Impaired structural connectivity of socio-emotional circuits in autism spectrum disorders: a diffusion tensor imaging study

Background

Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.

Methods/Principal Findings

DTI scans were acquired for 19 children and adolescents with ASD (∼8–18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8–18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.

Conclusions/Significance

Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder.     

Spatio-Temporal Correlation Tensors Reveal Functional Structure in Human Brain

Resting state functional magnetic resonance imaging (fMRI) has been commonly used to measure functional connectivity between cortical regions, while diffusion tensor imaging (DTI) can be used to characterize structural connectivity of white matter tracts. In principle combining resting state fMRI and DTI data could allow characterization of structure-function relations of distributed neural networks. However, due to differences in the biophysical origins of their signals and in the tissues to which they apply, there has been no direct integration of these techniques to date. We demonstrate that MRI signal variations and power spectra in a resting state are largely comparable between gray matter and white matter, that there are temporal correlations of fMRI signals that persist over long distances within distinct white matter structures, and that neighboring intervoxel correlations of low frequency resting state signals showed distinct anisotropy in many regions. These observations suggest that MRI signal variations from within white matter in a resting state may convey similar information as their corresponding fluctuations of MRI signals in gray matter. We thus derive a local spatio-temporal correlation tensor which captures directional variations of resting-state correlations and which reveals distinct structures in both white and gray matter. This novel concept is illustrated with in vivo experiments in a resting state, which demonstrate the potential of the technique for mapping the functional structure of neural networks and for direct integration of structure-function relations in the human brain.     

CSF T-Tau/Aβ42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease

Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.     

New Insights into the Developing Rabbit Brain Using Diffusion Tensor Tractography and Generalized q-Sampling MRI

The use of modern neuroimaging methods to characterize the complex anatomy of brain development at different stages reveals an enormous wealth of information in understanding this highly ordered process and provides clues to detect neurological and neurobehavioral disorders that have their origin in early structural and functional cerebral maturation. Non-invasive diffusion tensor magnetic resonance imaging (DTI) is able to distinguish cerebral microscopic structures, especially in the white matter regions. However, DTI is unable to resolve the complicated neural structure, i.e., the fiber crossing that is frequently observed during the maturation process. To overcome this limitation, several methods have been proposed. One such method, generalized q-sampling imaging (GQI), can be applied to a variety of datasets, including the single shell, multi-shell or grid sampling schemes that are believed to be able to resolve the complicated crossing fibers. Rabbits have been widely used for neurodevelopment research because they exhibit human-like timing of perinatal brain white matter maturation. Here, we present a longitudinal study using both DTI and GQI to demonstrate the changes in cerebral maturation of in vivo developing rabbit brains over a period of 40 weeks. Fractional anisotropy (FA) of DTI and generalized fractional anisotropy (GFA) of GQI indices demonstrated that the white matter anisotropy increased with age, with GFA exhibiting an increase in the hippocampus as well. Normalized quantitative anisotropy (NQA) of GQI also revealed an increase in the hippocampus, allowing us to observe the changes in gray matter as well. Regional and whole brain DTI tractography also demonstrated refinement in fiber pathway architecture with maturation. We concluded that DTI and GQI results were able to characterize the white matter anisotropy changes, whereas GQI provided further information about the gray matter hippocampus area. This developing rabbit brain DTI and GQI database could also be used for educational purposes and neuroscience investigations.     

