The pattern of cortical thickness associated with executive dysfunction in MCI and SCC: The MEMENTO cohort.

BACKGROUND: The association between the pattern of cortical thickness (CT) and executive dysfunction (ED) in mild cognitive impairment (MCI) and subjective cognitive complaints (SCC) is still poorly understood. We aimed to investigate the association between CT and ED in a large French cohort (MEMENTO) of 2323 participants with MCI or SCC. METHODS: All participants with available CT and executive function data (verbal fluency and Trail Making Test [TMT]) were selected (n=1924). Linear regressions were performed to determine relationships between executive performance and the brain parenchymal fraction (BPF) and CT using FreeSurfer. RESULTS: The global executive function score was related to the BPF (sß: 0.091, P<0.001) and CT in the right supramarginal (sß: 0.060, P=0.041) and right isthmus cingulate (sß: 0.062, P=0.011) regions. Literal verbal fluency was related to the BPF (sß: 0.125, P<0.001) and CT in the left parsorbitalis region (sß: 0.045, P=0.045). Semantic verbal fluency was related to the BPF (sß: 0.101, P<0.001) and CT in the right supramarginal region (sß: 0.061, P=0.042). The time difference between the TMT parts B and A was related to the BPF (sß: 0.048, P=0.045) and CT in the right precuneus (sß: 0.073, P=0.019) and right isthmus cingulate region (sß: 0.054, P=0.032). CONCLUSIONS: In a large clinically based cohort of participants presenting with either MCI or SCC (a potential early stage of Alzheimer's disease [AD]), ED was related to the BPF and CT in the left pars orbitalis, right precuneus, right supramarginal, and right isthmus cingulate regions. This pattern of lesions adds knowledge to the conventional anatomy of ED and could contribute to the early diagnosis of AD.

Development of cortical folds in the human brain: An attempt to review biological hypotheses, early neuroimaging investigations and functional correlates.

The folding of the human brain mostly takes place in utero, making it challenging to study. After a few pioneer studies looking into it in post-mortem foetal specimen, modern approaches based on neuroimaging have allowed the community to investigate the folding process in vivo, its normal progression, its early disturbances, and its relationship to later functional outcomes. In this review article, we aimed to first give an overview of the current hypotheses on the mechanisms governing cortical folding. After describing the methodological difficulties raised by its study in fetuses, neonates and infants with magnetic resonance imaging (MRI), we reported our current understanding of sulcal pattern emergence in the developing brain. We then highlighted the functional relevance of early sulcal development, through recent insights about hemispheric asymmetries and early factors influencing this dynamic such as prematurity. Finally, we outlined how longitudinal studies have started to relate early folding markers and the child's sensorimotor and cognitive outcome. Through this review, we hope to raise awareness on the potential of studying early sulcal patterns both from a fundamental and clinical perspective, as a window into early neurodevelopment and plasticity in relation to growth in utero and postnatal environment of the child.

Biomarkers of Age-Related Frailty and Frailty Related to Diseases: An Exploratory, Cross-Sectional Analysis from the MAPT Study.

BACKGROUND: Frailty may in most cases result from two main causes: the aging process (age-related frailty) and diseases (evolving chronic conditions or acute medical illnesses - disease-related frailty). The biological determinants characterizing these two main causes of frailty may be different. OBJECTIVES: The aim of this study is to compare the biological and neuroimaging profile of people without frailty, those with age-related frailty, and subjects with disease-related frailty in community-dwelling older adults. MATERIAL AND METHODS: We performed a secondary, cross-sectional analysis from the Multidomain Alzheimer Preventive Trial (MAPT). We included 1199 subjects without frailty throughout the 5-year follow-up, 82 subjects with incident age-related frailty, and 53 with incident disease-related frailty. Available blood biomarkers involved nutritional (eg, vitamin D, omega-3 fatty acids), inflammatory-related (IL-6, TNFR1, GDF15), neurodegenerative (eg, beta-amyloid, neurofilament light chain) and neuroimaging markers (MRI, Amyloid-PET). RESULTS: Although not statistically significant, the results of the unadjusted model showed increasing gradients for inflammatory markers (GDF15, TNFR1) and decreasing gradients for nutritional and neuroimaging markers (omega 3 index, hippocampal volume) from age-related frailty participants to individuals with disease-related frailty. Considering the linear models we observed higher GDF15 values in disease-related frailty group compared to age-related frailty individuals [ß = 242.8 (49.5, 436.2)]. We did not find any significant difference between subjects without frailty and those with age-related frailty. Subjects with disease-related frailty compared to subjects without frailty had lower values of DHA [ß = -2.42 (-4.76, -0.08)], Omega 3 Index [ß = -0.50 (-0.95, -0.06)] and hippocampal volume [ß = -0.22 (-0.42,-0.02)]. They also had higher values of GDF15 [ß = 246.1 (88.9, 403.4)] and TNFR1 [ß = 157.5 (7.8, 307.2)]. CONCLUSION: Age-related frailty and disease-related frailty may represent different degrees of frailty severity on a biological level. Further research is needed to identify biomarkers potentially able to distinguish these classifications of frailty.

