White matter microstructure of children with sensory over-responsivity is associated with affective behavior.

BACKGROUND: Sensory processing dysfunction (SPD) is linked to altered white matter (WM) microstructure in school-age children. Sensory over-responsivity (SOR), a form of SPD, affects at least 2.5% of all children and has substantial deleterious impact on learning and mental health. However, SOR has not been well studied using microstructural imaging such as diffusion MRI (dMRI). Since SOR involves hypersensitivity to external stimuli, we test the hypothesis that children with SOR require compensatory neuroplasticity in the form of superior WM microstructural integrity to protect against internalizing behavior, leaving those with impaired WM microstructure vulnerable to somatization and depression. METHODS: Children ages 8-12 years old with neurodevelopmental concerns were assessed for SOR using a comprehensive structured clinical evaluation, the Sensory Processing 3 Dimensions Assessment, and underwent 3 Tesla MRI with multishell multiband dMRI. Tract-based spatial statistics was used to measure diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics from global WM and nineteen selected WM tracts. Correlations of DTI and NODDI measures with measures of somatization and emotional disturbance from the Behavioral Assessment System for Children, 3rd edition (BASC-3), were computed in the SOR group and in matched children with neurodevelopmental concerns but not SOR. RESULTS: Global WM fractional anisotropy (FA) is negatively correlated with somatization and with emotional disturbance in the SOR group but not the non-SOR group. Also observed in children with SOR are positive correlations of radial diffusivity (RD) and free water fraction (FISO) with somatization and, in most cases, emotional disturbance. These effects are significant in boys with SOR, whereas the study is underpowered for girls. The most affected white matter are medial lemniscus and internal capsule sensory tracts, although effects of SOR are observed in many cerebral, cerebellar, and brainstem tracts. CONCLUSION: White matter microstructure is related to affective behavior in children with SOR.

Neurite orientation dispersion and density imaging of white matter microstructure in sensory processing dysfunction with versus without comorbid ADHD.

Introduction: Sensory Processing Dysfunction (SPD) is common yet understudied, affecting up to one in six children with 40% experiencing co-occurring challenges with attention. The neural architecture of SPD with Attention Deficit and Hyperactivity Disorder (ADHD) (SPD+ADHD) versus SPD without ADHD (SPD-ADHD) has yet to be explored in diffusion tensor imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) has yet to be examined. Methods: The present study computed DTI and NODDI biophysical model parameter maps of one hundred children with SPD. Global, regional and voxel-level white matter tract measures were analyzed and compared between SPD+ADHD and SPD-ADHD groups. Results: SPD+ADHD children had global WM Fractional Anisotropy (FA) and Neurite Density Index (NDI) that trended lower than SPD-ADHD children, primarily in boys only. Data-driven voxelwise and WM tract-based analysis revealed statistically significant decreases of NDI in boys with SPD+ADHD compared to those with SPD-ADHD, primarily in projection tracts of the internal capsule and commissural fibers of the splenium of the corpus callosum. Conclusion: We conclude that WM microstructure is more delayed/disrupted in boys with SPD+ADHD compared to SPD-ADHD, with NODDI showing a larger effect than DTI. This may represent the combined WM pathology of SPD and ADHD, or it may result from a greater degree of SPD WM pathology causing the development of ADHD.

Hemispheric lateralization of white matter microstructure in children and its potential role in sensory processing dysfunction.