Advanced diffusion MRI fiber tracking in neurosurgical and neurodegenerative disorders and neuroanatomical studies: A review

Diffusion MRI enabled in vivo microstructural imaging of the fiber tracts in the brain resulting in its application in a wide range of settings, including in neurological and neurosurgical disorders. Conventional approaches such as diffusion tensor imaging (DTI) have been shown to have limited applications due to the crossing fiber problem and the susceptibility of their quantitative indices to partial volume effects. To overcome these limitations, the recent focus has shifted to the advanced acquisition methods and their related analytical approaches. Advanced white matter imaging techniques provide superior qualitative data in terms of demonstration of multiple crossing fibers in their spatial orientation in a three dimensional manner in the brain. In this review paper, we discuss the advancements in diffusion MRI and introduce their roles. Using examples, we demonstrate the role of advanced diffusion MRI-based fiber tracking in neuroanatomical studies. Results from its preliminary application in the evaluation of intracranial space occupying lesions, including with respect to future directions for prognostication, are also presented. Building upon the previous DTI studies assessing white matter disease in Huntington's disease and Amyotrophic lateral sclerosis; we also discuss approaches which have led to encouraging preliminary results towards developing an imaging biomarker for these conditions.     

Microembolism Induces Anhedonia but No Detectable Changes in White Matter Integrity in Aged Rats

Microvascular disease leads to alterations of cerebral vasculature including the formation of microembolic (ME) strokes. Though ME are associated with changes in mood and the severity and progression of cognitive decline, the effect of ME strokes on cerebral microstructure and its relationship to behavioral endpoints is unknown. Here, we used adult and aged male rats to test the hypotheses that ME lesions result in subtle changes to white and gray matter integrity as detected by high-throughput diffusion tensor imaging (DTI) and that these structural disruptions correspond to behavioral deficits. Two weeks post-surgery, aged animals showed depressive-like behaviors in the sucrose consumption test in the absence of altered cerebral diffusivity as assessed by ex-vivo DTI. Furthermore, DTI indices did not correlate with the degree of behavioral disruption in aged animals or in a subset of animals with observed tissue cavitation and subtle DTI alterations. Together, data suggest that behavioral deficits are not the result of damage to brain regions or white matter tracts, rather the activity of other systems may underlie functional disruption and recovery.     

Microstructure of temporo-parietal white matter as a basis for reading ability: evidence from diffusion tensor magnetic resonance imaging

Diffusion tensor magnetic resonance imaging (MRI) was used to study the microstructural integrity of white matter in adults with poor or normal reading ability. Subjects with reading difficulty exhibited decreased diffusion anisotropy bilaterally in temporoparietal white matter. Axons in these regions were predominantly anterior-posterior in direction. No differences in T1-weighted MRI signal were found between poor readers and control subjects, demonstrating specificity of the group difference to the microstructural characteristics measured by diffusion tensor imaging (DTI). White matter diffusion anisotropy in the temporo-parietal region of the left hemisphere was significantly correlated with reading scores within the reading-impaired adults and within the control group. The anisotropy reflects microstructure of white matter tracts, which may contribute to reading ability by determining the strength of communication between cortical areas involved in visual, auditory, and language processing.     

Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit

Autism spectrum disorder (ASD) is a frequent neurodevelopmental disorder characterized by variable clinical severity. Core symptoms are qualitatively impaired communication and social behavior, highly restricted interests and repetitive behaviors. Although recent work on genetic mutations in ASD has shed light on the pathophysiology of the disease, classifying it essentially as a synaptopathy, no treatments are available to date. To develop and test novel ASD treatment approaches, validated and informative animal models are required. Of particular interest, in this context are loss-of-function mutations in the postsynaptic cell adhesion protein neuroligin-4 and point mutations in its homologue neuroligin-3 (NL-3) that were found to cause certain forms of monogenic heritable ASD in humans. Here, we show that NL-3-deficient mice display a behavioral phenotype reminiscent of the lead symptoms of ASD: reduced ultrasound vocalization and a lack of social novelty preference. The latter may be related to an olfactory deficiency observed in the NL-3 mutants. Interestingly, such olfactory phenotype is also present in a subgroup of human ASD patients. Tests for learning and memory showed no gross abnormalities in NL-3 mutants. Also, no alterations were found in time spent in social interaction, prepulse inhibition, seizure propensity and sucrose preference. As often seen in adult ASD patients, total brain volume of NL-3 mutant mice was slightly reduced as assessed by magnetic resonance imaging (MRI). Our findings show that the NL-3 knockout mouse represents a useful animal model for understanding pathophysiological events in monogenic heritable ASD and for developing novel treatment strategies in this devastating human disorder.     

