Integrity Of White Matter Tracts Research Articles

Aging, cognition, and the brain: effects of age-related variation in white matter integrity on neuropsychological function

ABSTRACTAlterations in brain structure are viewed as neurobiological indicators which are closely tied to cognitive changes in healthy human aging. The current study used diffusion tensor imaging (DTI) tractography to investigate the relationship between age, brain variation in white matter (WM) integrity, and cognitive function. Sixteen younger adults (aged 20–28 years) and 18 healthy older adults (aged 60–75 years) underwent DTI scanning and a standardized battery of neuropsychological measures. Behaviorally, older adults exhibited poorer performance on multiple cognitive measures compared to younger adults. At the neural level, the effects of aging on theWM integrity were evident within interhemispheric (the anterior portion of corpus callosum) and transverse (the right uncinate fasciculus) fibers of the frontal regions, and the cingulum-angular fibers. Our correlation results showed that age-related WM differentially influenced cognitive function, with increased fractional anisotropy values in both the anterior corpus callosum and the right cingulum/angular fibers positively correlated with performance on the visuospatial task in older adults. Moreover, mediation analysis further revealed that the WM tract integrity of the frontal interhemspheric fibers was a significant mediator of age–visuospatial performance relation in older adults, but not in younger adults. These findings support the vulnerability of the frontal WM fibers to normal aging and push forward our understanding of cognitive aging by providing a more integrative view of the neural basis of linkages among aging, cognition, and brain.

Gait Asymmetry in People With Parkinson's Disease Is Linked to Reduced Integrity of Callosal Sensorimotor Regions.

Individuals with Parkinson's disease (PD) often manifest significant temporal and spatial asymmetries of the lower extremities during gait, which significantly contribute to mobility impairments. While the neural mechanisms underlying mobility asymmetries within this population remain poorly understood, recent evidence points to altered microstructural integrity of white matter fiber tracts within the corpus callosum as potentially playing a substantial role. The purpose of this study was to quantify spatial and temporal gait asymmetries as well as transcallosal microstructural integrity of white matter fiber tracts connecting the primary and secondary sensorimotor cortices in people with PD and age-matched control participants. Spatial and temporal gait asymmetry in the levodopa off state was assessed using an instrumented walkway. On the next day, diffusion-weighted images were collected to assess white matter microstructural integrity in transcallosal fibers connecting the homologous sensorimotor cortical regions. People with PD exhibited significantly more temporal and spatial gait asymmetry than healthy control subjects. Furthermore, people with PD had significantly reduced white matter microstructural integrity of transcallosal fibers connecting homologous regions of the pre-supplementary motor and supplementary motor areas (SMAs), but not the primary motor or somatosensory cortices. Finally, reduced transcallosal fiber tract integrity of the pre-SMA and S1 was associated with greater step length asymmetry in people with PD. People with PD showed increased step length asymmetries and decreased microstructural integrity of callosal white matter tracts connecting the higher-order sensorimotor cortices (pre-SMA and SMA). The strong association between gait asymmetries and corpus collosum integrity, supports the hypothesis that reduced transcallosal structural connectivity is a significant mechanism underlying gait asymmetries in people with PD.

T182. SHARED AND DISTINCT ALTERATIONS IN THE WHITE MATTER TRACTS OF REMITTED AND NON-REMITTED PATIENTS WITH SCHIZOPHRENIA