Enhanced Automatic Segmentation for Superficial White Matter Fiber Bundles for Probabilistic Tractography Datasets.

This paper presents an enhanced algorithm for automatic segmentation of superficial white matter (SWM) bundles from probabilistic dMRI tractography datasets, based on a multi-subject bundle atlas. Previous segmentation methods use the maximum Euclidean distance between corresponding points of the subject fibers and the atlas centroids. However, this scheme might include noisy fibers. Here, we propose a three step approach to discard noisy fibers improving the identification of fibers. The first step applies a fiber clustering and the segmentation is performed between the centroids of the clusters and the atlas centroids. This step removes outliers and enables a better identification of fibers with similar shapes. The second step applies a fiber filter based on two different fiber similarities. One is the Symmetrized Segment-Path Distance (SSPD) over 2D ISOMAP and the other is an adapted version of SSPD for 3D space. The last step eliminates noisy fibers by removing those that connect regions that are far from the main atlas bundle connections. We perform an experimental evaluation using ten subjects of the Human Connectome (HCP) database. The evaluation only considers the bundles connecting precentral and postcentral gyri, with a total of seven bundles per hemisphere. For comparison, the bundles of the ten subjects were manually segmented. Bundles segmented with our method were evaluated in terms of similarity to manually segmented bundles and the final number of fibers. The results show that our approach obtains bundles with a higher similarity score than the state-of-the-art method and maintains a similar number of fibers.Clinical relevance-Many brain pathologies or disorders can occur in specific regions of the SWM automatic segmentation of reliable SWM bundles would help applications to clinical research.

Cerebellar parcellation in schizophrenia and bipolar disorder.

OBJECTIVE: The cerebellum is involved in cognitive processing and emotion control. Cerebellar alterations could explain symptoms of schizophrenia spectrum disorder (SZ) and bipolar disorder (BD). In addition, literature suggests that lithium might influence cerebellar anatomy. Our aim was to study cerebellar anatomy in SZ and BD, and investigate the effect of lithium. METHODS: Participants from 7 centers worldwide underwent a 3T MRI. We included 182 patients with SZ, 144 patients with BD, and 322 controls. We automatically segmented the cerebellum using the CERES pipeline. All outputs were visually inspected. RESULTS: Patients with SZ showed a smaller global cerebellar gray matter volume compared to controls, with most of the changes located to the cognitive part of the cerebellum (Crus II and lobule VIIb). This decrease was present in the subgroup of patients with recent-onset SZ. We did not find any alterations in the cerebellum in patients with BD. However, patients medicated with lithium had a larger size of the anterior cerebellum, compared to patients not treated with lithium. CONCLUSION: Our multicenter study supports a distinct pattern of cerebellar alterations in SZ and BD.

The effect of the number of fibers in tractography reconstruction of white matter bundles.

The study of white matter (WM) through diffusion Magnetic Resonance Imaging (dMRI) is crucial to obtain a better understanding of human brain connections and functions, at a macroscopic level. A large number of works have focused on long range brain connections, while recently, several studies have also analyzed superficial WM connectivity. In recent years, with the massive use of HCP database, and its processing with known softwares like DSI Studio and MRtrix, it is necessary to evaluate the influence of tractography parameters on the reconstruction of fiber bundles and further analyses. We study the effect of the number of fibers, for whole brain tractography, on the reconstruction of deep and superficial WM bundles based on their segmentation using multi-subject bundle atlases. For DSI Studio (deterministic algorithm), a value of 1M fibers could reconstruct most of deep white matter (DWM) bundles, while a value of 1.5M was required for superficial white matter (SWM) bundles. In the case of MRtrix (probabilistic algorithm), a value of 3M fibers was found to be suitable for the study of both kinds of fibers. Furthermore, we found the tracking of SWM bundles to be more sensitive to several parameters than DWM, for DSI Studio.