MRI Markers for Mild Cognitive Impairment: Comparisons between White Matter Integrity and Gray Matter Volume Measurements

The aim of the study was to evaluate the value of assessing white matter integrity using diffusion tensor imaging (DTI) for classification of mild cognitive impairment (MCI) and prediction of cognitive impairments in comparison to brain atrophy measurements using structural MRI. Fifty-one patients with MCI and 66 cognitive normal controls (CN) underwent DTI and T1-weighted structural MRI. DTI measures included fractional anisotropy (FA) and radial diffusivity (DR) from 20 predetermined regions-of-interest (ROIs) in the commissural, limbic and association tracts, which are thought to be involved in Alzheimer''s disease; measures of regional gray matter (GM) volume included 21 ROIs in medial temporal lobe, parietal cortex, and subcortical regions. Significant group differences between MCI and CN were detected by each MRI modality: In particular, reduced FA was found in splenium, left isthmus cingulum and fornix; increased DR was found in splenium, left isthmus cingulum and bilateral uncinate fasciculi; reduced GM volume was found in bilateral hippocampi, left entorhinal cortex, right amygdala and bilateral thalamus; and thinner cortex was found in the left entorhinal cortex. Group classifications based on FA or DR was significant and better than classifications based on GM volume. Using either DR or FA together with GM volume improved classification accuracy. Furthermore, all three measures, FA, DR and GM volume were similarly accurate in predicting cognitive performance in MCI patients. Taken together, the results imply that DTI measures are as accurate as measures of GM volume in detecting brain alterations that are associated with cognitive impairment. Furthermore, a combination of DTI and structural MRI measurements improves classification accuracy.     

Population Differences in Brain Morphology and Microstructure among Chinese,Malay, and Indian Neonates

We studied a sample of 75 Chinese, 73 Malay, and 29 Indian healthy neonates taking part in a cohort study to examine potential differences in neonatal brain morphology and white matter microstructure as a function of ethnicity using both structural T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). We first examined the differences in global size and morphology of the brain among the three groups. We then constructed the T2-weighted MRI and DTI atlases and employed voxel-based analysis to investigate ethnic differences in morphological shape of the brain from the T2-weighted MRI, and white matter microstructure measured by fractional anisotropy derived from DTI. Compared with Malay neonates, the brains of Indian neonates’ tended to be more elongated in anterior and posterior axis relative to the superior-inferior axis of the brain even though the total brain volume was similar among the three groups. Although most anatomical regions of the brain were similar among Chinese, Malay, and Indian neonates, there were anatomical variations in the spinal-cerebellar and cortical-striatal-thalamic neural circuits among the three populations. The population-related brain regions highlighted in our study are key anatomical substrates associated with sensorimotor functions.     

Convergent Findings of Altered Functional and Structural Brain Connectivity in Individuals with High Functioning Autism: A Multimodal MRI Study

Brain tissue changes in autism spectrum disorders seem to be rather subtle and widespread than anatomically distinct. Therefore a multimodal, whole brain imaging technique appears to be an appropriate approach to investigate whether alterations in white and gray matter integrity relate to consistent changes in functional resting state connectivity in individuals with high functioning autism (HFA). We applied diffusion tensor imaging (DTI), voxel-based morphometry (VBM) and resting state functional connectivity magnetic resonance imaging (fcMRI) to assess differences in brain structure and function between 12 individuals with HFA (mean age 35.5, SD 11.4, 9 male) and 12 healthy controls (mean age 33.3, SD 9.0, 8 male). Psychological measures of empathy and emotionality were obtained and correlated with the most significant DTI, VBM and fcMRI findings. We found three regions of convergent structural and functional differences between HFA participants and controls. The right temporo-parietal junction area and the left frontal lobe showed decreased fractional anisotropy (FA) values along with decreased functional connectivity and a trend towards decreased gray matter volume. The bilateral superior temporal gyrus displayed significantly decreased functional connectivity that was accompanied by the strongest trend of gray matter volume decrease in the temporal lobe of HFA individuals. FA decrease in the right temporo-parietal region was correlated with psychological measurements of decreased emotionality. In conclusion, our results indicate common sites of structural and functional alterations in higher order association cortex areas and may therefore provide multimodal imaging support to the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration.     

