induce brain changes. Fifteen healthy young males completed five supervised exercise training sessions over seven days. This was preceded and followed by a multi-modal magnetic resonance imaging (MRI) scan (diffusion-weighted MRI, perfusion-weighted MRI, dual-calibrated functional MRI) acquired 1 week apart, and blood sampling for BDNF. A diffusion tractography analysis showed, after exercise, a significant reduction relative to baseline in restricted fraction-an axon-specific metric-in the corpus callosum, uncinate fasciculus, and parahippocampal cingulum. A voxel-based approach found an increase in fractional anisotropy and reduction in radial diffusivity symmetrically, in voxels predominantly localised in the corpus callosum. A selective increase in hippocampal blood flow was found following exercise, with no change in vascular reactivity. BDNF levels were not altered. Thus, we demonstrate that 1 week of exercise is sufficient to induce microstructural and vascular brain changes on a group level, independent of BDNF, providing new insight into the temporal dynamics of plasticity, necessary to exploit the therapeutic potential of exercise.

Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain.

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N = 608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.