Mapping the asynchrony of cortical maturation in the infant brain: A MRI multi-parametric clustering approach.

While the main neural networks are in place at term birth, intense changes in cortical microstructure occur during early infancy with the development of dendritic arborization, synaptogenesis and fiber myelination. These maturational processes are thought to relate to behavioral acquisitions and the development of cognitive abilities. Nevertheless, in vivo investigations of such relationships are still lacking in healthy infants. To bridge this gap, we aimed to study the cortical maturation using non-invasive Magnetic Resonance Imaging, over a largely unexplored period (1-5 post-natal months). In a first univariate step, we focused on different quantitative parameters: longitudinal relaxation time (T1), transverse relaxation time (T2), and axial diffusivity from diffusion tensor imaging (λ//) These individual maps, acquired with echo-planar imaging to limit the acquisition time, showed spatial distortions that were first corrected to reliably match the thin cortical ribbon identified on high-resolution T2-weighted images. Averaged maps were also computed over the infants group to summarize the parameter characteristics during early infancy. In a second step, we considered a multi-parametric approach that leverages parameters complementarity, avoids reliance on pre-defined regions of interest, and does not require spatial constraints. Our clustering strategy allowed us to group cortical voxels over all infants in 5 clusters with distinct microstructural T1 and λ// properties The cluster maps over individual cortical surfaces and over the group were in sound agreement with benchmark post mortem studies of sub-cortical white matter myelination, showing a progressive maturation of 1) primary sensori-motor areas, 2) adjacent unimodal associative cortices, and 3) higher-order associative regions. This study thus opens a consistent approach to study cortical maturation in vivo.

A framework based on sulcal constraints to align preterm, infant and adult human brain images acquired in vivo and post mortem.

Robust spatial alignment of post mortem data and in vivo MRI acquisitions from different ages, especially from the early developmental stages, into standard spaces is still a bottleneck hampering easy comparison with the mainstream neuroimaging results. In this paper, we test a landmark-based spatial normalization strategy as a framework for the seamless integration of any macroscopic dataset in the context of the Human Brain Project (HBP). This strategy stems from an approach called DISCO embedding sulcal constraints in a registration framework used to initialize DARTEL, the widely used spatial normalization approach proposed in the SPM software. We show that this strategy is efficient with a heterogeneous dataset including challenging data as preterm newborns, infants, post mortem histological data and a synthetic atlas computed from averaging the ICBM database, as well as more commonly studied data acquired in vivo in adults. We then describe some perspectives for a research program aiming at improving folding pattern matching for atlas inference in the context of the future HBP's portal.

Optogenetic Tractography for anatomo-functional characterization of cortico-subcortical neural circuits in non-human primates.

Dissecting neural circuitry in non-human primates (NHP) is crucial to identify potential neuromodulation anatomical targets for the treatment of pharmacoresistant neuropsychiatric diseases by electrical neuromodulation. How targets of deep brain stimulation (DBS) and cortical targets of transcranial magnetic stimulation (TMS) compare and might complement one another is an important question. Combining optogenetics and tractography may enable anatomo-functional characterization of large brain cortico-subcortical neural pathways. For the proof-of-concept this approach was used in the NHP brain to characterize the motor cortico-subthalamic pathway (m_CSP) which might be involved in DBS action mechanism in Parkinson's disease (PD). Rabies-G-pseudotyped and Rabies-G-VSVg-pseudotyped EIAV lentiviral vectors encoding the opsin ChR2 gene were stereotaxically injected into the subthalamic nucleus (STN) and were retrogradely transported to the layer of the motor cortex projecting to STN. A precise anatomical mapping of this pathway was then performed using histology-guided high angular resolution MRI tractography guiding accurately cortical photostimulation of m_CSP origins. Photoexcitation of m_CSP axon terminals or m_CSP cortical origins modified the spikes distribution for photosensitive STN neurons firing rate in non-equivalent ways. Optogenetic tractography might help design preclinical neuromodulation studies in NHP models of neuropsychiatric disease choosing the most appropriate target for the tested hypothesis.

Physical Activity and Changes in White Matter Hyperintensities over Three Years.