Cognitive Processing Speed in Older Adults: Relationship with White Matter Integrity

Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55–87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed.     

MRI Characterization of Paranodal Junction Failure and Related Spinal Cord Changes in Mice

The paranodal junction is a specialized axon-glia contact zone that is important for normal neuronal activity and behavioral locomotor function in the central nervous system (CNS). Histological examination has been the only method for detecting pathological paranodal junction conditions. Recently, diffusion tensor MRI (DTI) has been used to detect microstructural changes in various CNS diseases. This study was conducted to determine whether MRI and DTI could detect structural changes in the paranodal junctions of the spinal cord in cerebroside sulfotransferase knock-out (CST-KO) mice. Here, we showed that high-resolution MRI and DTI characteristics can reflect paranodal junction failure in CST-KO mice. We found significantly lower T1 times and significantly higher T2 times in the spinal cord MRIs of CST-KO mice as compared to wild-type (WT) mice. Spinal cord DTI showed significantly lower axial diffusivity and significantly higher radial diffusivity in CST-KO mice as compared to WT mice. In contrast, the histological differences in the paranodal junctions of WT and CST-KO mice were so subtle that electron microscopy or immunohistological analyses were necessary to detect them. We also measured gait disturbance in the CST-KO mice, and determined the conduction latency by electrophysiology. These findings demonstrate the potential of using MRI and DTI to evaluate white matter disorders that involve paranodal junction failure.     

Regional Variation in Brain White Matter Diffusion Index Changes following Chemoradiotherapy: A Prospective Study Using Tract-Based Spatial Statistics

Purpose

There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in white matter changes following chemoradiotherapy.

Methods

Fourteen patients receiving two or three weeks of whole-brain radiation therapy (RT) ± chemotherapy underwent DTI pre-RT, at end-RT, and one month post-RT. Three diffusion indices were measured: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). We determined significant individual voxel changes of diffusion indices using tract-based spatial statistics, and mean changes of the indices within fourteen white matter structures of interest.

Results

Voxels of significant FA decreases and RD increases were seen in all structures (p<0.05), with the largest changes (20–50%) in the fornix, cingula, and corpus callosum. There were highly significant between-structure differences in pre-RT to end-RT mean FA changes (p<0.001). The inferior cingula had a mean FA decrease from pre-RT to end-RT significantly greater than 11 of the 13 other structures (p<0.00385).

Conclusions

Brain white matter structures varied greatly in their response to chemoradiotherapy as measured by DTI changes. Changes in FA and RD related to white matter demyelination were prominent in the cingula and fornix, structures relevant to radiation-induced neurocognitive impairment. Future research should evaluate DTI as a predictive biomarker of brain chemoradiotherapy adverse effects.     

Voxel-Based Diffusion Tensor Imaging of an APP/PS1 Mouse Model of Alzheimer’s Disease

