Brain Structure and Function

Background and PurposeBrain arteriovenous malformations may be associated with atypical language lateralization, but whether individual variation in task-derived hemispheric dominance is reflected in time-varying intrinsic connectivity is unclear. We examined task-based language lateralization and resting-state dynamic connectivity in unruptured, untreated brain arteriovenous malformations and controls. MethodsThirty patients and 23 controls underwent language-task fMRI and resting-state fMRI. Language lateralization indices were derived from threshold-swept activation maps. Resting-state time series were modeled with hidden Markov models and canonical clustering across three atlases, yielding fractional occupancy, mean dwell time, and flexibility. The prespecified primary analysis used Schaefer-100 with four canonical states. ResultsPatients showed reduced leftward language lateralization compared with controls, most clearly in left-sided lesions. Canonical dynamic summary metrics did not differ robustly between groups after false-discovery-rate correction. Within-group partial least squares models showed that language lateralization was associated with dynamic state metrics in both groups. In patients, stronger leftward lateralization was linked mainly to flexibility; in controls, it was linked more consistently to longer dwell time. Exploratory perfusion analysis did not show a clear relationship between gross hemispheric perfusion asymmetry and language lateralization. ConclusionsDynamic resting-state features tracked individual variation in language lateralization despite limited group-level differences in dynamic state usage. These findings provide proof-of-concept evidence of brain-behavior coupling rather than an AVM-specific dynamic biomarker or a validated clinical prediction tool.

BackgroundVisual training can improve residual vision in hemianopia, but there is significant variability in patient outcomes which may reflect differences in neural structures preserved after injury. Diffusion MRI tractography offers a means of assessing white-matter microstructure in vivo, however substantial overlap between neighbouring visual pathways complicates attribution of differences to specific tracts. We quantified tract overlap to identify relatively unique pathway segments to assess training-related microstructural change. MethodsDiffusion MRI data was acquired in six participants with homonymous hemianopia before and after 3-6 months of visual training. Tractography was used to reconstruct three pathways implicated in residual vision: lateral geniculate nucleus (LGN)-V1, LGN-V5 and pulvinar-V5, together with secondary superior colliculus-LGN and superior colliculus-pulvinar pathways. Streamline overlap was quantified along neighbouring tracts, and comparison of pre- to post-training fractional anisotropy was restricted to unique or pair-specific non-overlapping segments. Exploratory relationships with visual outcomes were also examined. ResultsFractional anisotropy increased after training in both early and late pair-specific segments of the LGN-V5 pathway in the lesioned hemisphere. In the late segment, this increase was significantly greater than in the corresponding unique LGN-V1 segment, whereas change in the early LGN-V5 segment did not differ significantly from the unique pulvinar-V5 segment. No significant training-related changes were observed in collicular pathways. Brain-behaviour analyses also preferentially implicated LGN-V5: baseline fractional anisotropy was strongly associated with post-training Gabor detection, and training-related fractional anisotropy change showed a positive association with improvement in Gabor detection, although the latter did not survive multiple comparison correction. ConclusionThese findings support a role for the LGN-V5 pathway in visual plasticity after hemianopia and demonstrate the importance of explicitly quantifying tract overlap when attributing microstructural change to small, neighbouring white-matter pathways.

Background Cardiovascular autonomic dysfunction and cognition associate with each other throughout the disease course in Lewy body disease, and this relationship is poorly understood. Methods We performed a cross-sectional imaging analysis to investigate the locus coeruleus basal forebrain tract. Deterministic tractography based on quantitative anisotropy was performed. Using Bayesian semiparametric proportional-odds modeling, we evaluated the association between neurogenic orthostatic hypotension and tract characteristics with adjustment for age at imaging, sex, and education. Results In the demographic adjusted model, neurogenic orthostatic hypotension was associated with lower bilateral fourth-quarter volume (OR = 0.19; Pr[OR < 1] = 0.987), left fourth-quarter volume (OR = 0.13; Pr[OR < 1] = 0.997), left total surface area (OR = 0.19; Pr[OR < 1] = 0.990), and left total volume (OR = 0.22; Pr[OR < 1] = 0.982). These associations were directionally consistent and of similar magnitude after additional adjustment for cognitive severity, high blood pressure, disease duration, and combined high blood pressure and disease duration. Participants with impaired cognition showed lower bilateral fourth quartervolume (OR = 0.33; Pr[OR < 1] = 0.964) Conclusion Neurogenic orthostatic hypotension is associated with lower locus coeruleus basal forebrain tract volume. The inverse correlation between volume and cognitive impairment suggest a mechanistic relationship.