BackgroundAntipsychotic drugs are the standard treatment for schizophrenia; however, the treatment outcomes vary. Different treatment outcomes may be attributed to the genetic and molecular heterogeneity of patients, which may be represented in the white matter structures of the brain. In the present study, we assessed the association between white matter tract integrity and treatment outcomes in patients with schizophrenia.MethodsWe evaluated 96 patients with schizophrenia (remitted, 53; non-remitted, 43) and 50 healthy controls through diffusion spectrum imaging with a 3 Tesla magnetic resonance imaging scanner. Patients were categorized into the remission and non-remission groups according to the criteria proposed by The Remission in Schizophrenia Working Group (RSWG) on the basis of PANSS scores. White matter tract integrity was assessed through an automatic tract-specific analysis method to determine the mean generalized fractional anisotropy (GFA) values of the 76 white matter tract bundles in each participant.ResultsAnalysis of covariance revealed that 7 tracts, namely the bilateral fornices, the bilateral uncinate fasciculi, and the callosal fibers (CFs) of the bilateral temporal poles, bilateral hippocampi, and bilateral amygdalae, had significantly different GFA values among the 3 groups. Posthoc between-groups analysis showed that the non-remission group had lower GFA values in all 7 tracts than the control group; the remission group had lower GFA values than the control group only in 4 tracts, namely the bilateral fornices and the CFs of the bilateral temporal poles, and bilateral hippocampi. Compared with the remission group, the non-remission group had lower GFA values in all 7 tracts.DiscussionAll 7 tracts that were altered in the non-remission group are a part of the limbic system, which supports various functions, including emotions, memory, and learning. Our results suggest that patients who had poor outcomes to antipsychotic treatments might have more severe disruptions in the limbic system. The 7 altered tracts in the non-remission group are compatible with those reported in previous studies on white matter or gray matter alterations. In a cross-sectional tractography-based study on 3 pairs of association fibers (i.e., the cingulum, superior longitudinal fasciculus, and uncinate fasciculus), Luck et al reported that compared with patients with good outcomes, patients with poor outcomes had reduced FA in the uncinate fasciculus and superior longitudinal fasciculus. Marques et al performed a longitudinal study using tract-based spatial statistics and reported that non-responders had more tracts with a significantly lower FA than did the responders, particularly in the uncinate fasciculus and corpus callosum. In addition to the uncinate fasciculus, we also observed reduced fiber integrity in the bilateral fornices and the CFs of the bilateral temporal poles, bilateral hippocampi, and bilateral amygdalae; these tracts connect the gray matter in the limbic system. Jääskeläinen et al revealed that a reduction in gray matter volume in the frontal and limbic areas is associated with overall poor outcomes. In addition, Van Haren et al reported significantly reduced gray matter volumes in the frontal and temporal cortices of the individuals with poor outcomes. Because the gray matter regions are anatomically connected by the fiber tracts, gray matter reduction in the limbic system might affect the interconnecting fiber tracts; this finding accords with the findings of the present study.In conclusion, differences in the severity of white matter tract alterations in the remission and non-remission groups might indicate biologically distinct subgroups in schizophrenia.

S171. ALTERED WHITE MATTER CONNECTIVITY IN PATIENTS WITH SCHIZOPHRENIA USING PUBLIC NEUROIMAGING DATA FROM SCHIZCONNECT

BackgroundSeveral studies have produced a large body of evidence for white matter abnormalities related to schizophrenia. The literature has yet to achieve a state of consistency and reproducibility, and reported low integrity of white matter tracts vary between studies. Whole brain image study with large sample size is needed to address this issue. We investigated white matter integrity in connections between regions of interests (ROI) in the same hemisphere in patients with schizophrenia and healthy controls with public neuroimaging data from SchizConnect (http://schizconnect.org).MethodsA final data set was consisted of 129 healthy controls and 122 schizophrenia patients. For each diffusion weighted image (DWI), a two-tensor full-brain tractography was performed, and DWI images were parcellated by processing and registering the T1 images with FreeSurfer and the Advanced Normalization Tools. We extracted a total of 36 tracts in the both hemisphere connecting ROIs in the same hemisphere with white matter query language. We compared means of diffusion measures between patients and controls, and evaluated correlations with Letter-number sequencing (LNS) test, Vocabulary test, letter fluency test, category fluency test, and trails A of the Trail Making Test (TMT). The Benjamini-Hochberg procedure with false discovery rate (FDR) of 0.05 was used to correct for multiple comparisons.ResultsWe found a significant RD and TR increase of the left thalamo-occipital tracts and the right uncinate fascicle (UF), and a significant RD increase of the right middle longitudinal fascicle (MDLF), and the right superior longitudinal fascicle (SLF) ii in schizophrenia. There were correlations between the TR in the left thalamo-occipital tracts and letter fluency test, and the RD in the right SLF ii and LNS test, which did not survive after correction for multiple comparisons.DiscussionThese results indicate widespread abnormalities of white matter fiber tracts in schizophrenia, contributing to the pathophysiology of schizophrenia.