Increasing evidence has demonstrated that white matter (WM) disruptions, due to the injury of the axon and myelin, play an important role in the pathogenesis of Alzheimer’s disease (AD). Diffusion tensor imaging (DTI) is a sensitive modality to evaluate the WM integrity in both AD patients and animal models. In this study, an advanced DTI modality, employing a 7.0-T magnetic resonance imaging system, was used to analyze WM changes across the whole brain of an amyloid precursor protein/presenilin 1 (APP/PS1) mouse model. A voxel-based analysis was used to compare the quantitative DTI parameters automatically in both APP/PS1 mice (n?=?9) and wild-type (WT) controls (n?=?9). After DTI examination, the ultrastructure analysis was compared with DTI findings. Compared with WT controls, gray matter (GM) areas in APP/PS1 mice such as the cingulate cortex and the striatum showed significant fractional anisotropy (FA) and axial diffusivity (DA) increase, while the thalamus only showed a significant FA increase (p?<?0.01). Similarly, a significant mean diffusivity, DA, and radial diffusivity increase was observed in the bilateral neocortex (p?<?0.01). The left hippocampus only showed significant FA increase in APP/PS1 mice (p?<?0.01). The changes in WM regions were detected in the forceps minor of the corpus callosum, the anterior part of the anterior commissure, and the internal capsule, with a significant FA or DA increase (p?<?0.01). Abnormalities derived from diffusion measurements were in-line with the ultrastructure findings, including extensive pathological damage of the neurons, neutrophils, and vessels. In conclusion, voxel-based diffusion tensor imaging can detect diffusion alterations not only in GM but also in WM areas in AD models, reflecting the extensive pathological changes of AD.     

Dorsal Visual Pathway Changes in Patients with Comitant Extropia

Background

Strabismus is a disorder in which the eyes are misaligned. Persistent strabismus can lead to stereopsis impairment. The effect of strabismus on human brain is not unclear. The present study is to investigate whether the brain white structures of comitant exotropia patients are impaired using combined T1-weighted imaging and diffusion tensor imaging (DTI).

Principal Findings

Thirteen patients with comitant strabismus and twelve controls underwent magnetic resonance imaging (MRI) with acquisition of T1-weighted and diffusion tensor images. T1-weighted images were used to analyze the change in volume of white matter using optimized voxel-based morphology (VBM) and diffusion tensor images were used to detect the change in white matter fibers using voxel-based analysis of DTI in comitant extropia patients. VBM analysis showed that in adult strabismus, white matter volumes were smaller in the right middle occipital gyrus, right occipital lobe/cuneus, right supramarginal gyrus, right cingulate gyrus, right frontal lobe/sub-gyral, right inferior temporal gyrus, left parahippocampa gyrus, left cingulate gyrus, left occipital lobe/cuneus, left middle frontal gyrus, left inferior parietal lobule, and left postcentral gyrus, while no brain region with greater white matter volume was found. Voxel-based analysis of DTI showed lower fractional anisotropy (FA) values in the right middle occipital gyrus and right supramarginal gyrus in strabismus patients, while brain region with increased FA value was found in the right inferior frontal gyrus.

Conclusion

By combining VBM and voxel-based analysis of DTI results, the study suggests that the dorsal visual pathway was abnormal or impaired in patients with comitant exotropia.     

Increased Global and Local Efficiency of Human Brain Anatomical Networks Detected with FLAIR-DTI Compared to Non-FLAIR-DTI

Diffusion-weighted MRI (DW-MRI), the only non-invasive technique for probing human brain white matter structures in vivo, has been widely used in both fundamental studies and clinical applications. Many studies have utilized diffusion tensor imaging (DTI) and tractography approaches to explore the topological properties of human brain anatomical networks by using the single tensor model, the basic model to quantify DTI indices and tractography. However, the conventional DTI technique does not take into account contamination by the cerebrospinal fluid (CSF), which has been known to affect the estimated DTI measures and tractography in the single tensor model. Previous studies have shown that the Fluid-Attenuated Inversion Recovery (FLAIR) technique can suppress the contribution of the CSF to the DW-MRI signal. We acquired DTI datasets from twenty-two subjects using both FLAIR-DTI and conventional DTI (non-FLAIR-DTI) techniques, constructed brain anatomical networks using deterministic tractography, and compared the topological properties of the anatomical networks derived from the two types of DTI techniques. Although the brain anatomical networks derived from both types of DTI datasets showed small-world properties, we found that the brain anatomical networks derived from the FLAIR-DTI showed significantly increased global and local network efficiency compared with those derived from the conventional DTI. The increases in the network regional topological properties derived from the FLAIR-DTI technique were observed in CSF-filled regions, including the postcentral gyrus, periventricular regions, inferior frontal and temporal gyri, and regions in the visual cortex. Because brain anatomical networks derived from conventional DTI datasets with tractography have been widely used in many studies, our findings may have important implications for studying human brain anatomical networks derived from DW-MRI data and tractography.     

