We developed a novel method for mapping the location, surface area, thickness, and volume of frontoinsular cortex (FI) using structural and diffusion magnetic resonance imaging. FI lies in the ventral part of anterior insular cortex and is characterized by its distinctive population von Economo neurons (VENs). Functional neuroimaging studies have revealed its involvement in affective processing, and histopathology has implicated VEN loss in behavioral-variant frontotemporal dementia and chronic alcoholism; however, structural neuroimaging of FI has been relatively limited. We delineated FI by jointly modeling cortical surface geometry and its coincident diffusion microstructure parameters. We found that neurite orientation dispersion in cortical gray matter can be used to map FI in specific individuals, and the derived measures reflect a range of behavioral factors in young adults from the Human Connectome Project (N=1052). FI volume was larger in the left hemisphere than the right (31%), and the percentage volume of FI was larger in women than men (15.3%). FI volume was associated with measures of decision-making (delay discounting, substance abuse), emotion (negative intrusive thinking and perception of hostility), and social behavior (theory of mind and working memory for faces). The common denominator is that larger FI size is related to greater self-control and social awareness.

In this work, we show for the first time that the tangential diffusion component is orientationally coherent at the human cortical surface. Using diffusion magnetic resonance imaging (dMRI), we have succeeded in tracking intracortical fiber pathways running tangentially within the cortex. In contrast with histological methods, which reveal little regarding 3-dimensional organization in the human brain, dMRI delivers additional understanding of the layer dependence of the fiber orientation. A postmortem brain block was measured at very high angular and spatial resolution. The dMRI data had adequate resolution to allow analysis of the fiber orientation within 4 notional cortical laminae. We distinguished a lamina at the cortical surface where diffusion was tangential along the surface, a lamina below the surface where diffusion was mainly radial, an internal lamina covering the Stria of Gennari, where both strong radial and tangential diffusion could be observed, and a deep lamina near the white matter, which also showed mainly radial diffusion with a few tangential compartments. The measurement of the organization of the tangential diffusion component revealed a strong orientational coherence at the cortical surface.

Auditory processing disorder (APD) is a listening impairment that some school-aged children may experience despite having normal peripheral hearing. Recent resting-state functional magnetic resonance imaging (MRI) has revealed an alteration in regional functional brain topology in children with APD. However, little is known about the structural organization in APD. We used diffusion MRI data to investigate the structural connectome of 58 children from 8 to 14 years old diagnosed with APD (n = 29) and children without hearing complaints (healthy controls, HC; n = 29). We investigated the rich-club organization and structural connection differences between groups. The APD group showed similar rich-club organization and edge-wise connection compared with the HC group. However, at the regional level, we observed increased average path length (APL) and betweenness centrality in the right inferior parietal lobule and inferior precentral gyrus, respectively, in the APD group. Only HCs demonstrated a positive association between APL and the listening-in-spatialized-noise-sentences task in the left orbital gyrus. In line with previous findings, the current results provide evidence for altered structural networks at the regional level in the APD group, suggesting the involvement of multimodal deficits and a role for structure-function alteration in the listening difficulties of children with APD.

Noninvasive diffusion-weighted magnetic resonance imaging (dMRI) can be used to map the neural connectivity between distinct areas in the intact brain, but the standard resolution achieved fundamentally limits the sensitivity of such maps. We investigated the sensitivity and specificity of high-resolution postmortem dMRI and probabilistic tractography in rhesus macaque brains to produce retinotopic maps of the lateral geniculate nucleus (LGN) and extrastriate cortical visual area V5/MT based on their topographic connections with the previously established functional retinotopic map of primary visual cortex (V1). We also replicated the differential connectivity of magnocellular and parvocellular LGN compartments with V1 across visual field positions. Predicted topographic maps based on dMRI data largely matched the established retinotopy of both LGN and V5/MT. Furthermore, tractography based on in vivo dMRI data from the same macaque brains acquired at standard field strength (3T) yielded comparable topographic maps in many cases. We conclude that tractography based on dMRI is sensitive enough to reveal the intrinsic organization of ordered connections between topographically organized neural structures and their resultant functional organization.