S159. REDUCED PROCESSING SPEED IN SCHIZOPHRENIA IS MEDIATED BY WHITE MATTER INTEGRITY

BackgroundMeta-analysis suggest that processing speed deficit is the largest single cognitive impairment in schizophrenia. Processing speed predicts functional outcome and indicates a vulnerability marker for schizophrenia. Several authors have proposed that abnormalities in white matter is related to reduced processing speed in schizophrenia. The purpose of this research was to investigate the relationship between processing speed and structural properties of white matter pathways in schizophrenia and healthy controls.MethodsThe data using this study were from the SchizConnect. Participants included 64 patients with schizophrenia and 71 healthy controls. Diffusion tensor imaging(DTI) method was used to measure fractional anisotropy along white matter tracts. Group differences in white matter integrity-inferred from fractional anisotropy (FA), processing speed, verbal memory were examined. Mediation analysis were applied to inspect the relationship between FA and cognitive performance.ResultsParticipants with schizophrenia had significantly reduced processing speed, verbal memory deficits, and whole-brain fractional anisotropy deficit. There were significant group differences in white matter integrity of the left thalamus occipital, right extreme capsule, and right thalamus occipital. FA in left thalamus occipital and right extreme capsule mediated group differences in processing speed, but not other cognitive domains.DiscussionStudy findings indicate that mediation effect of processing speed is regional tract-specific. These finding suggest that the structural integrity of white matter tracts associated with left thalamus occipital, right extreme capsule is closely related to reduced processing speed in schizophrenia, but not verbal memory and verbal learning.

Brain Connectivity and Cognitive Flexibility in Nonirradiated Adult Survivors of Childhood Leukemia.

This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy. Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1-weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearman's rank and Pearson's correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided. Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P = .04) and lower orientation dispersion index (ODI; P = .008) at the left centrum semiovale, which could-given that several fiber bundles cross this region-suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r = -0.53, P = .003) and higher ODI (r = 0.40, P = .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose. Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility.

Impaired White Matter Integrity and Social Cognition in High-Function Autism: Diffusion Tensor Imaging Study.

ObjectiveIt is known that many of the cognitive and social deficits associated with autism can arise from abnormal functional connectivity between brain networks. This aberrant functional connectivity in autism spectrum disorders (ASD) can be explained by impaired integrity of white matter tracts that link distant regions of the networks. MethodsWe investigated white matter in 9 children with high-function autism (HFA) compared to 13 typically developing controls using diffusion tensor imaging (DTI). The aim of this research is to provide supporting evidence for abnormalities in neural connectivity as an underlying pathophysiology of the main characteristics of ASD. ResultsWe found impairment of neural connectivity, mainly in association fiber tracts as evidenced by decreased fractional anisotropy (FA), the index of white matter integrity, of these tracts. Among them, inferior fronto-occipital fasciculus (IFOF) had a significant relationship with ADI-R score. The inferior longitudinal fasciculus (ILF) and superior longitudinal fasciculus (SLF) also showed decreased FA. Decreased FA of ILF and SLF had negative correlations with scores of social interaction. ConclusionThese findings suggest that widespread abnormalities in association fiber tracts may contribute to both core and associated symptoms of ASD.

The structural and functional brain networks that support human social networks

Social skills rely on a specific set of cognitive processes, raising the possibility that individual differences in social networks are related to differences in specific brain structural and functional networks. Here, we tested this hypothesis with multimodality neuroimaging. With diffusion MRI (DMRI), we showed that differences in structural integrity of particular white matter (WM) tracts, including cingulum bundle, extreme capsule and arcuate fasciculus were associated with an individual’s social network size (SNS). A voxel-based morphology analysis demonstrated correlations between gray matter (GM) volume and SNS in limbic and temporal lobe regions. These structural changes co-occured with functional network differences. As a function of SNS, dorsomedial and dorsolateral prefrontal cortex showed altered resting-state functional connectivity with the default mode network (DMN). Finally, we integrated these three complementary methods, interrogating the relationship between social GM clusters and specific WM and resting-state networks (RSNs). Probabilistic tractography seeded in these GM nodes utilized the SNS-related WM pathways. Further, the spatial and functional overlap between the social GM clusters and the DMN was significantly closer than other control RSNs. These integrative analyses provide convergent evidence of the role of specific circuits in SNS, likely supporting the adaptive behavior necessary for success in extensive social environments.