The mechanism underlying persistent COVID-19-related olfactory dysfunction (OD) remains unknown. There are indications for both peripheral (within the nose) and central (in the brain) mechanisms. Patients can experience a decrease in olfactory ability (quantitative OD) or a distorted odour perception (qualitative OD). The mechanisms might differ between these two symptom presentations. In this (f)MRI study, we investigated structural and functional brain alterations in patients with persistent (> 1 month) quantitative OD (Sniffin Sticks score < 30.75, n=21) or parosmia (self-reported, n=27) following SARS-CoV-2 infection, aged 19-60 years and, on average, included 472 days after diagnosis (the COVORTS study). Additionally, a control group of 49 normosmic subjects aged 22-60 years was included. Olfactory bulb volume (OBV) was determined by manual segmentation; whole-brain and regional grey matter density (GMD) of olfactory-related areas was assessed using voxel-based morphometry; and odour-induced brain activation was examined with an olfactory fMRI task. When grouped together, patients with OD had a smaller OBV than controls (84.4 vs 95.3 mm3, p=0.026). The two patient groups did not differ in OBV. ROI analysis of olfactory-related brain regions at an exploratory threshold showed lower GMD in primary and secondary olfactory regions in patients compared to controls, which appears to be mainly driven by quantitative OD. No difference in odour-induced brain activation was found. The observed smaller olfactory bulbs, along with modest findings beyond this primary olfactory structure, provide important insights into potential mechanisms of persistent COVID-19-related OD and highlight the need for longer follow-up to evaluate further neural degradation or recovery.

The lateral habenula (LHb) shapes reward and aversion learning via projections to midbrain monoaminergic centers. Recent studies have demonstrated significant genetic, anatomical, and electrophysiological diversity within the LHb. However, it remains unclear how genetic or intrinsic electrophysiological characteristics relate to in vivo neuronal activity patterns. Additionally, there are few descriptions of transgenic mouse lines labeling specific LHb neuronal subtypes. Here we describe spatial gene expression patterns, electrophysiological characteristics, and projection targets for specific subpopulations of neurons in the LHb targeted via existing transgenic mouse lines. Furthermore, we demonstrate that two genetically defined subpopulations differentially respond to value, prediction errors, and directional movement during flexible, reward-guided behavior. These findings indicate that specific, genetically targetable, neuronal subpopulations in LHb may control discrete aspects of motivated behavior through parallel circuits targeting serotonergic and dopaminergic midbrain centers.

In-vivo examination of neurites to understand microstructural properties of white matter tissue utilizing neurite orientation dispersion and density imaging (NODDI) has shown sensitivity to healthy aging as well as disease biomarkers and status. Neurite density index (NDI), which is a proxy for the amount of neurites, in white matter tissue typically decreases with age. However, orientation dispersion index (ODI), which is a proxy for neurite dispersion or fanning, has been mixed with studies finding both increases and decreases with age. Furthermore, white matter tracts are not uniform and hold its own unique spatial pattern or gradient in microstructural properties. In addition to the spatial pattern of the microstructural property, age-related effects have also shown spatial patterns with stronger age effects in the medial, anterior, and dorsal portions of white matter tissue. However, spatial gradients along cardinal axes within an individual's tract have yet to be examined with age in an adult lifespan sample. The current aim of the study was to examine whether average and spatial gradients of neurite microstructural properties within tracts related to the cortico-striato-pallido-thalamic (CSPT) loop were age-sensitive. An adult lifespan sample aged 20-90 years old was recruited from the Dallas-Fort Worth metroplex (N = 104, 62% females) as part of the Dallas Area Longitudinal Lifespan Area Study (DALLAS). Participants completed an MRI session that included a structural T1-weighted image as well as multi-shell diffusion weighted imaging (MS-DWI). MS-DWI were preprocessed and tracts of interest related to the CSPT loop were obtained using probabilistic tractography. For most tracts, a significant inverted-U association with age was found for both average NDI and ODI. Most tracts revealed a reliable spatial gradient of NDI and ODI in the medial-to-lateral, posterior-to-anterior, and ventral-to-dorsal direction. Tracts related to CSPT loop were age-sensitive such that the spatial gradient was becoming more homogenous with age. This loss of spatial gradients with age is analogous to network-level dedifferentiation observed in BOLD functional connectivity. These findings highlight that age effects in a fundamental circuit for both basic and higher-order function is significantly age sensitive and while organized into spatial gradients, these gradients are also vulnerable to aging.

