Brain Structure and Function

The lateral septum (LS) integrates afferents from multiple brain regions, including the raphe nuclei. The organization of these inputs contributes to the regionalization of LS functions, for example spatial coding in dorsal LS and emotional regulation in ventral LS. Raphe-LS projections include glutamatergic axons expressing the vesicular glutamate transporter type 3 (VGLUT3), which often form pericellular baskets around LS neurons. This study provides an anatomical characterization of the organization and origins of VGLUT3-positive (VGLUT3+) raphe inputs to the LS. We mapped VGLUT3+ axon terminal density across the rostro-caudal extent of the LS and quantified colocalization with serotonin (5-HT) using immunohistochemistry. Our results showed that VGLUT3 density was highest in the ventral LS, whereas VGLUT3/5-HT colocalization was strongest in the dorsal LS. Retrograde viral vector-mediated tracing identified predominant inputs from the median raphe and B9 neuron group. Interestingly, the ventral hippocampus, a functionally related region which is known to also receive raphe VGLUT3 inputs, showed collaterals with the LS. Additional VGLUT3+ inputs to the LS arose from the interpeduncular nucleus, bed nucleus of the stria terminalis, nucleus incertus and pontine central gray. Anterograde tracing revealed that inputs from these brain regions target distinct and largely non-overlapping domains in the LS. Our findings highlight multiple sources of VGLUT3+ inputs to the LS, beyond the raphe nuclei, and suggest that distinct VGLUT3 circuits could contribute to LS functional specialization.

Post-stroke semantic aphasia is characterised by multimodal semantic deficits and reflects disruption of a distributed brain network spanning frontal and temporal regions. Connectivity gradients, which capture key dimensions of whole-brain variation in functional connectivity, offer a promising framework for understanding the global impact of stroke on brain function. This study investigated whether changes in connectivity gradients following stroke can explain semantic aphasia deficits. First, we evaluated whether lesion-location and lesion-load information from structural MRI could predict the gradient changes observed in resting-state fMRI, as a proof-of-principle analysis. Second, we tested whether simulated gradient changes predict the severity of semantic impairment. Results show that post-stroke gradient changes simulated from structural MRI are correlated with actual changes in resting-state fMRI, particularly for the principal gradient that separates unimodal and heteromodal regions. Semantic deficits were related to simulated connectivity changes along this gradient: left prefrontal areas involved in controlled semantic retrieval exhibited stronger connectivity to unimodal cortex in patients with more severe deficits. Semantic deficits also correlated with changes in the second gradient, which distinguishes visual and motor cortex. Particularly, the right parahippocampal gyrus, typically visually biased--showed reduced visual connectivity in more impaired patients. These results help explain controlled semantic retrieval deficits in semantic aphasia. More broadly, the findings suggest that functional connectivity gradients capture post-stroke reorganisation of global brain networks linked to cognitive impairment, and that these changes can be estimated from structural MRI alone, enhancing clinical utility of gradient-based approaches. HighlightsO_LIFunctional connectivity gradients explain the multimodal impairments in semantic aphasia from a dimensional perspective, using the unimodal-transmodal and motor-visual axes. C_LIO_LIPost-stroke functional changes are explored through alterations in connectivity gradient patterns. C_LIO_LICortical lesion information from structural MRI can be used to simulate changes in connectivity gradients, offering potential clinical relevance. C_LI

Reconciling the anatomical observation that the human brain comprises two asymmetrical halves with the phenomenal unity of the mind is a puzzle that has challenged neuroscientists since the dawn of research in the field. White-matter commissural fibres of the corpus callosum constitute a critical anatomical substrate for the functional resolution of this anatomical duality. However, the extent of the functional involvement of the callosum in different domains of cognition represents, to this day, a mostly uncharted territory. Here we present a probabilistic characterization of callosal involvement in a set of cognitive functions. In particular, we estimated structural callosal connections by means of the Disconnectome approach applied to a reference sample of healthy participants while using the macro-anatomical cortical areas contained in the Harvard-Oxford template as seeds. By multiplying structural connectivity by the involvement of each cortical area in a set of cognitive functions (as derived from Neurosynth meta-analyses), we produced a voxel-wise characterization of the corpus callosum in different functional domains. We were able to highlight greater involvement of posterior callosal regions in vision and episodic memory, greater involvement of more anterior callosal regions in decision making and working memory, with somatosensory and motor functions more related to the central dorsal portion of the callosum.