Interest in structural brain connectivity has grown with the understanding that abnormal neural connections may play a role in neurologic and psychiatric diseases. Small animal connectivity mapping techniques are particularly important for identifying aberrant connectivity in disease models. Diffusion magnetic resonance imaging tractography can provide nondestructive, 3D, brain-wide connectivity maps, but has historically been limited by low spatial resolution, low signal-to-noise ratio, and the difficulty in estimating multiple fiber orientations within a single image voxel. Small animal diffusion tractography can be substantially improved through the combination of ex vivo MRI with exogenous contrast agents, advanced diffusion acquisition and reconstruction techniques, and probabilistic fiber tracking. Here, we present a comprehensive, probabilistic tractography connectome of the mouse brain at microscopic resolution, and a comparison of these data with a neuronal tracer-based connectivity data from the Allen Brain Atlas. This work serves as a reference database for future tractography studies in the mouse brain, and demonstrates the fundamental differences between tractography and neuronal tracer data.

Short association fibers (U-fibers) connect proximal cortical areas and constitute the majority of white matter connections in the human brain. U-fibers play an important role in brain development, function, and pathology but are underrepresented in current descriptions of the human brain connectome, primarily due to methodological challenges in diffusion magnetic resonance imaging (dMRI) of these fibers. High spatial resolution and dedicated fiber and tractography models are required to reliably map the U-fibers. Moreover, limited quantitative knowledge of their geometry and distribution makes validation of U-fiber tractography challenging. Submillimeter resolution diffusion MRI-facilitated by a cutting-edge MRI scanner with 300 mT/m maximum gradient amplitude-was used to map U-fiber connectivity between primary and secondary visual cortical areas (V1 and V2, respectively) in vivo. V1 and V2 retinotopic maps were obtained using functional MRI at 7T. The mapped V1-V2 connectivity was retinotopically organized, demonstrating higher connectivity for retinotopically corresponding areas in V1 and V2 as expected. The results were highly reproducible, as demonstrated by repeated measurements in the same participants and by an independent replication group study. This study demonstrates a robust U-fiber connectivity mapping in vivo and is an important step toward construction of a more complete human brain connectome.

Human brain maturation is characterized by the prolonged development of structural and functional properties of large-scale networks that extends into adulthood. However, it is not clearly understood which features change and which remain stable over time. Here, we examined structural connectivity based on diffusion tensor imaging (DTI) in 121 participants between 4 and 40 years of age. DTI data were analyzed for small-world parameters, modularity, and the number of fiber tracts at the level of streamlines. First, our findings showed that the number of fiber tracts, small-world topology, and modular organization remained largely stable despite a substantial overall decrease in the number of streamlines with age. Second, this decrease mainly affected fiber tracts that had a large number of streamlines, were short, within modules and within hemispheres; such connections were affected significantly more often than would be expected given their number of occurrences in the network. Third, streamline loss occurred earlier in females than in males. In summary, our findings suggest that core properties of structural brain connectivity, such as the small-world and modular organization, remain stable during brain maturation by focusing streamline loss to specific types of fiber tracts.

Even though deficits in social cognition constitute a core characteristic of autism spectrum disorders, a large heterogeneity exists regarding individual social performances and its neural basis remains poorly investigated. Here, we used eye-tracking to objectively measure interindividual variability in social perception and its correlation with white matter microstructure, measured with diffusion tensor imaging MRI, in 25 children with autism spectrum disorder (8.5 ± 3.8 years). Beyond confirming deficits in social perception in participants with autism spectrum disorder compared 24 typically developing controls (10.5 ± 2.9 years), results revealed a large interindividual variability of such behavior among individuals with autism spectrum disorder. Whole-brain analysis showed in both autism spectrum disorder and typically developing groups a positive correlation between number of fixations to the eyes and fractional anisotropy values mainly in right and left superior longitudinal tracts. In children with autism spectrum disorder a correlation was also observed in right and left inferior longitudinal tracts. Importantly, a significant interaction between group and number of fixations to the eyes was observed within the anterior portion of the right inferior longitudinal fasciculus, mainly in the right anterior temporal region. This additional correlation in a supplementary region suggests the existence of a compensatory brain mechanism, which may support enhanced performance in social perception among children with autism spectrum disorder.

