Associations between atypical intracortical myelin content and neuropsychological functions in middle to older aged adults with ASD.

INTRODUCTION: In vivo myeloarchitectonic mapping based on Magnetic Resonance Imaging (MRI) provides a unique view of gray matter myelin content and offers information complementary to other morphological indices commonly employed in studies of autism spectrum disorder (ASD). The current study sought to determine if intracortical myelin content (MC) and its age-related trajectories differ between middle aged to older adults with ASD and age-matched typical comparison participants. METHODS: Data from 30 individuals with ASD and 36 age-matched typical comparison participants aged 40-70 years were analyzed. Given substantial heterogeneity in both etiology and outcomes in ASD, we utilized both group-level and subject-level analysis approaches to test for signs of atypical intracortical MC as estimated by T1w/T2w ratio. RESULTS: Group-level analyses showed no significant differences in average T1w/T2w ratio or its associations with age between groups, but revealed significant positive main effects of age bilaterally, with T1w/T2w ratio increasing with age across much of the cortex. In subject-level analyses, participants were classified into subgroups based on presence or absence of clusters of aberrant T1w/T2w ratio, and lower neuropsychological function was observed in the ASD subgroup with atypically high T1w/T2w ratio in spatially heterogeneous cortical regions. These differences were observed across several neuropsychological domains, including overall intellectual functioning, processing speed, and aspects of executive function. CONCLUSIONS: The group-level and subject-level approaches employed here demonstrate the value of examining inter-individual variability and provide important preliminary insights into relationships between brain structure and cognition in the second half of the lifespan in ASD, suggesting shared factors contributing to atypical intracortical myelin content and poorer cognitive outcomes for a subset of middle aged to older autistic adults. These atypicalities likely reflect diverse histories of neurodevelopmental deficits, and possible compensatory changes, compounded by processes of aging, and may serve as useful markers of vulnerability to further cognitive decline in older adults with ASD.

Functional dysregulation of the auditory cortex in bilateral perisylvian polymicrogyria: Multiparametric case analysis of the absent speech phenotype.

The absence of speech is a clinical phenotype seen across neurodevelopmental syndromes, offering insights for neural language models. We present a case of bilateral perisylvian polymicrogyria (BPP) and complete absence of speech with considerable language comprehension and production difficulties. We extensively characterized the auditory speech perception and production circuitry by employing a multimodal neuroimaging approach. Results showed extensive cortical thickening in motor and auditory-language regions. The auditory cortex lacked sensitivity to speech stimuli despite relatively preserved thalamic projections yet had no intrinsic functional organization. Subcortical structures implicated in early stages of processing exhibited heightened sensitivity to speech. The arcuate fasciculus, a suggested marker of language in BPP, showed similar volume and integrity to a healthy control. The frontal aslant tract, linked to oromotor function, was partially reconstructed. These findings highlight the importance of assessing the auditory cortex beyond speech production structures to understand absent speech in BPP. Despite profound cortical alterations, the intrinsic motor network and motor-speech pathways remained largely intact. This case underscores the need for comprehensive phenotyping using multiple MRI modalities to uncover causes of severe disruption in language development.

Reduced asymmetry of the hand knob area and decreased sensorimotor u-fiber connectivity in middle-aged adults with autism.