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.

The human cerebral cortex is organized along a unimodal-to-transmodal hierarchy, which provides a putative substrate for the integration of sensory signals from primary cortical fields with information from other modalities. Diverse structural and functional properties of the cortex, including myelination, gene expression, neurodevelopmental timing, and inter-regional functional connectivity are patterned along this hierarchy. One exception to this hierarchy are the dominant eigenmodes of cortical geometry, which are instead patterned along rostrocaudal, mediolateral, and dorsoventral axes, each anchored by a primary sensory area at one extreme. Recent work has reconstructed the unimodal-to-transmodal hierarchy by integrating seed-based functional connectivity from three primary sensory areas, suggesting hierarchical organization may be driven by converging sensory input. Although geometric eigenmodes do not directly express the unimodal-to-transmodal hierarchy, they may encode modality-specific sensory organization originating from primary areas. Using MRI data from the Human Connectome Project, we tested whether geometric eigenmodes encode sensory function by modelling multisensory integration directly from cortical geometry. Specifically, we substituted functional connectivity maps from each primary sensory area with the rostrocaudal, mediolateral, and dorsoventral geometric eigenmodes, following a previously validated sensory integration mapping framework. Each geometric eigenmode corresponded to a distinct sensory domain (rostrocaudal-visual: |r| = 0.516; mediolateral-somatosensory: |r| = 0.551; dorsoventral-auditory: |r| = 0.342). Together, the three geometric eigenmodes created a mapping space that differentiated between unimodal brain regions with similar accuracy as fMRI-based models ({delta} = 64.74{degrees}; p < .001); however, differences between geometric and functional maps were largest within the transmodal association cortex. Reproducing the full unimodal-to-transmodal hierarchy required additional higher-frequency geometric eigenmodes (15 eigenmodes: r2 = 0.64). These findings suggest that the unimodal anchors of sensory integration are shaped by cortical geometry, with low-frequency geometric eigenmodes providing a structural basis for sensory organization, while the transmodal apex requires additional structural information to emerge.

Neurobiological models of emotion have proposed the existence of multiple direct subcortical pathways in humans, often referred to as "low roads", linking the thalamus to the amygdala and implicated in affective function. Among these, pulvinar-amygdala structural connectivity has been associated with individual differences in anxiety and anxiety-related conditions. However, whether distinct thalamo-amygdala pathways across thalamic subnuclei differentially relate to anxiety remains unknown. Using diffusion MRI in 34 healthy participants, we reconstructed four candidate subcortical "low roads" bilaterally from the medial geniculate body (MGB), as well as the medial, inferior and lateral pulvinar to the basolateral amygdala (BLA). We then tested whether their structural connectivity strength was associated with individual differences in state and trait anxiety. Linear regression analyses revealed that fiber density in three left thalamo-amygdala pathways predicted state, but not trait, anxiety. Importantly, our results showed a functional dissociation across pathways. While fiber density in MGB-BLA and medial pulvinar-BLA pathways was negatively related to state anxiety, the inferior pulvinar-BLA tract showed the opposite association. These findings support differentiated contributions across thalamo-amygdala pathways in humans to state anxiety. The results highlight these subcortical pathways as potentially relevant neurobiological substrates for understanding anxiety and affective function. Key pointsO_LIFiber density of three left thalamo-amygdala pathways explained 24.1% of the variance in state anxiety across 34 healthy individuals C_LIO_LIFiber density in the left medial geniculate body and left medial pulvinar-amygdala pathways was negatively associated with state anxiety C_LIO_LIFiber density in the left inferior pulvinar-amygdala pathway was positively associated with state anxiety C_LI