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

The APOE ɛ4 allele is associated with a risk of Alzheimer's disease in the elderly, with the association being pronounced in females. Conversely, findings of the effects of the APOE ɛ4 allele in young adults are mixed. Here, we investigated the sex-genotype interaction effects of the APOE ɛ4 allele on cognitive functions as well as brain structures among 1258 young adults. After adjusting for multiple comparisons, there were significant effects of the interaction between sex and the number of APOE ɛ4 allele on some speed tasks (e.g., simple processing speed tasks and the reverse Stroop task) as well as on regional white matter volume (rWMV). The observed sex-genotype interaction conferred better cognitive performance and greater rWMV in the anterior frontal and precentral white matter areas in females having more APOE ɛ4 alleles and reduced rWMV in the same areas in male having more APOE ɛ4 alleles. These findings support the long-debated antagonistic pleiotropic effects of the APOE ɛ4 allele in females.

Fluid intelligence encompasses a wide range of abilities such as working memory, problem-solving, and relational reasoning. In the human brain, these abilities are associated with the Multiple Demand Network, traditionally thought to involve combined activity of specific regions predominantly in the prefrontal and parietal cortices. However, the structural basis of the interactions between areas in the Multiple Demand Network, as well as their evolutionary basis among primates, remains largely unexplored. Here, we exploit diffusion MRI to elucidate the major white matter pathways connecting areas of the human core and extended Multiple Demand Network. We then investigate whether similar pathways can be identified in the putative homologous areas of the Multiple Demand Network in the macaque monkey. Finally, we contrast human and monkey networks using a recently proposed approach to compare different species' brains within a common organizational space. Our results indicate that the core Multiple Demand Network relies mostly on dorsal longitudinal connections and, although present in the macaque, these connections are more pronounced in the human brain. The extended Multiple Demand Network relies on distinct pathways and communicates with the core Multiple Demand Network through connections that also appear enhanced in the human compared with the macaque.

Musical training is thought to be related to improved language skills, for example, understanding speech in background noise. Although studies have found that musicians and nonmusicians differed in morphology of bilateral arcuate fasciculus (AF), none has associated such white matter features with speech-in-noise (SIN) perception. Here, we tested both SIN and the diffusivity of bilateral AF segments in musicians and nonmusicians using diffusion tensor imaging. Compared with nonmusicians, musicians had higher fractional anisotropy (FA) in the right direct AF and lower radial diffusivity in the left anterior AF, which correlated with SIN performance. The FA-based laterality index showed stronger right lateralization of the direct AF and stronger left lateralization of the posterior AF in musicians than nonmusicians, with the posterior AF laterality predicting SIN accuracy. Furthermore, hemodynamic activity in right superior temporal gyrus obtained during a SIN task played a full mediation role in explaining the contribution of the right direct AF diffusivity on SIN performance, which therefore links training-related white matter plasticity, brain hemodynamics, and speech perception ability. Our findings provide direct evidence that differential microstructural plasticity of bilateral AF segments may serve as a neural foundation of the cross-domain transfer effect of musical experience to speech perception amid competing noise.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, which is accompanied by differences in gray matter neuroanatomy and white matter connectivity. However, it is unknown whether these differences are linked or reflect independent aetiologies. Using a multimodal neuroimaging approach, we therefore examined 51 male adults with ASD and 48 neurotypical controls to investigate the relationship between gray matter local gyrification (lGI) and white matter diffusivity in associated fiber tracts. First, ASD individuals had a significant increase in gyrification around the left pre- and post-central gyrus. Second, white matter fiber tracts originating and/or terminating in the cluster of increased lGI had a significant increase in axial diffusivity. This increase in diffusivity was predominantly observed in tracts in close proximity to the cortical sheet. Last, we demonstrate that the increase in lGI was significantly correlated with increased diffusivity of short tracts. This relationship was not significantly modulated by a main effect of group (i.e., ASD), which was more closely associated with gray matter gyrification than white matter diffusivity. Our findings suggest that differences in gray matter neuroanatomy and white matter connectivity are closely linked, and may reflect common rather than distinct aetiological pathways.