The Visual Word Form Area (VWFA), located in ventral occipitotemporal cortex, plays a critical role in skilled reading. Researchers have theorized that the VWFA develops in its specific anatomical location due to the convergence of major white matter tracts and proximity to functionally similar regions. This suggests that precise anatomical positioning may be crucial for optimal VWFA function. Previous research has identified several functional differences in this region between typical and struggling readers (i.e. dyslexia): struggling readers show weaker text-selective responses and often exhibit a smaller or even absent VWFA. However, it remains unexplored whether the precise anatomical location of this region also differs between typical and struggling readers. We tested whether VWFA anatomy differs between children with and without dyslexia (N=87). Participants completed a functional localizer, which we used to manually define the VWFA in each individuals native anatomy. We examined whether: (1) VWFA anatomical location relates to reading ability, (2) children with dyslexia show greater variability in VWFA location compared to typical readers, and (3) VWFA location with respect to white matter tracts relates to reading ability. Results reveal that, despite being smaller in children with dyslexia, there is no relationship between VWFA location and reading ability. Specifically, individual VWFA location relative to anatomy, relative to others VWFAs, and relative to white matter tracts, is not related to reading ability. These findings suggest that while the VWFAs general anatomy may be facilitated by development, its precise location remains stable and unrelated to reading proficiency.

Accurate alignment of hippocampal anatomy across individuals remains challenging due to complex and highly variable folding patterns that are not well captured by conventional volumetric approaches. HippUnfold introduced a surface-based representation of the hippocampus, but key components--including coordinate estimation and inter-subject correspondence--were defined in the volumetric domain, making them susceptible to topological errors and interpolation artifacts. Here, we introduce a surface-intrinsic formulation of hippocampal unfolding in which geometry, intrinsic coordinates, and correspondence are defined directly on subject-specific surface manifolds. Intrinsic anterior-posterior and proximal-distal coordinates are computed by solving Laplace equations on the surface, and correspondence is established through surface-based resampling in unfolded space, replacing inverse volumetric warping. Relative to the original HippUnfold approach, this formulation improves test-retest consistency, subject identifiability, and mesh quality, while better preserving subject-specific gyral and sulcal morphology. Surface representations show reduced distortion between folded and unfolded spaces and eliminate misplaced or outlier vertices associated with volumetric warping. These improvements translate to enhanced sensitivity in a clinical application, improving lateralization of temporal lobe epilepsy. These results demonstrate that a surface-intrinsic formulation provides a principled and robust foundation for hippocampal unfolding, enabling topology-preserving alignment and more accurate characterization of inter-individual variability in health and disease.

Objective: Patients with persistent postural-perceptual dizziness (PPPD) perceive unsteadiness associated with abnormal ego- or visual motion perception. Maladaptive multisensory integration and visual dependency have been proposed implicating abnormal functional connectivity (FC). Based on the crucial impact of the cerebellum for prediction errors of sensory perception, we specifically investigated group-related differences in FC between visual cortex, multisensory vestibular cortical areas and the cerebellum. Methods: Resting-state activity (seed-based functional connectivity using a priori regions of interest and fractional amplitude of low-frequency fluctuations, fALFF) was compared between a large cohort of 53 PPPD patients and 54 age- and sex-matched HC and related to various disease parameters and baseline postural sway speed. Results: FC between the patients' posterior insula and the visual (lingual) cortex, as well as the supramarginal gyrus was lower. In contrast, it was markedly larger between the patients' (i) visual motion-related area MT/V5 and cerebellar Crus I, (ii) multisensory operculum and caudal vermis, (iii) OP3 and Crus II, and (iv) inferior parietal lobe and vermis. fALFF was larger in the patients' right hippocampus. Interpretation: The abnormally low cortical visual-vestibular FC may provide a neural substrate for the patients' maladaptive multisensory integration with aberrant inter-sensory reweighting. The larger cerebro-cerebellar FC with cerebellar areas involved in sensory and postural prediction errors control (required for updating internal models of motion) might account for the abnormally high sensory precision weighting leading to the patients' altered egomotion perception. Longitudinal studies are required to investigate whether the larger cerebrocerebellar connectivity is compensatory or dysfunctional in nature.