Working Memory And Brain Tissue Microstructure: White Matter Tract Integrity Based On Multi-Shell Diffusion MRI

Working memory is a complex cognitive process at the intersection of sensory processing, learning, and short-term memory and also has a general executive attention component. Impaired working memory is associated with a range of neurological and psychiatric disorders, but very little is known about how working memory relates to underlying white matter (WM) microstructure. In this study, we investigate the association between WM microstructure and performance on working memory tasks in healthy adults (right-handed, native English speakers). We combine compartment specific WM tract integrity (WMTI) metrics derived from multi-shell diffusion MRI as well as diffusion tensor/kurtosis imaging (DTI/DKI) metrics with Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) subtests tapping auditory working memory. WMTI is a novel tool that helps us describe the microstructural characteristics in both the intra- and extra-axonal environments of WM such as axonal water fraction (AWF), intra-axonal diffusivity, extra-axonal axial and radial diffusivities, allowing a more biophysical interpretation of WM changes. We demonstrate significant positive correlations between AWF and letter-number sequencing (LNS), suggesting that higher AWF with better performance on complex, more demanding auditory working memory tasks goes along with greater axonal volume and greater myelination in specific regions, causing efficient and faster information process.

Frontal and temporal cortical volume, white matter tract integrity, and hemispheric asymmetry in schizotypal personality disorder

Abnormalities in temporal and frontal cortical volume, white matter tract integrity, and hemispheric asymmetry have been implicated in schizophrenia-spectrum disorders. Schizotypal personality disorder can provide insight into vulnerability and protective factors in these disorders without the confounds associated with chronic psychosis. However, multimodal imaging and asymmetry studies in SPD are sparse. Thirty-seven individuals with SPD and 29 healthy controls (HC) received clinical interviews and 3T magnetic resonance T1-weighted and diffusion tensor imaging scans. Mixed ANOVAs were performed on gray matter volumes of the lateral temporal regions involved in auditory and language processing and dorsolateral prefrontal cortex involved in executive functioning, as well as fractional anisotropy (FA) of prominent white matter tracts that connect frontal and temporal lobes. In the temporal lobe regions, there were no group differences in volume, but SPD had reduced right>left middle temporal gyrus volume asymmetry compared to HC and lacked the right>left asymmetry in the inferior temporal gyrus volume seen in HC. In the frontal regions, there were no differences between groups on volume or asymmetry. In the white matter tracts, SPD had reduced FA in the left sagittal stratum and superior longitudinal fasciculus, and increased right>left asymmetry in sagittal stratum FA compared to HC. In the SPD group, lower left superior longitudinal fasciculus FA was associated with greater severity of disorganization symptoms. Findings suggest that abnormities in structure and asymmetry of temporal regions and frontotemporal white matter tract integrity are implicated in SPD pathology.

Diffusion-weighted MRI measures suggest increased white-matter integrity in Internet gaming disorder: Evidence from the comparison with recreational Internet game users

Several studies have suggested that Internet gaming disorder (IGD) is related to altered brain white matter integrity. However, seeming inconsistencies exist and may reflect comparison groups not matched well for certain gaming characteristics. In order to address this possible concern, we recruited in the present study individuals with recreational Internet game use (RGU) comprised of individuals who spend similar amounts of time as IGD subjects playing online games without developing IGD. Diffusion tensor imaging data were collected from 42 IGD and 44 RGU subjects. Whole-brain comparisons showed that IGD subjects demonstrated increased fractional anisotropy (FA) in the bilateral anterior thalamic radiation, anterior limb of the internal capsule, bilateral corticospinal tract, bilateral inferior fronto-occipital fasciculus, corpus callosum, and bilateral inferior longitudinal fasciculus. In addition, Internet-addiction severity was positively correlated with FA values. Taken together, we conclude that IGD is associated with measures of increased white-matter integrity in tracts linking reward circuitry and sensory and motor control systems.

T-Cell Densities in Brain Metastases Are Associated with Patient Survival Times and Diffusion Tensor MRI Changes.

