White matter microstructural alterations in broadly defined sensory processing dysfunction

Consistent with the premise of reduced white matter microstructural integrity of specific neural networks, we have previously reported that children born prematurely show increased sensory processing differences, particularly in the auditory domain, and that these children are also known to have brain injury that is “regional,” in the posterior periventricular white matter [2, 3]. This regional predilection is thought to be related to vulnerability of oligodendrocyte precursors—thus “at-risk” territory [4]. Furthermore, children with agenesis of the corpus callosum, a syndrome of hemispheric disconnection, also show differences in sensory processing [5, 6]. However, in the extant literature, sensory dysfunction in children with genetic and injury-based conditions is approached with a broad sensory framework that does not answer the question of whether SOR results from a regional disruption and/or plasticity of dedicated neuronal networks. Without this information, it becomes impossible to quantify network neuroplasticity with targeted treatment interventions. However, posterior periventricular WM contains particularly broad and dense connectivity within the cerebral cortical connectome and can therefore affect many different cognitive and behavioral domains [56].

Biophysical modeling of diffusion MRI advances understanding of white matter microstructure

Although DTI is a useful tool for studying brain development, it represents only a basic statistical description of water diffusion within a voxel from images typically acquired at a single relatively low diffusion-weighting factor (b value) representing only a single spherical shell in q-space. The assumption of Gaussian diffusion that underpins the DTI model breaks down at b values in excess of 1000 s/mm2, whereas the investigation of restricted and strongly hindered diffusion, such as within the intracellular space, requires higher diffusion-weighting factors. Therefore, common DTI measures, specifically FA, MD, AD, and RD, lack the specificity to differentiate between intracellular and extracellular disruption [57, 58].

In contrast to DTI, NODDI is a multi-compartment biophysical model of brain microstructure that computes the non-collinear properties of neurite orientation dispersion index (ODI) and neurite density index (NDI) within each imaging voxel. NODDI employs a tissue model that distinguishes three types of microstructural environment: (1) restricted intra-cellular compartment modeled with orientation dispersion using a Watson distribution, (2) extra-cellular compartment with Gaussian anisotropically hindered diffusion, and (3) cerebrospinal fluid (CSF) compartment with freely isotropic diffusion [36, 37]. One advantage of NODDI over previous biophysical diffusion models is that the multi-shell HARDI imaging data is within the current MR scanner’s hardware, pulse sequence, and acquisition time constraints for clinical studies. Additionally, free water diffusion is isolated into a separate biophysical compartment (FISO); therefore, CSF partial volume averaging does not contaminate estimates of tissue microstructure as it can with DTI.

Global white matter microstructure in children with SOR and its association with behavior

In this study, we provide evidence for our a priori hypotheses that microstructural WM differences in SOR are associated with variation in affective behavior, particularly somatization and the consequent emotional disturbance characterized by generalized unhappiness and withdrawal. This relationship is strong in boys with SOR, but not in girls. However, the sample size of girls in our cohort is too small to detect small to moderate effect sizes, given that fewer females are affected by SOR or other forms of SPD than males. No significant correlation of global WM microstructure with somatization or generalized depression is observed in children with neurodevelopmental concerns but not SOR specifically, whether boys or girls. Although statistically significant differences in global WM DTI and NODDI metrics were found between girls with versus without SOR, these findings need replication in larger studies given the relatively small female sample size of the present investigation.

Boys with SOR who have greater global WM microstructural integrity on DTI in the form of higher FA and lower RD are relatively protected against somatization and emotional disturbance, whereas those with reduced FA and elevated RD have greater susceptibility. NODDI analysis shows that these differences in WM microstructural intergity are primarily due to differences in free water content as measured by FISO. Free water has a much higher diffusivity rate than brain tissue and essentially zero diffusion anisotropy. Therefore, all else being equal, high FISO necessarily results in low FA and high RD, and is thus a marker of poor microstructural integrity. There are several possible etiologies for elevated FISO, including neuroinflammation with vasogenic edema as well as expansion of the CSF-filled perivascular spaces. These two processes can be interrelated in dysfunction of the glympatic system [59].