Evidence from in-silico, ex vivo and invasive animal studies suggested the function of neural tissue to be inextricably linked to its structural and microstructural organization. However, this link has never been assessed non-invasively in humans. Here, we established a simple quantitative framework linking cerebral oxygen metabolism to gray matter microstructural features in healthy humans using advanced non-invasive MRI methods. The cerebral metabolic rate of oxygen consumption (CMRO2) was quantified with calibrated fMRI, whereas microstructural properties were estimated from diffusion MRI data fitted to the Soma and Neurite Density Imaging (SANDI) model, yielding soma radius (R soma) and soma volume fraction (fsoma) metrics, from which we derived maps of soma surface area density (SAD) and soma numerical density (ND) under the assumption of a spherical soma. CMRO2 was positively associated with SAD (r = 0.29, p < 0.01), fsoma (r = 0.28, p < 0.05) and ND (r = 0.25, p < 0.05), and negatively associated with Rsoma (r = -0.23, p < 0.05) across cortical brain regions. These relationships are consistent with predictions from experimental and theoretical studies, providing the first quantitative evidence that cerebral metabolic demand is coupled to microstructure in humans. The positive association of energy consumption with SAD is consistent with the notion that both the number of synapses (energy-demanding structures), and the energy required to maintain a membrane potential, scale with soma surface area. Our findings establish a non-invasive MRI framework for investigating the microstructural determinants of brain energy metabolism in health and potentially in disease.

The choroid plexus (ChP) is a highly vascularized structure located in the brain ventricles that plays important roles in multiple central nervous system functions. ChP enlargement has been implicated in many neuropsychiatric conditions such as multiple sclerosis, depression, schizophrenia, and Alzheimer's disease. However, limitation in the accuracy of the current segmentation tools highlight the need for more reliable methods to quantify ChP volume in healthy and clinical human populations. The shape and size of the ChP vary drastically from person to person, and currently there are no large ChP datasets which allow comprehensive training of segmentation models. Here we introduce DataPlex, a collection of 700 structural MRI brain images where the lateral ventricle ChP has been manually labeled and checked by expert human raters. DataPlex is balanced and representative across a wide range of scanning parameters, demographics, and clinical profiles, and subject-level information will be available for each labeled image. DataPlex will be open source to support the creation of reliable segmentation tools for the human lateral ventricle ChP.

Vesicular glutamate transporters 1 and 2 (VGluT1 and VGluT2) exhibit largely complementary distributions and have been proposed as molecular markers of descending modulatory and ascending driver-like pathways, respectively. However, this correspondence has rarely been tested directly in anatomically identified projections. We combined anterograde Phaseolus vulgaris leucoagglutinin tracing with simultaneous VGluT1 and VGluT2 immunofluorescence to characterize glutamatergic boutons arising from the primary and secondary visual cortices, lateral geniculate nucleus, lateral posterior thalamic nucleus, and superior colliculus in adult mice. Among 2,178 singly labelled boutons, VGluT1 predominated in corticothalamic, corticopontine, corticotectal, corticostriatal, and corticocortical feedback projections. Conversely, thalamocortical, tectothalamic, thalamostriatal, and tectopontine projections were almost exclusively VGluT2-positive. Projection direction did not fully predict transporter phenotype: ascending corticocortical projections remained predominantly VGluT1-positive, whereas the descending tectopontine projection was exclusively VGluT2-positive. Only 12 of 2,190 VGluT-immunoreactive boutons exhibited detectable VGluT1/VGluT2 colocalization. Morphometric analyses further revealed an interaction between VGluT isoform and projection direction. Within ascending projections, VGluT2-positive boutons and puncta were larger than their VGluT1-positive counterparts, whereas no isoform-related difference in bouton area was detected within descending projections. These findings demonstrate an association between VGluT phenotype and projection class in the mouse visual system. VGluT isoforms therefore provide informative markers of pathway organization, but neither transporter identity nor terminal size alone constitutes an invariant molecular indicator of projection direction or driver-modulator function.