The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is increasingly used as a non-invasive MRI biomarker of glymphatic and perivascular function, yet the anatomical validity and measurement stability of the metric remain incompletely characterised. Using diffusion MRI data from 850 healthy young adults and 150 healthy ageing participants from the Human Connectome Project, I systematically evaluated the influence of region-of-interest (ROI) placement and ventricular anatomy on ALPS measurements. Reference ALPS implementations demonstrated substantial hemispheric variability, with a median left-right difference of 12.5% and marked asymmetry in the underlying numerator and denominator tensor components. A two-stage optimisation framework incorporating fibre-pool alignment, hemispheric symmetry, component stability, and directional purity identified anatomically improved ROI configurations that significantly increased fibre specificity and reduced measurement variability in independent validation cohorts. Despite these improvements, residual hemispheric asymmetry persisted, suggesting an intrinsic anatomical contribution to ALPS variability. In the healthy ageing cohort, ventricular volume emerged as the strongest predictor of ALPS, explaining substantially more variance than chronological age. Voxel-wise deformation-based morphometry demonstrated that lower ALPS values were associated with ventricular and periventricular expansion, while optimisation increased coupling between ALPS and ventricular anatomy. Collectively, these findings indicate that ALPS measurements are strongly influenced by ROI definition, ventricular morphology, and surrounding periventricular tissue architecture. Rather than functioning as a direct measure of glymphatic transport in isolation, ALPS appears to represent a composite anatomical diffusion biomarker shaped by both methodological implementation and underlying neuroanatomy. These results provide a framework for improving methodological standardisation and interpretation of ALPS measurements in future neuroimaging studies.

The human brainstem is a complex division of the brain comprised of more than 200 nuclei and fiber tracts. The brainstem is essential for the functioning of the entire body. We introduce here the most detailed human brainstem Atlas across the human lifespan: fetus, child, adult. ANCHOR, the Atlas of Neurochemical Characterization of the Human Brainstem, is an online platform that includes more than 800 serial histological sections, stained for Nissl and seven immunochemical (IHC) markers, from the human brainstem of three ages: 25 fetal gestational weeks (GW), 9 years old, and 54 years old. This makes ANCHOR the most comprehensive human brainstem Atlas to date. In these three brainstems, we identified and manually annotated over 200 structures. We further characterized these structures with the seven IHC markers. We specifically describe the catecholaminergic groups in the human brainstem across all three age groups. In addition, we identified the protoplasmic commissural dendrites of the hypoglossal nucleus and we describe the pretectal nuclei in the Nissl-stained fetal 25 GW brainstem. ANCHOR includes an online viewer that integrates multimodal data, from magnetic resonance imaging and block face imaging to Nissl- and IHC-stained serial sections and 3D reconstruction of the entire brainstem. For the 9-year-old specimen, the online viewer allows simultaneous navigation of annotated sections with corresponding IHC, for viewing the specific region-wise cellular features accessible at https://anchor.humanbrain.in/.

The human thalamus is composed of multiple nuclei that differ in structure and function. From early development onwards, these nuclei form reciprocal, nucleus-specific connections with the cerebral cortex, contributing to sensory and cognitive processing. In childhood and adolescence, a key period of neurocognitive development, these connections undergo widespread refinement, yet how developmental trajectories of thalamocortical connections vary across nuclei remains unknown. Here, we leveraged the Human Connectome Project in Development dataset (HCP-D, N = 604, age range 8-21) and segmented 10 thalamic nuclei using a segmentation approach optimized for intrathalamic contrast. Applying probabilistic tractography, we reconstructed nucleus-specific thalamocortical connections and charted their maturational profiles based on changes in fractional anisotropy (FA) using generalized additive models. We found FA to increase in thalamocortical connections, with nucleus-specific variation in temporal profiles and magnitude of age effects. Connections of core-cell-rich, sensory-projecting nuclei, such as the lateral geniculate nucleus, showed earlier maturational plateaus, whereas matrix-cell-rich, association-projecting nuclei, such as ventral anterior nucleus, showed more sustained maturation. This links maturational heterochronicity to thalamic organization of cell distribution and connectivity embedding. In parallel, functional thalamocortical connectivity decreased with age, with FA and functional connectivity age effects coupled in nucleus-connections showing prolonged maturation. Finally, concordant age effects in connectivity and nucleus volumes suggest that intra-nucleus remodeling may support refinement of structural connections while reducing thalamocortical functional synchrony. Together, our work reveals that thalamocortical maturation is anchored in the developmental and organizational heterogeneity of thalamic nuclei, offering a framework for understanding how diverse thalamic nuclei contribute to neurocognitive development.

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.