Brain metastases are common and are usually detected by MRI. Diffusion tensor imaging (DTI) is a derivative MRI technique that can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain-tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity and fractional anisotropy (FA). The tissue samples were analyzed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13. A lower FA in the peritumoral region indicated more white matter tract disruption and independently predicted longer overall survival times (HR for death = 0.21; 95% confidence interval, 0.06-0.82; P = 0.024). Of all the biological markers studied, only increased density of CD3+ lymphocytes in the same region correlated with decreased FA (Mann-Whitney U, P = 0.037) as well as confounding completely the effect of FA on multivariate survival analyses. We conclude that the T-cell response to brain metastases is not a surrogate of local tumor invasion, primary cancer type, or aggressive phenotype and is associated with patient survival time regardless of these biological factors. Furthermore, it can be assayed by DTI, potentially offering a quick, noninvasive, clinically available method to detect an active immune microenvironment and, in principle, to measure susceptibility to immunotherapy.Significance: These findings show that white matter tract integrity is degraded in areas where T-cell infiltration is highest, providing a noninvasive method to identify immunologically active microenvironments in secondary brain tumors. Cancer Res; 78(3); 610-6. ©2017 AACR.

Diffusion Kurtosis Imaging Shows Similar Cerebral Axonal Damage in Patients with HIV Infection and Multiple Sclerosis.

In this pilot study, we sought to investigate the pathological changes in the white matter (WM) of medically complex, combination antiretroviral therapy (cART)-treated patients with human immunodeficiency virus (HIV), comparing them to patients with long-standing, secondary progressive multiple sclerosis (SPMS). Using diffusion kurtosis imaging (DKI)-derived WM tract integrity (WMTI) metrics, 15 HIV and 15 age- and sex-matched SPMS patients with similar disease duration underwent magnetic resonance imaging analysis. Maps of WMTI metrics were created. Tract-based spatial statistics analysis of the whole brain and regions of interest analysis of the corpus callosum (CC) and the anterior thalamic radiations (ATRs) were performed and the derived WMTI metrics were compared between the groups of patients. Axonal water fraction, an index of chronic axonal loss, showed similarities between HIV and the chronic MS patients in all regions; in contrast, tortuosity, a measure more sensitive to myelin loss, was regionally variable. In addition, in HIV patients, WMTI metrics of the CC and left ATR were associated with cognitive test scores, suggesting clinical relevance for these measures of WM damage. We conclude that DKI-derived WMTI metrics may be a valuable tool in assessing the WM changes of medically complex HIV-infected individuals. While not powered to examine potential etiologies of WM changes in this pilot sample, regional variations in WMTI metrics were seen. When contrasted with changes consequent to chronic MS of similar duration, HIV and its comorbidities appear to result in similar degrees of axonal damage, but regionally variable amounts of myelin loss and extraxonal abnormality.

Shared and distinct alterations of white matter tracts in remitted and nonremitted patients with schizophrenia.

Patients with schizophrenia do not usually achieve remission state even after adequate antipsychotics treatment. Previous studies found significant difference in white matter integrity between patients with good outcomes and those with poor outcomes, but difference is still unclear at individual tract level. This study aimed to use a systematic approach to identify the tracts that were associated with remission state in patients with schizophrenia. We evaluated 91 patients with schizophrenia (remitted, 50; nonremitted, 41) and 50 healthy controls through diffusion spectrum imaging. White matter tract integrity was assessed through an automatic tract-specific analysis method to determine the mean generalized fractional anisotropy (GFA) values of the 76 white matter tract bundles in each participant. Analysis of covariance among the 3 groups revealed 12 tracts that were significantly different in GFA values. Post-hoc analysis showed that compared with the healthy controls, the nonremission group had reduced integrity in all 12 tracts, whereas the remission group had reduced integrity in only 4 tracts. Comparison between the remission and nonremission groups revealed 4 tracts with significant difference (i.e., the right fornix, bilateral uncinate fasciculi, and callosal fibers connecting the temporal poles) even after adjusting age, sex, education year, illness duration, and medication dose. Furthermore, all the 4 tracts were correlated with negative symptoms scores of the positive and negative syndrome scale. In conclusion, our study identified the tracts that were associated with remission state of schizophrenia. These tracts might be a potential prognostic marker for the symptomatic remission in patients with schizophrenia.

Early-Life Iron Deficiency Reduces Brain Iron Content and Alters Brain Tissue Composition Despite Iron Repletion: A Neuroimaging Assessment.