Lateralization patterns are a major structural feature of brain white matter and have been investigated as a neural architecture that indicates and supports the specialization of cognitive processing and observed behaviors, e.g. language skills. Many neurodevelopmental disorders have been associated with atypical lateralization, reinforcing the need for careful measurement and study of this structural characteristic. Unfortunately, there is little consensus on the direction and magnitude of lateralization in major white matter tracts during the first months and years of life-the period of most rapid postnatal brain growth and cognitive maturation. In addition, no studies have examined white matter lateralization in a longitudinal pediatric sample-preventing confirmation of if and how white matter lateralization changes over time. Using a densely sampled longitudinal data set from neurotypical infants aged 0-6 months, we aim to (i) chart trajectories of white matter lateralization in 9 major tracts and (ii) link variable findings from cross-sectional studies of white matter lateralization in early infancy. We show that patterns of lateralization are time-varying and tract-specific and that differences in lateralization results during this period may reflect the dynamic nature of lateralization through development, which can be missed in cross-sectional studies.

Cortical spreading depression is a slowly propagating wave of near-complete depolarization of brain cells followed by temporary suppression of neuronal activity. Accumulating evidence indicates that cortical spreading depression underlies the migraine aura and that similar waves promote tissue damage in stroke, trauma, and hemorrhage. Cortical spreading depression is characterized by neuronal swelling, profound elevation of extracellular potassium and glutamate, multiphasic blood flow changes, and drop in tissue oxygen tension. The slow speed of the cortical spreading depression wave implies that it is mediated by diffusion of a chemical substance, yet the identity of this substance and the pathway it follows are unknown. Intercellular spread between gap junction-coupled neurons or glial cells and interstitial diffusion of K(+) or glutamate have been proposed. Here we use extracellular direct current potential recordings, K(+)-sensitive microelectrodes, and 2-photon imaging with ultrasensitive Ca(2+) and glutamate fluorescent probes to elucidate the spatiotemporal dynamics of ionic shifts associated with the propagation of cortical spreading depression in the visual cortex of adult living mice. Our data argue against intercellular spread of Ca(2+) carrying the cortical spreading depression wavefront and are in favor of interstitial K(+) diffusion, rather than glutamate diffusion, as the leading event in cortical spreading depression.

The dorsal hippocampal commissure (DHC) is a white matter tract that provides interhemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted magnetic resonance imaging (DW-MRI) and white matter tractography to reconstruct the DHC in both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate a close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived diffusion tensor MRI metrics from the DHC in a large sample of human subjects to investigate whether interindividual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC correlated with performance in a standardized recognition memory task, an effect that was not reproduced in a comparison commissure tract-the anterior commissure. These findings highlight a potential role for the DHC in recognition memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