Introduction Understanding the mechanisms of human neuromaturation constitutes one of the fundamental questions of neuroscience. While it is well described that large-scale brain maturation is initiated within sensorimotor brain regions and progresses to associative cortex, the underlying developmental neurobiology remains to be fully characterized. Animal models have indicated that cortical inhibitory upregulation might be a driver of neurodevelopment. To investigate the hypothesis that cortical inhibitory upregulation plays a similar role in human neuromaturation, we developed a The Virtual Brain (TVB) based computational model (TVB-Child) to explore potential mechanisms of human neurodevelopment. Material and method We created neurodevelopmental dynamic brain network models capturing neurobiological maturation by using the large-scale brain simulator TVB and fitting brain network models to developmental functional MRI (fMRI) from the Human Connectome Project-Development (HCP-D) data set with 640 subjects with an age range of 6-21 years. Age-dependent trajectories in the fMRI data set were first analyzed by combined group-ICA/Dual Regression extracting subject-specific resting-state networks (RSN). Maturational topographical and topological redistribution of these networks were analyzed by linear and non-linear regression of RSN size and degree and strength centrality. Brain network models were fitted to the fMRI functional connectivity obtained from the HCP-D data set. Hypothesizing that cortical inhibition is a driver of neuromaturation, we analyzed spatiotemporal inhibition parameter gradients in the dynamic brain network model for the hypothesized significant correlations with fMRI RSN maturational trajectories. Results While during development frontoparietal (FP) and default mode network (DMN) grew and exhibited an increase in both degree and strength centrality, becoming dominant network hubs, the attention network underwent network pruning with a decrease in size and node degree. The primary sensory network changed little. For the fitted brain network models, we obtained a high degree of reproduction with correlation coefficients between empirical and simulated functional connectivities ranging between 0.80 and 0.95. Values of the feed forward inhibition model parameter wijFFI representing the strength of regional feedforward inhibitory input exhibited the most significant increase with age within the FP and DMN networks. A less pronounced, but significant, age-dependent increase of the inhibitory parameter values were seen in attention networks and no change within primary sensory networks. Conclusion Our study shows that high order (FP, DMN), attention and primary sensory networks exhibit distinct topographical and topological maturation trajectories. Moreover, brain network modeling revealed RSN-specific age-dependent inhibition trajectories, indicating that the model is able to reproduce and thus support candidate mechanisms of neurodevelopment.

The noradrenergic locus coeruleus (LC) and the cholinergic nucleus basalis of Meynert (nBM) are key hubs of ascending neuromodulatory systems that shape large-scale brain dynamics. However, the behavioral relevance of the structural and functional connectivity between these nuclei remains poorly understood. Here, we investigated whether LC-nBM structural or functional connectivity is related to cognitive-motor dual-task performance in healthy younger and older adults. Fifty-four participants (36 older, 18 younger) underwent diffusion MRI, resting-state fMRI, and behavioral assessment using an MRI-compatible cognitive-motor dual-task paradigm. LC-nBM structural connectivity was estimated using tractography, whereas resting-state functional connectivity was quantified as Fisher z-transformed correlations between LC and nBM time series. LC-nBM structural connectivity was better explained by a quadratic rather than a linear or cubic age model, indicating non-linear age-related variation, whereas functional connectivity showed no significant age-related association. Higher LC-nBM structural connectivity was associated with greater cognitive dual-task cost, but not with motor dual-task cost or single- or dual-task reaction times. This association was not moderated by age group and was not statistically explained by attentional and executive performance as measured by the Test of Attentional Performance. These findings suggest that LC-nBM structural connectivity is selectively associated with cognitive-motor interference, potentially reflecting a neuromodulatory pathway that constrains the balance between task-specific stabilization and flexible cross-domain coordination during a cognitive-motor dual-tasking.

Subcortical structures play a key role in shaping cortical computation through distributed cortico-subcortical networks, yet it remains unclear whether individual differences in subcortical anatomy are reflected in resting-state cortical oscillations. We analysed resting-state magnetoencephalography (MEG) and structural MRI from 533 healthy adults in the Cambridge Centre for Ageing and Neuroscience (CamCAN) cohort to test whether hemispheric asymmetries in subcortical volume predict asymmetries in cortical oscillatory power. Lateralisation indices were calculated for subcortical volumes and for oscillatory power across homologous MEG sensor pairs. Cluster-based permutation testing revealed frequency-specific associations between subcortical anatomy and cortical activity. Globus pallidus asymmetry was positively associated with posterior alpha-band power lateralisation, putamen and caudate asymmetries were associated with beta-band lateralisation, and hippocampal asymmetry was negatively associated with delta-band lateralisation. These findings extend previous task-based observations linking pallidal anatomy with alpha oscillations to the resting state and demonstrate that distinct subcortical structures are associated with specific cortical frequency bands. Our results suggest that resting-state MEG captures functional signatures of cortico-subcortical organisation and provides a non-invasive framework for studying healthy ageing and disorders involving subcortical degeneration.