Diffusion tensor imaging (DTI) studies have demonstrated white matter microstructural differences between the left and right hemispheres of the brain. However, the basis of these hemispheric asymmetries is not yet understood in terms of the biophysical properties of white matter microstructure, especially in children. There are reports of altered hemispheric white matter lateralization in ASD; however, this has not been studied in other related neurodevelopmental disorders such as sensory processing disorder (SPD). Firstly, we postulate that biophysical compartment modeling of diffusion MRI (dMRI), such as Neurite Orientation Dispersion and Density Imaging (NODDI), can elucidate the hemispheric microstructural asymmetries observed from DTI in children with neurodevelopmental concerns. Secondly, we hypothesize that sensory over-responsivity (SOR), a common type of SPD, will show altered hemispheric lateralization relative to children without SOR. Eighty-seven children (29 females, 58 males), ages 8-12 years, presenting at a community-based neurodevelopmental clinic were enrolled, 48 with SOR and 39 without. Participants were evaluated using the Sensory Processing 3 Dimensions (SP3D). Whole brain 3 T multi-shell multiband dMRI (b = 0, 1,000, 2,500 s/mm2) was performed. Tract Based Spatial Statistics were used to extract DTI and NODDI metrics from 20 bilateral tracts of the Johns Hopkins University White-Matter Tractography Atlas and the lateralization Index (LI) was calculated for each left-right tract pair. With DTI metrics, 12 of 20 tracts were left lateralized for fractional anisotropy and 17/20 tracts were right lateralized for axial diffusivity. These hemispheric asymmetries could be explained by NODDI metrics, including neurite density index (18/20 tracts left lateralized), orientation dispersion index (15/20 tracts left lateralized) and free water fraction (16/20 tracts lateralized). Children with SOR served as a test case of the utility of studying LI in neurodevelopmental disorders. Our data demonstrated increased lateralization in several tracts for both DTI and NODDI metrics in children with SOR, which were distinct for males versus females, when compared to children without SOR. Biophysical properties from NODDI can explain the hemispheric lateralization of white matter microstructure in children. As a patient-specific ratio, the lateralization index can eliminate scanner-related and inter-individual sources of variability and thus potentially serve as a clinically useful imaging biomarker for neurodevelopmental disorders.

Emotional Resilience Predicts Preserved White Matter Microstructure Following Mild Traumatic Brain Injury.

BACKGROUND: Adult patients with mild traumatic brain injury (mTBI) exhibit distinct phenotypes of emotional and cognitive functioning identified by latent profile analysis of clinical neuropsychological assessments. When discerned early after injury, these latent clinical profiles have been found to improve prediction of long-term outcomes from mTBI. The present study hypothesized that white matter (WM) microstructure is better preserved in an emotionally resilient mTBI phenotype compared with a neuropsychiatrically distressed mTBI phenotype. METHODS: The present study used diffusion magnetic resonance imaging to investigate and compare WM microstructure in major association, projection, and commissural tracts between the two phenotypes and over time. Diffusion magnetic resonance images from 172 patients with mTBI were analyzed to compute individual diffusion tensor imaging maps at 2 weeks and 6 months after injury. RESULTS: By comparing the diffusion tensor imaging parameters between the two phenotypes at global, regional, and voxel levels, emotionally resilient patients were shown to have higher axial diffusivity compared with neuropsychiatrically distressed patients early after mTBI. Longitudinal analysis revealed greater compromise of WM microstructure in neuropsychiatrically distressed patients, with greater decrease of global axial diffusivity and more widespread decrease of regional axial diffusivity during the first 6 months after injury compared with emotionally resilient patients. CONCLUSIONS: These results provide neuroimaging evidence of WM microstructural differences underpinning mTBI phenotypes identified from neuropsychological assessments and show differing longitudinal trajectories of these biological effects. These findings suggest that diffusion magnetic resonance imaging can provide short- and long-term imaging biomarkers of resilience.

Brief Report: Characterization of Sensory Over-Responsivity in a Broad Neurodevelopmental Concern Cohort Using the Sensory Processing Three Dimensions (SP3D) Assessment.

Sensory Over-Responsivity (SOR) is an increasingly recognized challenge among children with neurodevelopmental concerns (NDC). To investigate, we characterized the incidence of auditory and tactile over-responsivity (AOR, TOR) among 82 children with NDC. We found that 70% of caregivers reported concern for their child's sensory reactions. Direct assessment further revealed that 54% of the NDC population expressed AOR, TOR, or both - which persisted regardless of autism spectrum disorder (ASD) diagnosis. These findings support the high prevalence of SOR as well as its lack of specificity to ASD. Additionally, AOR is revealed to be over twice as prevalent as TOR. These conclusions present several avenues for further exploration, including deeper analysis of the neural mechanisms and genetic contributors to sensory processing challenges.