Early-life iron deficiency has lifelong influences on brain structure and cognitive function, however characterization of these changes often requires invasive techniques. There is a need for non-invasive assessment of early-life iron deficiency with potential to translate findings to the human clinical setting. In this study, 28 male pigs were provided either a control diet (CONT; n = 14; 23.5 mg Fe/L milk replacer) or an iron-deficient diet (ID; n = 14; 1.56 mg Fe/L milk replacer) for phase 1 of the study, from postnatal day (PND) 2 until 32. Twenty pigs (n = 10/diet from phase 1 were used in phase 2 of the study from PND 33 to 61, where all pigs were provided a common iron-sufficient diet, regardless of their phase 1 dietary iron status. All pigs were subjected to magnetic resonance imaging at PND 32 and again at PND 61, and quantitative susceptibility mapping was used to assess brain iron content at both imaging time-points. Data collected on PND 61 were analyzed using voxel-based morphometry and tract-based spatial statistics to determine tissue concentration difference and white matter tract integrity, respectively. Quantitative susceptibility mapping outcomes indicated reduced iron content in the pons, medulla, cerebellum, left cortex, and left hippocampus of ID pigs compared with CONT pigs, regardless of imaging time-point. In contrast, iron contents were increased in the olfactory bulbs of ID pigs compared with CONT pigs. Voxel-based morphometric analysis indicated increased grey and white matter concentrations in CONT pigs compared with ID pigs that were evident at PND 61. Differences in tissue concentrations were predominately located in cortical tissue as well as the cerebellum, thalamus, caudate, internal capsule, and hippocampi. Tract-based spatial statistics indicated increased fractional anisotropy values along subcortical white matter tracts in CONT pigs compared with ID pigs that were evident on PND 61. All described differences were significant at p ≤ 0.05. Results from this study indicate that neuroimaging can sensitively detect structural and physiological changes due to early-life iron deficiency, including grey and white matter volumes, iron contents, as well as reduced subcortical white matter integrity, despite a subsequent period of dietary iron repletion.

Fingolimod-improved axonal and myelin integrity of white matter tracts associated with multiple sclerosis-related functional impairments.

Fingolimod hydrochloride is an effective immunomodulatory drug in improving relapsing-remitting multiple sclerosis (RRMS). However, data on the neuroradiologic effects on white matter (WM) have not been demonstrated. In this study, we aimed elucidating the impact of 1-year fingolimod treatment on WM integrity in patients with RRMS. Diffusion tensor imaging (DTI) was applied to assess axonal and myelin integrity in specific WM tracts of patients with RRMS prior to and 1year postfingolimod treatment (n=30). The fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity, and mean diffusivity were analyzed using tract-based spatial statistics on specific regions of interest associated with impaired Expanded Disability Status Scale functional scores before treatment. In patients with impaired pyramidal function at baseline (average score 2.3±0.2, n=25), fingolimod induced a significant increase in FA (P=0.002) and decrease in RD (P=0.03) in the corticospinal tract. In patients with impaired cerebellar function at baseline (average score 2.0±0.1, n=19), significant increases in FA and decreases in RD were observed in the superior (P=0.02, P=0.01, respectively) and inferior (P=0.03, P=0.05, respectively) cerebellar peduncles. The observed results suggest increased microstructural integrity and decreased demyelination of damaged WM tracts and support the possible direct mechanism of fingolimod action.

Application of neuroimaging to neuropsychiatric diseases, including imaging biomarkers that may predict treatment response

Antipsychotic drugs have become the standard treatment for schizophrenia, however, the treatment outcomes vary. Some patients achieve symptomatic remission and others continue to experience some or most symptoms. A brain correlate characteristic of the treatment outcomes is desirable to ensure an adequate trial for patients who are likely to benefit from taking antipsychotics. We evaluated 91 patients with schizophrenia (remitted, 50; non-remitted, 41) and 50 healthy controls using diffusion spectrum imaging. White matter tract integrity was assessed by an automatic tract-specific analysis method to determine white matter integrity of the 76 white matter tract bundles in each participant. We found that 12 tracts were significantly different in tract integrity values among the 3 groups. Post-hoc analysis showed that compared with the healthy controls, the non-remission group had reduced integrity in all 12 tracts, whereas the remission group had reduced integrity in only 4 tracts. Comparison between the remission and non-remission groups revealed 4 tracts with significant difference (i.e. the right fornix, bilateral uncinate fasciculi and callosal fibers connecting the temporal poles) even after adjusting age, sex, education year, illness duration and medication dose. Furthermore, all of the 4 tracts were correlated with negative symptoms scores of the positive and negative syndrome scale. In conclusion, our study identified the tracts that were associated with remission state of schizophrenia. These tracts might be a potential prognostic marker for the symptomatic remission in patients with schizophrenia.