OBJECTIVES: Since physical activity (PA) has demonstrated benefits for cardiovascular health, it is possible to hypothesize that higher or increasing PA slows the progression of white matter hyperintensities (WMH). We investigated the association between PA and the progression of WMH in non-demented older adults with memory complaints. DESIGN: We included 152 participants (mean age 74.7±3.8 years; 63.8% women) in the analyses, in whom information on self-reported PA and MRI was available at both baseline and 3-year follow-up. From the PA questionnaire, the baseline metabolic equivalent of task (MET-minute/week) and changes in MET-minute/week over three years were separately calculated for overall, leisure-time, and non-leisure time PA. WMH volume at baseline and 3-year follow-up was obtained by using an automated segmentation algorithm. RESULTS: Mixed-effect linear regression models showed that none of the baseline PA variables was associated with progression of WMH over time. People who had decreased their PA levels over three years tended to show greater progression of WMH compared with those who had maintained PA levels of ≥1200 MET-min/week (roughly equivalent to ≥300 minutes of brisk walking) in the unadjusted model (ß±SE=4.85±2.42, p=0.045); however, this association was no longer significant after adjustment for confounders (ß±SE =3.63±2.18, p=0.096). CONCLUSIONS: We did not find any significant association between PA and WMH in non-demented older adults with memory complaints. However, decrease over time in PA levels tended to be associated with progression of WMH. A larger longitudinal study with data on PA assessed using objective measures would provide important information in this field.

Association between Red Blood Cells Omega-3 Polyunsaturated Fatty Acids and White Matter Hyperintensities: The MAPT Study.

OBJECTIVES: The association between circulating biomarkers of red blood cells (RBC) omega-3 polyunsaturated fatty acids (PUFAs) and cerebral white matter hyperintensities (WMH) on the brain MRI remains yet unclear. We investigated the cross-sectional and prospective associations of RBC omega-3 PUFAs with WMH in dementia-free older adults with subjective memory complaints. DESIGN: Participants were 234 older adults with assessments for both PUFA and MRI near to baseline; among them, 79 also had an MRI assessment at 3-year follow-up. The measurement of WMH volume was obtained by an automated segmentation algorithm. We related individual or combinational baseline RBC omega-3 PUFAs levels with baseline WMH volumes and WMH evolution over 3 years. We carried out multiple (cross-sectional) and mixed-effect (prospective analysis, with random effects at participant's level) linear regressions with adjustment for age, sex, time interval between date of blood draw for measurement of fatty acids and date of brain MRI, the status of APOE e4 carrier, body mass index, and vascular risk factors. Associations were considered significant at p ≤ 0.006 to take into account multiplicity (8 comparisons). RESULTS: None of the eight RBC omega-3 PUFAs tested was significantly associated with WMH at both cross-sectional and prospective analyses. CONCLUSIONS: We did not find any association between omega-3 PUFAs and WMH in non-demented older adults with memory complaints. A longer longitudinal study with data on omega-3 PUFAs and WMH would contribute important information to this field.

Social cognition in autism is associated with the neurodevelopment of the posterior superior temporal sulcus.

OBJECTIVE: The posterior superior temporal sulcus (pSTS) plays a critical role in the 'social brain'. Its neurodevelopment and relationship with the social impairment in autism spectrum disorders (ASD) are not well understood. We explored the relationship between social cognition and the neurodevelopment of the pSTS in ASD. METHOD: We included 44 adults with high-functioning ASD and 36 controls. We assessed their performances on the 'Reading the mind in the eyes' test (for 34 of 44 subjects with ASD and 30 of 36 controls), their fixation time on the eyes with eye tracking (for 35 of 44 subjects with ASD and 30 of 36 controls) and the morphology of the caudal branches of the pSTS (length and depth), markers of the neurodevelopment, with structural MRI. RESULTS: The right anterior caudal ramus of the pSTS was significantly longer in patients with ASD compared with controls (52.6 mm vs. 38.3 mm; P = 1.4 × 10-3 ; Cohen's d = 0.76). Its length negatively correlated with fixation time on the eyes (P = 0.03) in the ASD group and with the 'Reading the mind in the eyes' test scores in both groups (P = 0.03). CONCLUSION: Our findings suggest that the neurodevelopment of the pSTS is related to the ASD social impairments.

Lower Magnetization Transfer Ratio in the Forceps Minor Is Associated with Poorer Gait Velocity in Older Adults.