Thalamocortical pathways are considered crucial in the sensorimotor functioning of children with cerebral palsy (CP). However, previous research has been limited by non-specific tractography seeding and the lack of comparison between different CP subtypes. We compared limb-specific thalamocortical tracts between children with hemiplegic (HP, N = 15) or diplegic (DP, N = 10) CP and typically developed peers (N = 19). The cortical seed-points for the upper and lower extremities were selected (i) manually based on anatomical landmarks or (ii) using functional magnetic resonance imaging (fMRI) activations following proprioceptive-limb stimulation. Correlations were investigated between tract structure (mean diffusivity, MD; fractional anisotropy, FA; apparent fiber density, AFD) and sensorimotor performance (hand skill and postural stability). Compared to controls, our results revealed increased MD in both upper and lower limb thalamocortical tracts in the non-dominant hemisphere in HP and bilaterally in DP subgroup. MD was strongly lateralized in participants with hemiplegia, while AFD seemed lateralized only in controls. fMRI-based tractography results were comparable. The correlation analysis indicated an association between the white matter structure and sensorimotor performance. These findings suggest distinct impairment of functionally relevant thalamocortical pathways in HP and DP subtypes. Thus, the organization of thalamocortical white matter tracts may offer valuable guidance for targeted, life-long rehabilitation in children with CP.

Studying white matter connections with tractography is a promising approach to understand the development of different brain processes, such as proprioception. An emerging method is to use functional brain imaging to select the cortical seed points for tractography, which is considered to improve the functional relevance and validity of the studied connections. However, it is unknown whether different functional seeding methods affect the spatial and microstructural properties of the given white matter connection. Here, we compared functional magnetic resonance imaging, magnetoencephalography, and manual seeding of thalamocortical proprioceptive tracts for finger and ankle joints separately. We showed that all three seeding approaches resulted in robust thalamocortical tracts, even though there were significant differences in localization of the respective proprioceptive seed areas in the sensorimotor cortex, and in the microstructural properties of the obtained tracts. Our study shows that the selected functional or manual seeding approach might cause systematic biases to the studied thalamocortical tracts. This result may indicate that the obtained tracts represent different portions and features of the somatosensory system. Our findings highlight the challenges of studying proprioception in the developing brain and illustrate the need for using multimodal imaging to obtain a comprehensive view of the studied brain process.

Human skill learning requires fine-scale coordination of distributed networks of brain regions linked by white matter tracts to allow for effective information transmission. Yet how individual differences in these anatomical pathways may impact individual differences in learning remains far from understood. Here, we test the hypothesis that individual differences in structural organization of networks supporting task performance predict individual differences in the rate at which humans learn a visuomotor skill. Over the course of 6 weeks, 20 healthy adult subjects practiced a discrete sequence production task, learning a sequence of finger movements based on discrete visual cues. We collected structural imaging data, and using deterministic tractography generated structural networks for each participant to identify streamlines connecting cortical and subcortical brain regions. We observed that increased white matter connectivity linking early visual regions was associated with a faster learning rate. Moreover, the strength of multiedge paths between motor and visual modules was also correlated with learning rate, supporting the potential role of extended sets of polysynaptic connections in successful skill acquisition. Our results demonstrate that estimates of anatomical connectivity from white matter microstructure can be used to predict future individual differences in the capacity to learn a new motor-visual skill, and that these predictions are supported both by direct connectivity in visual cortex and indirect connectivity between visual cortex and motor cortex.

There is an increasing awareness of the involvement of thalamic connectivity on higher level cortical functioning in the human brain. This is reflected by the influence of thalamic stimulation on cortical activity and behavior as well as apparently cortical lesion syndromes occurring as a function of small thalamic insults. Here, we attempt to noninvasively test the correspondence of structural and functional connectivity of the human thalamus using diffusion-weighted and resting-state functional MRI. Using a large sample of 102 adults, we apply tensor independent component analysis to diffusion MRI tractography data to blindly parcellate bilateral thalamus according to diffusion tractography-defined structural connectivity. Using resting-state functional MRI collected in the same subjects, we show that the resulting structurally defined thalamic regions map to spatially distinct, and anatomically predictable, whole-brain functional networks in the same subjects. Although there was significant variability in the functional connectivity patterns, the resulting 51 structural and functional patterns could broadly be reduced to a subset of 7 similar core network types. These networks were distinct from typical cortical resting-state networks. Importantly, these networks were distributed across the brain and, in a subset, map extremely well to known thalamocortico-basal-ganglial loops.