White Matter Changes Associated with Resting Sympathetic Tone in Frontotemporal Dementia vs. Alzheimer’s Disease

Background

Resting sympathetic tone, a measure of physiological arousal, is decreased in patients with apathy and inertia, such as those with behavioral variant frontotemporal dementia (bvFTD) and other frontally-predominant disorders.

Objective

To identify the neuroanatomical correlates of skin conductance levels (SCLs), an index of resting sympathetic tone and apathy, among patients with bvFTD, where SCLs is decreased, compared to those with Alzheimer’s disease (AD), where it is not.

Methods

This study analyzed bvFTD (n = 14) patients and a comparison group with early-onset AD (n = 19). We compared their resting SCLs with gray matter and white matter regions of interest and white matter measures of fiber integrity on magnetic resonance imaging and diffusion tensor imaging.

Results

As expected, bvFTD patients, compared to AD patients, had lower SCLs, which correlated with an apathy measure, and more gray matter loss and abnormalities of fiber integrity (fractional anisotropy and mean diffusivity) in frontal-anterior temporal regions. After controlling for group membership, the SCLs were significantly correlated with white matter volumes in the cingulum and inferior parietal region in the right hemisphere.

Conclusion

Among dementia patients, SCLs, and resting sympathetic tone, may correlate with quantity of white matter, rather than with gray matter or with white matter fiber integrity. Loss of white matter volumes, especially involving a right frontoparietal network, may reflect chronic loss of cortical axons that mediate frontal control of resting sympathetic tone, changes that could contribute to the apathy and inertia of bvFTD and related disorders.     

Microstructural White Matter Changes Underlying Cognitive and Behavioural Impairment in ALS – An In Vivo Study Using DTI

Background

A relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients.

Methods

We assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures.

Results

Patients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts.

Conclusion

In non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients.     

Autism and Sensory Processing Disorders: Shared White Matter Disruption in Sensory Pathways but Divergent Connectivity in Social-Emotional Pathways

Over 90% of children with Autism Spectrum Disorders (ASD) demonstrate atypical sensory behaviors. In fact, hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment is now included in the DSM-5 diagnostic criteria. However, there are children with sensory processing differences who do not meet an ASD diagnosis but do show atypical sensory behaviors to the same or greater degree as ASD children. We previously demonstrated that children with Sensory Processing Disorders (SPD) have impaired white matter microstructure, and that this white matter microstructural pathology correlates with atypical sensory behavior. In this study, we use diffusion tensor imaging (DTI) fiber tractography to evaluate the structural connectivity of specific white matter tracts in boys with ASD (n = 15) and boys with SPD (n = 16), relative to typically developing children (n = 23). We define white matter tracts using probabilistic streamline tractography and assess the strength of tract connectivity using mean fractional anisotropy. Both the SPD and ASD cohorts demonstrate decreased connectivity relative to controls in parieto-occipital tracts involved in sensory perception and multisensory integration. However, the ASD group alone shows impaired connectivity, relative to controls, in temporal tracts thought to subserve social-emotional processing. In addition to these group difference analyses, we take a dimensional approach to assessing the relationship between white matter connectivity and participant function. These correlational analyses reveal significant associations of white matter connectivity with auditory processing, working memory, social skills, and inattention across our three study groups. These findings help elucidate the roles of specific neural circuits in neurodevelopmental disorders, and begin to explore the dimensional relationship between critical cognitive functions and structural connectivity across affected and unaffected children.