Diffusion-weighted imaging evidence of altered white matter development from late childhood to early adulthood in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is thought to reflect disrupted development of brain connectivity characterized by white matter abnormalities and dyscoordination of activity across brain regions that give rise to core features. But there is little consensus about the nature, timing and location of white matter abnormalities as quantified with diffusion-weighted MRI. Inconsistent findings likely reflect small sample sizes, motion confounds and sample heterogeneity, particularly different age ranges across studies. We examined the microstructural integrity of major white matter tracts in relation to age in 38 high functioning ASD and 35 typically developing (TD) participants, aged 8–25, whose diffusion-weighted scans met strict data-quality criteria and survived group matching for motion. While there were no overall group differences in diffusion measures, the groups showed different relations with age. Only the TD group showed the expected positive correlations of fractional anisotropy with age. In parallel, axial diffusivity was unrelated to age in TD, but showed inverse correlations with age in ASD. Younger participants with ASD tended to have higher fractional anisotropy and axial diffusivity than their TD peers, while the opposite was true for older participants. Most of the affected tracts – cingulum bundle, inferior and superior longitudinal fasciculi – are association bundles related to cognitive, social and emotional functions that are abnormal in ASD. The manifestations of abnormal white matter development in ASD as measured by diffusion-weighted MRI depend on age and this may contribute to inconsistent findings across studies. We conclude that ASD is characterized by altered white matter development from childhood to early adulthood that may underlie abnormal brain function and contribute to core features.

White matter integrity alterations in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating condition which can develop after exposure to traumatic stressors. Seventy-five adults were recruited from the community, 25 diagnosed with PTSD along with 25 healthy and 25 trauma-exposed age- and gender-matched controls. Participants underwent clinical assessment and magnetic resonance imaging. A previous voxel based morphometry (VBM) study using the same subject cohort identified decreased grey matter (GM) volumes within frontal/subcortical brain regions including the hippocampus, amygdala, and anterior cingulate cortex (ACC). This study examines the microstructural integrity of white matter (WM) tracts connecting the aforementioned regions/structures. Using diffusion tensor imaging, we investigated the integrity of frontal/subcortical WM tracts between all three subject groups. Trauma exposed subjects with and without PTSD diagnosis were identified to have significant disruption in WM integrity as indexed by decreased fractional anisotropy (FA) in the uncinate fasciculus (UF), cingulum cingulate gyrus (CCG), and corpus callosum (CC), when compared with healthy non-trauma-exposed controls. Significant negative correlations were found between total Clinician Administered PTSD scale (CAPS) lifetime clinical subscores and FA values of PTSD subjects in the right UF, CCG, CC body, and right superior longitudinal fasciculus (SLF). An analysis between UF and SLF FA values and VBM determined rostral ACC GM values found a negative correlation in PTSD subjects. Findings suggest that compromised WM integrity in important tracts connecting limbic structures such as the amygdala to frontal regions including the ACC (i.e., the UF and CCG) may contribute to impairments in threat/fear processing associated with PTSD.

White Matter Tract Integrity: An Indicator of Axonal Pathology after Mild Traumatic Brain Injury.

We seek to elucidate the underlying pathophysiology of injury sustained after mild traumatic brain injury (mTBI) using multi-shell diffusion magnetic resonance imaging, deriving compartment-specific white matter tract integrity (WMTI) metrics. WMTI allows a more biophysical interpretation of white matter (WM) changes by describing microstructural characteristics in both intra- and extra-axonal environments. Thirty-two patients with mTBI within 30 days of injury and 21 age- and sex-matched controls were imaged on a 3 Tesla magnetic resonance scanner. Multi-shell diffusion acquisition was performed with five b-values (250-2500 sec/mm2) along 6-60 diffusion encoding directions. Tract-based spatial statistics (TBSS) was used with family-wise error (FWE) correction for multiple comparisons. TBSS results demonstrated focally lower intra-axonal diffusivity (Daxon) in mTBI patients in the splenium of the corpus callosum (sCC; p < 0.05, FWE-corrected). The area under the curve value for Daxon was 0.76 with a low sensitivity of 46.9% but 100% specificity. These results indicate that Daxon may be a useful imaging biomarker highly specific for mTBI-related WM injury. The observed decrease in Daxon suggests restriction of the diffusion along the axons occurring shortly after injury.