Abstract The importance of hypothalamic kisspeptin (Kiss1) neurons in controlling the reproductive axis is well established, while a population of extra-hypothalamic Kiss1 neurons is found in the medial amygdala (MeA) of both males and females in rodents and is less well understood. The MeA is connected with the olfactory bulbs, the hypothalamus and cortical areas. MeA Kiss1 neurons have been implicated in sexual behaviour and modulation of the reproductive axis; however, little is known about their action potential firing properties, which would influence kisspeptin release in target brain regions, nor whether their physiological properties are sex- or estrous cycle-dependent. In this study, whole-cell patch-clamp recordings were made from Kiss1 neurons in brain slices containing the MeA of adult female (estrous and diestrous) and male mice. MeA Kiss1 (Kiss1MeA) neurons were sexually dimorphic, with greater numbers in male compared to female mice and a slower change in excitability in estrous females compared with males. However, combining a range of electrophysiological parameters using principal component analysis did not reveal a distinct sex- or estrous cycle-linked phenotype, suggesting that the properties of Kiss1MeA neurons- and therefore kisspeptin release- are broadly similar. Interestingly, Kiss1MeA neurons had unique electrophysiological properties compared with anteroventral periventricular (AVPV) hypothalamic Kiss1 (Kiss1AVPV) neurons in female mice; with their reduced excitability, achieving action potential firing frequencies greater than 10Hz required a larger current input, indicating that Kiss1MeA neurons require stronger synaptic input to achieve firing frequencies that drive kisspeptin release. These findings provide new information about the physiological properties of Kiss1MeA neurons, showing subtle sex differences and profound regional differences between the MeA and AVPV.

Syntax processing impairment is a defining feature of primary progressive aphasia (PPA), particularly in the nonfluent/agrammatic variant. However, current models are derived largely from Indo-European languages, and it remains unclear whether the cognitive and neuroanatomical mechanisms of syntax processing generalize to Chinese, an analytic, pro-drop language that encodes grammatical relationships primarily through word order and function words rather than inflectional morphology. Participants were recruited from the international Chinese Language Assessment in PPA cohort and included 64 individuals with PPA (19 logopenic, 15 nonfluent/agrammatic, 15 semantic, and 15 unclassifiable/mixed) and 60 cognitively healthy controls. Participants completed sentence comprehension and production tasks with systematically manipulated syntactic features. Item-level linguistic determinants were examined using ridge regression, diagnostic performance using receiver operating characteristic analyses, and neuroanatomical correlates using voxel-based morphometry of structural MRI. Performance on sentence comprehension and production was influenced by grammatical and lexical features. Subject-relative clauses, passive constructions, a higher proportion of function words, longer character length, and greater lexical content were associated with poorer performance among participants with PPA. Sentence comprehension was impaired in the logopenic, nonfluent/agrammatic, and semantic variants, even when isolated to the syntactic component of the sentence comprehension task. Similarly, sentence production was impaired across all PPA variants (all P < 0.01 versus controls). No significant differences were observed among PPA variants. Adjusted receiver operating characteristic analyses demonstrated high discrimination between each PPA variant and controls, with areas under the curve ranging from 0.87 to 0.97 for sentence comprehension-syntax and from 0.91 to 0.97 for sentence production. However, pairwise comparisons showed no significant differences in discriminative performance among PPA variants after correction for multiple comparisons. Both sentence comprehension-syntax and sentence production showed associations with semantic and repetition measures in addition to motor speech measures. Voxel-based morphometry showed that higher sentence comprehension-syntax scores were associated with greater grey matter volume in left frontotemporal and cingulate regions, whereas higher sentence production scores were additionally associated with greater gray matter volume in frontostriatal structures, including the caudate, putamen, and thalamus. Syntactic processing impairment in Chinese-speaking individuals with PPA extends beyond the nonfluent/agrammatic variant and is associated with distributed frontotemporal and frontostriatal regions, as well as lexical-semantic and auditory verbal short term memory mechanisms. These findings suggest that the cognitive and neural manifestations of syntactic impairment may be shaped by language-specific typological properties, underscoring the need for linguistically informed approaches to the assessment and interpretation of PPA.