BACKGROUND AND PURPOSE: Gait disturbances in the elderly are disabling and a major public health issue but are poorly understood. In this multimodal MR imaging study, we used 2 voxel-based analysis methods to assess the voxelwise relationship of magnetization transfer ratio and white matter hyperintensity location with gait velocity in older adults. MATERIALS AND METHODS: We assessed 230 community-dwelling participants of the Austrian Stroke Prevention Family Study. Every participant underwent 3T MR imaging, including magnetization transfer imaging. Voxel-based magnetization transfer ratio-symptom mapping correlated the white matter magnetization transfer ratio of each voxel with gait velocity. To assess a possible relationship between white matter hyperintensity location and gait velocity, we applied voxel-based lesion-symptom mapping. RESULTS: We found a significant association between the magnetization transfer ratio within the forceps minor and gait velocity (ß = 0.134; 95% CI, 0.011-0.258; P = .033), independent of demographics, general physical performance, vascular risk factors, and brain volume. White matter hyperintensities did not significantly change this association. CONCLUSIONS: Our study provides new evidence for the importance of magnetization transfer ratio changes in gait disturbances at an older age, particularly in the forceps minor. The histopathologic basis of these findings is yet to be determined.

Spatial normalization of brain images and beyond.

The deformable atlas paradigm has been at the core of computational anatomy during the last two decades. Spatial normalization is the variant endowing the atlas with a coordinate system used for voxel-based aggregation of images across subjects and studies. This framework has largely contributed to the success of brain mapping. Brain spatial normalization, however, is still ill-posed because of the complexity of the human brain architecture and the lack of architectural landmarks in standard morphological MRI. Multi-atlas strategies have been developed during the last decade to overcome some difficulties in the context of segmentation. A new generation of registration algorithms embedding architectural features inferred for instance from diffusion or functional MRI is on the verge to improve the architectural value of spatial normalization. A better understanding of the architectural meaning of the cortical folding pattern will lead to use some sulci as complementary constraints. Improving the architectural compliance of spatial normalization may impose to relax the diffeomorphic constraint usually underlying atlas warping. A two-level strategy could be designed: in each region, a dictionary of templates of incompatible folding patterns would be collected and matched in a way or another using rare architectural information, while individual subjects would be aligned using diffeomorphisms to the closest template. Manifold learning could help to aggregate subjects according to their morphology. Connectivity-based strategies could emerge as an alternative to deformation-based alignment leading to match the connectomes of the subjects rather than images.

Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

OBJECTIVE: High-functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design. METHODS: We scanned 79 male adult subjects with 3T MRI (23 with HFA, 24 with SZ and 32 healthy controls, with similar non-verbal IQ). We compared them using both diffusion-based whole-brain tractography and T1 voxel-based morphometry. RESULTS: HFA and SZ groups exhibited similar white matter alterations in the left fronto-occipital inferior fasciculus with a decrease in generalized fractional anisotropy compared with controls. In grey matter, the HFA group demonstrated bilateral prefrontal and anterior cingulate increases in contrast with prefrontal and left temporal reductions in SZ. CONCLUSION: HFA and SZ may share common white matter deficits in long-range connections involved in social functions, but opposite grey matter abnormalities in frontal regions that subserve complex cognitive functions. Our results are consistent with the fronto-occipital underconnectivity theory of HFA and the altered connectivity hypothesis of SZ and suggest the existence of both associated and diametrical liabilities to these two conditions.

Longitudinal stability of the folding pattern of the anterior cingulate cortex during development.

Prenatal processes are likely critical for the differences in cognitive ability and disease risk that unfold in postnatal life. Prenatally established cortical folding patterns are increasingly studied as an adult proxy for earlier development events - under the as yet untested assumption that an individual's folding pattern is developmentally fixed. Here, we provide the first empirical test of this stability assumption using 263 longitudinally-acquired structural MRI brain scans from 75 typically developing individuals spanning ages 7 to 32 years. We focus on the anterior cingulate cortex (ACC) - an intensely studied cortical region that presents two qualitatively distinct and reliably classifiable sulcal patterns with links to postnatal behavior. We show - without exception-that individual ACC sulcal patterns are fixed from childhood to adulthood, at the same time that quantitative anatomical ACC metrics are undergoing profound developmental change. Our findings buttress use of folding typology as a postnatally-stable marker for linking variations in early brain development to later neurocognitive outcomes in ex utero life.