A diffuse axonal disconnection that affects global white matter and causes general intellectual disability is not present in our sample of children with neurodevelopmental concerns, including those with SOR. There are no statistically significant differences of global WM DTI and NODDI metrics between boys with SOR and boys in the non-SOR group. Although some such DTI and NODDI differences are seen in girls with SOR vs non-SOR, these are based on a small sample size and will need to be confirmed in a larger investigation. Notably, no group mean differences in somatization or EDI4 are observed between the SOR and non-SOR groups, especially not in boys. What differs between SOR and non-SOR is the dependence of somatization and emotional disturbance on white matter tract microstructural integrity in the former but not the latter cohort. This represents an objective brain-based correlate for SOR and behavior, when SOR status is determined from a modern structured direct clinical assessment method, the SP3D:A.

Regional white matter microstructure in children with SOR and its association with behavior

The results of the exploratory tract ROI analysis showed that, for boys with SOR, there are significant WM microstructural correlations with somatization in major commissural, projection, association, and brainstem/cerebellar pathways. The strongest of these associations are found for FA in cortical-subcortical projection pathways of the bilateral PLIC and bilateral ML, all of which survived correction for multiple tract-wise comparisons. Similarly, the bilateral PLIC and bilateral ML are also the tracts most correlated with generalized unhappiness/withdrawal in SOR males, remaining significant for FA after multiple comparison correction. All of these regional correlations of FA, RD, and FISO are directionally consistent with what is found for global WM in boys with SOR. No significant relationship of regional WM microstructure with somatization is found in boys with neurodevelopmental concerns but not SOR. The right ML does show a significant correlation of FA with emotional disturbance in males of the non-SOR group, although its strength is less than that of the SOR group and does not survive multiple comparison correction.

The medial lemnisci are well known as the primary somatosensory tracts of the brainstem, containing axonal fibers transmitting information about fine touch and two-point discrimination as well as conscious proprioception and vibration. This second-order somatosensory pathway extends from the medulla to the ventral posterolateral (VPL) nucleus of the thalamus, bridging the first-order pathway in the dorsal column of the spinal cord and the third-order pathway from the VPL to the primary somatosensory cortex. The third-order somatosensory pathway extends into the posterior limb of the internal capsule, a structure that also contains auditory pathway fibers extending via the lateral lemniscus from the inferior colliculus to the temporal lobe [60]. Given that the SOR cohort in this study consists almost entirely of individuals with auditory and/or tactile over-responsivity, it is not at all surprising that microstructural WM integrity of the ML and PLIC would be important for behavioral sequelae in this condition. Posterior WM tracts have previously been implicated in broadly defined SPD, with Chang et al. [25] demonstrating significant correlations of FA in the PLIC with caregiver assessments of auditory and tactile dysfunction using the sensory profile as well as with objective testing of auditory and tactile function using the Acoustic Index of the Differential Screening Test for Processing (DSTP) and using graphesthesia, respectively. However, to our knowledge, WM microstructure of the ML has not previously been investigated in children with SPD.

Besides the ML and PLIC, several commissural, association, projection, and cerebellar tracts exhibit significant correlations with somatization that require confirmation in future hypothesis-driven studies. One such tract, the splenium of the corpus callosum, has been well recognized to have low FA and high RD in children with SPD compared to matched typically developing children (TDC) [32], that are related to auditory and tactile behavior and function [25]. The major cerebellar outflow tract (SCP) and inflow tract (MCP) are known to have reduced FA and increased RD in SPD compared to TDC as well as association with auditory behavior, multisensory integration, and attentional function [33]. Beyond these posterior cerebral and hindbrain tracts, our study also implicates the prefrontal WM pathways of the genu of the corpus callosum and left anterior corona radiata as relevant to somatization in boys with SOR. These two tracts, responsible for prefrontal interhemispheric communication and for prefrontal to subcortical connectivity respectively, are associated with affective behavior such as depression [61], but have not been previously investigated in the context of SPD and of SOR in particular.

Comparison to prior neuroimaging studies of affective behavior

There is a dearth of prior research in children on white matter microstructural correlates of somatization, and to our knowledge, none is related to sensory processing dysfunction. However, a recent gray matter morphometry study of adults with somatic symptoms disorder reveals that cerebellar gray matter volumes are negatively correlated with somatization and that cortico-cortical and basal gangla to cerebellar structural covariance is also associated with somatization [62]. This is in general agreement with our findings of a widespread network of white matter pathways related to somatization in boys with SOR, including cortico-cortical association tracts, cortico-subcortical projection tracts, and cerebellar pathways. Alterations of corticothalamic functional connectivity to somatosensory, auditory, and visual cortex have also been found in somatization disorder in adults using resting state functional MRI (fMRI) [63], which thereby implicates the PLIC and other posterior sensory WM tracts.