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.

Functional activity in response to increasing task difficulty (BOLD-modulation) in regions of the default mode network (DMN/task-negative) and multiple demand network (MDN/task-positive) shows age-related decline, which is associated with reduced cognitive performance. While BOLD-modulation in the DMN begins to decline in middle-age, white matter structural connectivity declines earlier in MDN regions. We conjecture that to maintain executive function (EF) performance with aging, altered BOLD-modulation in DMN during task engagement serves as a compensatory reaction to structural decline in MDN. To test this possibility, functionally-guided tractography was applied in 160 healthy adults aged 20-94 to locate white matter connecting MDN and/or DMN regions that were active during a distance judgement paradigm. Specifically, analyses examined the effects of 1) age on white matter tracts (fractional anisotropy; FA); 2) structure-function association between FA and BOLD-modulation; and 3) age, positive/negative BOLD-modulation, and quadratic FA on EF. Age-related decline was found in one MDN tract (U-shaped tract) and a significant structure-function association was found in inferior fronto-occipital fasciculus (IFOF). Additionally, an interaction effect between quadratic frontal-insular (U-shaped) tract FA, age, and positive/negative BOLD-modulation was found for inhibition performance, supporting the hypothesis of compensatory functional activity effects on executive function for older adults with altered white matter microstructure.

The subiculum (SUB) is a major hippocampal output hub that routes information to cortical and subcortical targets, and its long-range projections are considered excitatory. Using enhancer-driven adeno-associated viral vectors to selectively label {gamma}-aminobutyric acid (GABA)-releasing neurons across species, here we show that the dorsal SUB also sends an inhibitory projection to the dorsal part of the medial entorhinal cortex (MEC) in mice and rats. Anterograde tracing in mice revealed that the dorsal SUB contains GABAergic neurons that project sparsely to all layers of the dorsal MEC with enrichment in superficial layers, in contrast to the glutamatergic SUB axons targeting MEC layer V. Slice electrophysiology demonstrated that these GABAergic axons form inhibitory synapses in the MEC. A subset of projecting neurons expressed parvalbumin (PV), whereas somatostatin-positive neurons were rare. Consistently, PV neuron-specific anterograde tracing recapitulated the SUB-to-MEC projection. In rats, subicular GABAergic axons were enriched in MEC layer II, and SynaptoTAG2-labeled presynaptic boutons were positive for the vesicular GABA transporter, supporting inhibitory synapse formation. Anterograde tracing of PV neurons similarly recapitulated the laminar axonal distribution in the MEC. These results identify a conserved PV-associated inhibitory SUB-to-MEC projection with species-specific laminar organization, extending the canonical excitatory view of subicular output.

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.

The basal ganglia and thalamus are key nodes in subcortico-cortical loops involved in sensory, motor, and cognitive function. In adults, posterior regions of the subcortex link to cortical sensorimotor networks and anterior regions link to association networks. Alterations in the size, strength, and selectivity of these subcortical regional network representations are implicated in several neuropsychiatric disorders, many of which originate early in development. However, the organization of these network representations at birth remains incompletely understood, limiting our ability to devise normative and atypical developmental models of subcortico-cortical interactions. Using resting-state fMRI, we characterized the size, strength, and selectivity of cortical network representations in the basal ganglia and thalamus in a set of neonates (n=261) and compared results to children (age range 9-11 years, n=69) and adults (n=120). We found that the broad anterior-posterior organization of the subcortex is present at birth, yet representations of somatomotor networks were larger at birth compared to children and adults (p<0.001). The strength and selectivity of subcortico-cortical functional connectivity (FC) exhibited interactions between age group and network (all p<0.001), such that subcortical representations of sensorimotor networks exhibited stronger FC and higher selectivity in neonates, while subcortical representations of association networks exhibited stronger FC and higher selectivity in older cohorts. In parallel, data-driven clustering revealed areas with integration of multiple networks in the neonatal subcortex. These results suggest that subcortico-cortical FC evolves over development largely in a sensorimotor-association manner and provide a baseline for normative and disordered subcortical development.