Diffusion Tensor Imaging Reveals Elevated Diffusivity of White Matter Microstructure that Is Independently Associated with Long-Term Outcome after Mild Traumatic Brain Injury: A TRACK-TBI Study.

Diffusion tensor imaging (DTI) literature on single-center studies contains conflicting results regarding acute effects of mild traumatic brain injury (mTBI) on white matter (WM) microstructure and the prognostic significance. This larger-scale multi-center DTI study aimed to determine how acute mTBI affects WM microstructure over time and how early WM changes affect long-term outcome. From Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI), a cohort study at 11 United States level 1 trauma centers, a total of 391 patients with acute mTBI ages 17 to 60 years were included and studied at two weeks and six months post-injury. Demographically matched friends or family of the participants were the control group (n = 148). Axial diffusivity (AD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were the measures of WM microstructure. The primary outcome was the Glasgow Outcome Scale Extended (GOSE) score of injury-related functional limitations across broad life domains at six months post-injury. The AD, MD, and RD were higher and FA was lower in mTBI versus friend control (FC) at both two weeks and six months post-injury throughout most major WM tracts of the cerebral hemispheres. In the mTBI group, AD and, to a lesser extent, MD decreased in WM from two weeks to six months post-injury. At two weeks post-injury, global WM AD and MD were both independently associated with six-month incomplete recovery (GOSE <8 vs = 8) even after accounting for demographic, clinical, and other imaging factors. DTI provides reliable imaging biomarkers of dynamic WM microstructural changes after mTBI that have utility for patient selection and treatment response in clinical trials. Continued technological advances in the sensitivity, specificity, and precision of diffusion magnetic resonance imaging hold promise for routine clinical application in mTBI.

Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity.

BACKGROUND: The practice of "microdosing," or the use of repeated, very low doses of lysergic acid diethylamide (LSD) to improve mood or cognition, has received considerable public attention, but empirical studies are lacking. Controlled studies are needed to investigate both the therapeutic potential and the neurobiological underpinnings of this pharmacologic treatment. METHODS: The present study was designed to examine the effects of a single low dose of LSD (13 µg) versus placebo on resting-state functional connectivity and cerebral blood flow in healthy young adults. Twenty men and women, 18 to 35 years old, participated in 2 functional magnetic resonance imaging scanning sessions in which they received placebo or LSD under double-blind conditions. During each session, the participants completed drug effect and mood questionnaires, and physiological measures were recorded. During expected peak drug effect, they underwent resting-state blood oxygen level-dependent and arterial spin labeling scans. Cerebral blood flow as well as amygdala and thalamic connectivity were analyzed. RESULTS: LSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum, and decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala-middle frontal gyrus connectivity strength. CONCLUSIONS: These preliminary findings show that a very low dose of LSD, which produces negligible subjective changes, alters brain connectivity in limbic circuits. Additional studies, especially with repeated dosing, will reveal whether these neural changes are related to the drug's purported antidepressant effect.

Altered Cerebellar White Matter in Sensory Processing Dysfunction Is Associated With Impaired Multisensory Integration and Attention.

Sensory processing dysfunction (SPD) is characterized by a behaviorally observed difference in the response to sensory information from the environment. While the cerebellum is involved in normal sensory processing, it has not yet been examined in SPD. Diffusion tensor imaging scans of children with SPD (n = 42) and typically developing controls (TDC; n = 39) were compared for fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across the following cerebellar tracts: the middle cerebellar peduncles (MCP), superior cerebellar peduncles (SCP), and cerebral peduncles (CP). Compared to TDC, children with SPD show reduced microstructural integrity of the SCP and MCP, characterized by reduced FA and increased MD and RD, which correlates with abnormal auditory behavior, multisensory integration, and attention, but not tactile behavior or direct measures of auditory discrimination. In contradistinction, decreased CP microstructural integrity in SPD correlates with abnormal tactile and auditory behavior and direct measures of auditory discrimination, but not multisensory integration or attention. Hence, altered cerebellar white matter organization is associated with complex sensory behavior and attention in SPD, which prompts further consideration of diagnostic measures and treatments to better serve affected individuals.