In the related condition of internalizing problems, an early pilot DTI study of school-age children born preterm using TBSS found that the global WM FA is inversely correlated with internalizing behavior measured with the Child Behavior Checklist (CBCL) parent report form [64]. A regional analysis showed significant correlations with several WM tracts, most notably the forceps minor and major, which contain commissural fibers of the genu and splenium of the corpus callosum, respectively. Given the aformentioned high rate of SPD in children born preterm [2, 3], these WM microstructural changes might have been related to sensory processing dysfunction; however, no sensory behavioral testing was performed as part of the investigation. Our findings suggest a role for sensory over-responsivity in the relationship with FA and that this inverse association is driven by opposing changes in RD, with both the FA and RD alterations primarily the result of variation in the free water content of the affected white matter. A more recent DTI study of internalizing behavior using the BASC-2 rating scale in typically developing children indicates a correlation with MD of the bilateral cingulum; however, children with neurodevelopmental concerns were not included and there was no assessment of sensory behavior [65].

A recent DTI and NODDI voxelwise analysis of SOR in young adults with ASD compared to TDC controls discovered elevated NDI in the right superior temporal gyrus in ASD versus TDC as well as a positive correlation of NDI with adverse childhood experiences (ACE) in the ASD group but not the TDC controls [66]. Greater ACE was also related to SOR severity. This study is concordant with our findings in that it also indicates microstructural neuroplasticity associated with SOR. The determination of SOR status was from the adolescent/adult sensory profile, a self-report questionnaire, rather than the SP3D:A clinical assessment used in our work. Also, we excluded both ASD and TDC in our research, focusing on children with neurodevelopmental concerns but not ASD that represent the largest population referred for clinical evalution.

We also observed that, like somatization, reduced FA, elevated RD and/or elevated FISO in the bilateral PLIC and bilateral ML, as well as the left EC, are associated with the BASC-3 emotional disturbance index category 4 (generalized unhappiness and withdrawal) score in boys with SOR. Low FA and high RD of white matter have previously been found in adolescent and adult major depressive disorder [67, 68]. As with the global WM findings related to EDI4, our NODDI results suggest that, at least for those with SOR, these DTI alterations are driven by changes in free water content of these affected tracts. Recent DTI and NODDI research on school-age children with broadly defined SPD found that, in boys especially, those with comorbid ADHD have lower FA in the internal capsule and splenium of the corpus callosum than those without ADHD [69]. However, those attention- and impulsivity-related changes of WM FA are due to lower NDI and not somatization- and depression-related higher FISO like in our SOR group.

Limitations and future directions

Our results support the concept that compensatory neuroplasticity of white matter microstructure may influence affective behavior in children with SOR in a way that is not seen in other children with neurodevelopmental concerns. However, alternate interpretations of these cross-sectional data are possible, such as innate differences in white matter microstructure that are correlated with emotional responses in SOR that do not change appreciably during brain development. Hence, the observations reported herein require further investigation in a larger more diverse cohort with a broader array of cognitive and behavioral assessments, including multi-year follow-up of psychological, health, educational, social, and economic outcomes to investigate the long-term neurodevelopmental trajectory of SOR. Extending the age range studied to younger chidren would improve the ability to chart longitudinal changes during development [70, 71]; however, practical difficulties remain in performing advanced imaging of unsedated young chidren. Multimodal imaging incorporating fMRI can directly interrogate the activity and functional connectivity of gray matter to incorporate with microstructural and structural connectivity data from dMRI. The validation of neural correlates of SOR that are linked to affective behavior through these future studies would pave the way toward objective brain-based biomarker development that can better stratify risk for adverse mental health outcomes in children for patient selection in clinical trials of cognitive, behavioral, occupational, and pharmacological therapies and also for monitoring treatment efficacy as intermediate endpoints. This is a major and growing unmet public health need given the explosion of depression, loneliness/withdrawal, and suicidality among youth in recent years [72].