Neuroimaging research focusing on subcortical brain regions showed that they play a role in a wide range of cognitive functions and associated their structural alterations to various psychiatric disorders. Methods to analyse such structures were developed to observe changes, not simply in terms of volumes, but in terms of surfaces, which are able to detect subtle and local changes in shape and geometrical configuration. Such advanced analyses have however been largely restricted to command line environments with relatively limited access to Python users or researchers with low technical expertise. We present SubCortexMesh as a user-friendly toolbox which covers automated surface estimation from popular subcortical volume segmentations (FreeSurfer and the Functional Magnetic Resonance Imaging of the Brain Software Library (FSL)), computes shape-related vertex-wise metrics (thickness, surface area and curvature) for whole cohorts and includes statistical analyses. This is all done inside Python, automatically computing all subjects of a given preprocessed directory, with the explicit intent to minimise steps and manual coding required from the users. SubCortexMesh includes statistical tools which allow conventional random field theory-based cluster analyses on native subject metrics, standardised within common surface templates, thus containing a whole workflow necessary to run an up-to-date shape-wise subcortical analyses in one package.

The ventral motor and the centromedian (CM) nuclei receive prominent GABAergic inputs from the basal ganglia, massive glutamatergic projections from motor cortices and significant GABAergic afferents from the reticular thalamic nucleus. There is strong evidence that disrupted processing of information through these connections may contribute to the pathophysiology of the basal ganglia-thalamocortical loop in Parkinson's disease (PD). To further assess potential ultrastructural changes in synaptic connectivity and mitochondrial integrity that may contribute to these network dysfunctions, we used a 3D electron microscopic approach to determine whether the pattern of synaptic innervation and morphological integrity of dendritic mitochondria are altered in the basal ganglia-receiving parvocellular ventral anterior nucleus (VApc) and CM neurons of MPTP-treated parkinsonian monkeys. Three main conclusions can be drawn from our findings: (1) Although the overall pattern of synaptic innervation of VApc and CM neurons is not altered in parkinsonian monkeys, the volume of putative corticothalamic terminals is significantly increased in both nuclei, (2) the prevalence of corticothalamic terminals in contact with distal dendrites is several orders of magnitude higher in VApc than CM in both control and parkinsonian monkeys, (3) the complexity and ultrastructural integrity of dendritic mitochondria is altered in CM, but not in the VApc, of parkinsonian monkeys. These findings lay the foundation for future studies of changes in cortical neuromodulation of VApc and CM neurons in parkinsonism and suggest that mitochondrial defects may contribute to the degeneration of CM neurons in PD.

Axonal projections and precise synapse formation are essential for the establishment of functional neural circuits, and their dysregulation contributes to various psychiatric and neurodegenerative disorders. Although numerous extracellular cues secreted from surrounding tissues regulate axon guidance and synapse formation, the mechanisms by which neurons locally regulate terminal patterning within their projection fields remain poorly understood. Bone morphogenetic protein 4 (BMP4) is a classical morphogen that is involved in early neural tube patterning during development. However, its postnatal function remains unclear. Previous in vitro studies using hippocampal glutamatergic neurons demonstrated that BMP4 can act locally on axons to suppress synapse formation, raising the possibility that BMP4 regulates terminal differentiation after target innervation. Here, we investigated the role of BMP4 in postnatal cholinergic circuit development using cholinergic neuron-specific Bmp4 conditional knockout (Bmp4 cKO) mice, with adult analyses performed in males. Basal forebrain cholinergic neurons project extensively throughout the neocortex and are essential for higher brain functions, including arousal and attention. Bmp4 cKO mice exhibited increased cholinergic axon terminals in the neocortex, hippocampus, and amygdala, as well as increased axonal ramification in the neocortex without affecting cytoarchitectonic organization or cholinergic neuron numbers in the basal forebrain. These findings demonstrate that BMP4 functions as a negative regulator of cholinergic terminal formation and axonal arborization, suggesting that BMP4 may act locally to restrict cholinergic axonal expansion during neural circuit maturation.