Linking morphological and functional variability in hand movement and silent reading.

It is generally accepted in neuroscience that anatomy and function go hand in hand. Accordingly, a local morphological variability could lead to a corresponding functional variability. In this study, we tested this hypothesis by linking the variability of the cortical folding pattern of 252 right-handed subjects to the localization or the pattern of functional activations induced by hand motion or silent reading. Three regions are selected: the central sulcus, the precentral sulcus and the superior temporal sulcus (STS). "Essential morphological variability traits" are identified using a method building upon multidimensional scaling. The link between variability in anatomy and function is confirmed by the perfect match between the central sulcus morphological "hand knob" and the corresponding motor activation: as the location of the hand knob moves more or less dorsally along the central sulcus, the motor hand activation moves accordingly. Furthermore, the size of the left hand activation in the right hemisphere is correlated with the knob location in the central sulcus. A new link between functional and morphological variability is discovered relative to the location of a premotor activation induced by silent reading. While this reading activation is located next to the wall of the central sulcus when the hand knob has a ventral positioning, it is pushed into a deep gyrus interrupting the precentral sulcus when the knob is more dorsal. Finally, it is shown that the size of the reading activation along the STS is larger when the posterior branches are less developed.

Creation of a whole brain short association bundle atlas using a hybrid approach.

The Human brain connection map is far from being complete. In particular the study of the superficial white matter (SWM) is an unachieved task. Its description is essential for the understanding of human brain function and the study of pathogenesis triggered by abnormal connectivity. In this work we expanded a previously developed method for the automatic creation of a whole brain SWM bundle atlas. The method is based on a hybrid approach. First a cortical parcellation is used to extract fibers connecting two regions. Then an intra-and inter-subject hierarchical clustering are applied to find well-defined SWM bundles reproducible across subjects. In addition to the fronto-parietal and insula regions of the left hemisphere, the analysis was extended to the temporal and occipital lobes, including all their internal regions, for both hemispheres. Validation steps are performed in order to test the robustness of the method and the reproducibility of the obtained bundles. First the method was applied to two independent groups of subjects, in order to discard bundles without match across the two independent atlases. Then, the resulting intersection atlas was projected on a third independent group of subjects in order to filter out bundles without reproducible and reliable projection. The final multi-subject U-fiber atlas is composed of 100 bundles in total, 50 per hemisphere, from which 35 are common to both hemispheres. The atlas can be used in clinical studies for segmentation of the SWM bundles in new subjects, and measure DW values or complement functional data.

Short association bundle atlas based on inter-subject clustering from HARDI data.

This paper is focused on the study of short brain association fibers. We present an automatic method to identify short bundles of the superficial white matter based on inter-subject hierarchical clustering. Our method finds clusters of similar fibers, belonging to the different subjects, according to a distance measure between fibers. First, the algorithm obtains representative bundles and subsequently we perform an automatic labeling based on the anatomy, of the most stable connections. The analysis was applied to two independent groups of 37 subjects. Results between the two groups were compared, in order to keep reproducible connections for the atlas creation. The method was applied using linear and non-linear registration, where the non-linear registration showed significantly better results. A final atlas with 35 bundles in the left hemisphere and 27 in the right hemisphere from the whole brain was obtained. Finally results were validated using the atlas to segment 26 new subjects from another HARDI database.

Automatic segmentation of short association bundles using a new multi-subject atlas of the left hemisphere fronto-parietal brain connections.

Human brain connection map is far from being complete. In particular the study of the superficial white matter (SWM) is an unachieved task. Its description is essential for the understanding of human brain function and the study of the pathogenesis associated to it. In this work we developed a method for the automatic creation of a SWM bundle multi-subject atlas. The atlas generation method is based on a cortical parcellation for the extraction of fibers connecting two different gyri. Then, an intra-subject fiber clustering is applied, in order to divide each bundle into sub-bundles with similar shape. After that, a two-step inter-subject fiber clustering is used in order to find the correspondence between the sub-bundles across the subjects, fuse similar clusters and discard the outliers. The method was applied to 40 subjects of a high quality HARDI database, focused on the left hemisphere fronto-parietal and insula brain regions. We obtained an atlas composed of 44 bundles connecting 22 pair of ROIs. Then the atlas was used to automatically segment 39 new subjects from the database.