Individuals with autism spectrum disorder (ASD) frequently present with impairments in motor skills (e.g., limb coordination, handwriting and balance), which are observed across the lifespan but remain largely untreated. Many adults with ASD may thus experience adverse motor outcomes in aging, when physical decline naturally occurs. The 'hand knob' of the sensorimotor cortex is an area that is critical for motor control of the fingers and hands. However, this region has received little attention in ASD research, especially in adults after midlife. The hand knob area of the precentral (PrChand) and postcentral (PoChand) gyri was semi-manually delineated in 49 right-handed adults (25 ASD, 24 typical comparison [TC] participants, aged 41-70 years). Using multimodal (T1-weighted, diffusion-weighted, and resting-state functional) MRI, we examined the morphology, ipsilateral connectivity and laterality of these regions. We also explored correlations between hand knob measures with motor skills and autism symptoms, and between structural and functional connectivity measures. Bayesian analyses indicated moderate evidence of group effects with greater right PrChand volume and reduced leftward laterality of PrChand and PoChand volume in the ASD relative to TC group. Furthermore, the right PoC-PrChand u-fibers showed increased mean diffusivity in the ASD group. In the ASD group, right u-fiber volume positively correlated with corresponding functional connectivity but did not survive multiple comparisons correction. Correlations of hand knob measures and behavior were observed in the ASD group but did not survive multiple comparisons correction. Our findings suggest that morphological laterality and u-fiber connectivity of the sensorimotor network, putatively involved in hand motor/premotor function, may be diminished in middle-aged adults with ASD, perhaps rendering them more vulnerable to motor decline in old age. The altered morphology may relate to atypical functional motor asymmetries found in ASD earlier in life, possibly reflecting altered functional asymmetries over time.

Supplementary and Premotor Aspects of the Corticospinal Tract Show Links with Restricted and Repetitive Behaviors in Middle-Aged Adults with Autism Spectrum Disorder.

Individuals with autism spectrum disorder (ASD) show motor impairment into adulthood and risk decline during aging, but little is known about brain changes in aging adults with ASD. Few studies of ASD have directly examined the corticospinal tract (CST)-the major descending pathway in the brain responsible for voluntary motor behavior-outside its primary motor (M1) connections. In 26 middle-aged adults with ASD and 26 age-matched typical comparison participants, we used diffusion imaging to examine the microstructure and volume of CST projections from M1, dorsal premotor (PMd), supplementary motor area (SMA), and primary somatosensory (S1) cortices with respect to age. We also examined relationships between each CST sub-tract (-cst), motor skills, and autism symptoms. We detected no significant group or age-related differences in tracts extending from M1 or other areas. However, sub-tracts of the CST extending from secondary (but not primary) motor areas were associated with core autism traits. Increased microstructural integrity of left PMd-cst and SMA-cst were associated with less-severe restricted and repetitive behaviors (RRB) in the ASD group. These findings suggest that secondary motor cortical areas, known to be involved in selecting motor programs, may be implicated in cognitive motor processes underlying RRB in ASD.

Tractostorm: The what, why, and how of tractography dissection reproducibility.

Investigative studies of white matter (WM) brain structures using diffusion MRI (dMRI) tractography frequently require manual WM bundle segmentation, often called "virtual dissection." Human errors and personal decisions make these manual segmentations hard to reproduce, which have not yet been quantified by the dMRI community. It is our opinion that if the field of dMRI tractography wants to be taken seriously as a widespread clinical tool, it is imperative to harmonize WM bundle segmentations and develop protocols aimed to be used in clinical settings. The EADC-ADNI Harmonized Hippocampal Protocol achieved such standardization through a series of steps that must be reproduced for every WM bundle. This article is an observation of the problematic. A specific bundle segmentation protocol was used in order to provide a real-life example, but the contribution of this article is to discuss the need for reproducibility and standardized protocol, as for any measurement tool. This study required the participation of 11 experts and 13 nonexperts in neuroanatomy and "virtual dissection" across various laboratories and hospitals. Intra-rater agreement (Dice score) was approximately 0.77, while inter-rater was approximately 0.65. The protocol provided to participants was not necessarily optimal, but its design mimics, in essence, what will be required in future protocols. Reporting tractometry results such as average fractional anisotropy, volume or streamline count of a particular bundle without a sufficient reproducibility score could make the analysis and interpretations more difficult. Coordinated efforts by the diffusion MRI tractography community are needed to quantify and account for reproducibility of WM bundle extraction protocols in this era of open and collaborative science.

The cingulum and cingulate U-fibers in children and adolescents with autism spectrum disorders.