Human social perception relies on multiple visual signals, including object-directed actions and emotional facial expressions. It remains unclear whether responses to these signals converge within action-observation regions and whether apparent convergence depends on the spatial scale of analysis. We scanned 39 healthy human adults during two block-design fMRI tasks, hand action observations contrasted with paper-tube controls, and emotional expression observations contrasted with neutral faces. Using independently defined meta-analytic action observation network (AON) ROIs in the inferior frontal gyrus (IFG), inferior parietal lobule (IPL), and posterior superior temporal sulcus (pSTS), we analysed responses at whole-brain, ROI-average, and AON-constrained voxelwise scales. Whole-brain overlap between the two contrasts was localised primarily to the left lateral occipitotemporal extrastriate cortex, outside the AON. At the regional ROI-average scale, the IFG showed positive responses to both contrasts, whereas the IPL and pSTS showed opposing task preferences. Crucially, regional IFG co-engagement did not imply that the same voxels responded to both contrasts. Suprathreshold voxelwise overlap within the AON was virtually absent, and individual-level analysis revealed a small but reliable posterior displacement of hand action relative to emotional face within IFG. These findings show that spatial convergence between hand and emotion observation responses depends on the scale of analysis. The same IFG region can be engaged by both stimulus domains while retaining distinct local response topographies.

Dysfunctions in reward circuits, including projections from the orbitofrontal cortex (OFC) to the nucleus accumbens (NAcc), have been implicated in psychopathology. The OFC is functionally divided into the medial OFC (mOFC), which processes rewards, and the lateral OFC (lOFC), which responds to non-reward or punishment stimuli. We investigated the structural connectivity of the lOFC-NAcc and mOFC-NAcc pathways and their associations with psychopathological traits using tractography-defined ROI analysis. Diffusion-weighted imaging data from 165 participants (aged 22 - 35, 53% male) in the Human Connectome Project (HCP) were analysed using spherical deconvolution tractography. MegaTrack, a novel tool, enabled tract segmentation via a single manual dissection mapped back to native space. Virtual dissection identified four bilateral pathways connecting the lOFC and mOFC to the NAcc, from which fractional anisotropy (FA) was extracted, and an lOFC/mOFC ratio was computed. Psychopathological traits were measured using HCP Achenbach Adult Self-Report scores. The lOFC-NAcc pathway showed positive associations with psychopathology and the mOFC-NAcc pathway negative associations. The lOFC/mOFC ratio emerged as a stronger predictor than individual pathways, with significant associations for depression, somatic problems, anti-social personality traits, and inattention. Effects were lateralized to the left hemisphere. These findings show that the lOFC-NAcc and mOFC-NAcc pathways can be structurally separated with tractography and display opposing correlations with psychopathological traits in a healthy population. Their ratio may index reward-processing dysfunction, and future research should test whether it is sensitive to dysfunction in clinical populations.

Analytical variability in neuroimaging pipelines contributes to concerns about reproducibility in the field. In structural MRI, different segmentation tools produce discrepant morphometric estimates that may influence downstream analyses, such as predictive modeling. We tested whether integrating several segmentation pipelines improves brain age prediction, and characterized the spatial and demographic structure of pipeline differences across several datasets. T1-weighted scans from five open-access datasets were processed with four widely-used structural segmentation pipelines. Brain age models were trained using single-pipeline features and compared with multi-pipeline aggregation strategies. Inter-pipeline variability was assessed across shared subcortical structures and examined in relation to age and sex. Integrating features across distinct segmentation frameworks improved predictive performance relative to individual pipelines, whereas aggregation within closely related software versions provided limited benefit. Variability was spatially structured and volumetric measures were often systematically associated with age and sex. These results suggest that segmentation differences reflect structured, demographically sensitive variation rather than random noise, and that multi-pipeline feature integration can enhance robustness in neuroimaging-based prediction.