The cingulum is the major fiber system connecting the cingulate and surrounding medial cortex and medial temporal lobe internally and with other brain areas. It is important for social and emotional functions related to core symptomatology in autism spectrum disorders (ASDs). While the cingulum has been examined in autism, the extensive system of cingulate U-fibers has not been studied. Using probabilistic tractography, we investigated white matter fibers of the cingulate cortex by distinguishing its deep intra-cingulate bundle (cingulum proper) and short rostral anterior, caudal anterior, posterior, and isthmus cingulate U-fibers in 61 ASD and 54 typically developing children and adolescents. Increased mean and radial diffusivity of the left cingulum proper was observed in the ASD group, replicating previous findings on the cingulum. For cingulate U-fibers, an atypical age-related decline in right posterior cingulate U-fiber volume was found in the ASD group, which appeared to be driven by an abnormally large volume in younger children. History of repetitive and restrictive behavior was negatively associated with right caudal anterior cingulate U-fiber volume, linking cingulate motor areas with neighboring gyri. Aberrant development in U-fiber volume of the right posterior cingulate gyrus may underlie functional abnormalities found in this region, such as in the default mode network.

Atypical Functional Connectivity of Amygdala Related to Reduced Symptom Severity in Children With Autism.

OBJECTIVE: Converging evidence indicates that brain abnormalities in autism spectrum disorders (ASDs) involve atypical network connectivity. Given the central role of social deficits in the ASD phenotype, this investigation examined functional connectivity of the amygdala-a brain structure critically involved in processing of social information-in children and adolescents with ASDs, as well as age-dependent changes and links with clinical symptoms. METHOD: Resting-state functional magnetic resonance imaging (rs-fMRI) data from 55 participants with ASDs and 50 typically developing (TD) controls, aged 7 to 17 years, were included. Groups were matched for age, gender, IQ, and head motion. Functional connectivity MRI (fcMRI) analysis was applied to examine intrinsic functional connectivity (iFC) of the amygdala, including cross-sectional tests of age-related changes. RESULTS: Direct between-group comparisons revealed reduced functional connectivity between bilateral amygdalae and left inferior occipital cortex, accompanied by greater connectivity between right amygdala and right sensorimotor cortex in the ASD group. This atypical pattern of amygdala connectivity was associated with decreased symptom severity and better overall functioning, as specifically seen in an ASD subgroup with the most atypical amygdala iFC but the least impaired social functioning. Age-related strengthening of amygdala-prefrontal connectivity, as observed in the TD group, was not detected in children with ASDs. CONCLUSION: Findings support aberrant network sculpting in ASDs, specifically atypical integration between amygdala and primary sensorimotor circuits. Paradoxical links between atypical iFC and behavioral measures suggest that abnormal amygdala functional connections may be compensatory in some individuals with ASDs.

Recognition of white matter bundles using local and global streamline-based registration and clustering.

Virtual dissection of diffusion MRI tractograms is cumbersome and needs extensive knowledge of white matter anatomy. This virtual dissection often requires several inclusion and exclusion regions-of-interest that make it a process that is very hard to reproduce across experts. Having automated tools that can extract white matter bundles for tract-based studies of large numbers of people is of great interest for neuroscience and neurosurgical planning. The purpose of our proposed method, named RecoBundles, is to segment white matter bundles and make virtual dissection easier to perform. This can help explore large tractograms from multiple persons directly in their native space. RecoBundles leverages latest state-of-the-art streamline-based registration and clustering to recognize and extract bundles using prior bundle models. RecoBundles uses bundle models as shape priors for detecting similar streamlines and bundles in tractograms. RecoBundles is 100% streamline-based, is efficient to work with millions of streamlines and, most importantly, is robust and adaptive to incomplete data and bundles with missing components. It is also robust to pathological brains with tumors and deformations. We evaluated our results using multiple bundles and showed that RecoBundles is in good agreement with the neuroanatomical experts and generally produced more dense bundles. Across all the different experiments reported in this paper, RecoBundles was able to identify the core parts of the bundles, independently from tractography type (deterministic or probabilistic) or size. Thus, RecoBundles can be a valuable method for exploring tractograms and facilitating tractometry studies.

Revisiting the human uncinate fasciculus, its subcomponents and asymmetries with stem-based tractography and microdissection validation.

Despite its significant functional and clinical interest, the anatomy of the uncinate fasciculus (UF) has received little attention. It is known as a 'hook-shaped' fascicle connecting the frontal and anterior temporal lobes and is believed to consist of multiple subcomponents. However, the knowledge of its precise connectional anatomy in humans is lacking, and its subcomponent divisions are unclear. In the present study, we evaluate the anatomy of the UF and provide its detailed normative description in 30 healthy subjects with advanced particle-filtering tractography with anatomical priors and robustness to crossing fibers with constrained spherical deconvolution. We extracted the UF by defining its stem encompassing all streamlines that converge into a compact bundle, which consisted not only of the classic hook-shaped fibers, but also of straight horizontally oriented. We applied an automatic-clustering method to subdivide the UF bundle and revealed five subcomponents in each hemisphere with distinct connectivity profiles, including different asymmetries. A layer-by-layer microdissection of the ventral part of the external and extreme capsules using Klingler's preparation also demonstrated five types of uncinate fibers that, according to their pattern, depth, and cortical terminations, were consistent with the diffusion-based UF subcomponents. The present results shed new light on the UF cortical terminations and its multicomponent internal organization with extended cortical connections within the frontal and temporal cortices. The different lateralization patterns we report within the UF subcomponents reconcile the conflicting asymmetry findings of the literature. Such results clarifying the UF structural anatomy lay the groundwork for more targeted investigations of its functional role, especially in semantic language processing.

Cortical Terminations of the Inferior Fronto-Occipital and Uncinate Fasciculi: Anatomical Stem-Based Virtual Dissection.

We combined the neuroanatomists' approach of defining a fascicle as all fibers passing through its compact stem with diffusion-weighted tractography to investigate the cortical terminations of two association tracts, the inferior fronto-occipital fasciculus (IFOF) and the uncinate fasciculus (UF), which have recently been implicated in the ventral language circuitry. The aim was to provide a detailed and quantitative description of their terminations in 60 healthy subjects and to do so to apply an anatomical stem-based virtual dissection, mimicking classical post-mortem dissection, to extract with minimal a priori the IFOF and UF from tractography datasets. In both tracts, we consistently observed more extensive termination territories than their conventional definitions, within the middle and superior frontal, superior parietal and angular gyri for the IFOF and the middle frontal gyrus and superior, middle and inferior temporal gyri beyond the temporal pole for the UF. We revealed new insights regarding the internal organization of these tracts by investigating for the first time the frequency, distribution and hemispheric asymmetry of their terminations. Interestingly, we observed a dissociation between the lateral right-lateralized and medial left-lateralized fronto-occipital branches of the IFOF. In the UF, we observed a rightward lateralization of the orbito-frontal and temporal branches. We revealed a more detailed map of the terminations of these fiber pathways that will enable greater specificity for correlating with diseased populations and other behavioral measures. The limitations of the diffusion tensor model in this study are also discussed. We conclude that anatomical stem-based virtual dissection with diffusion tractography is a fruitful method for studying the structural anatomy of the human white matter pathways.

Time in perspective.

Perceptions of time and space are subject to strong contextual effects. Like their physical counterparts, they appear to be bound together. The perceived spatial extent of a constant retinal extent increases with its perceived distance from the observer. The perceived duration of a moving object increases with its covered angular trajectory. It follows that the perceived duration of moving objects covering identical angular trajectories should also increase with distance. Using three-dimensionally rendered balls rolling for 600 ms, 900 ms, and 1,200 ms and covering 5.5°, 11°, and 22° trajectories in fronto-parallel planes of a linear-perspective scene, we showed that perceived duration dilates by up to 50% as the fronto-parallel plane of the rolling ball recedes from the observer. Such time dilation is mostly contributed to by the smaller size of the distant ball. As in a three-dimensional world, objects' sizes and their covered trajectories per time unit decrease with distance, and as the two factors lead to opposite perceived-duration effects, the results suggest a form of time constancy in a three-dimensional world.