White matter integrity affected by depressive symptoms in migraine without aura: a tract‐based spatial statistics study

Protecting brain health is a goal of early intervention. We explored whether sleep quality or chronotype could predict white matter (WM) integrity in emerging mental disorders. Young people (N = 364) accessing early-intervention clinics underwent assessments for chronotype, subjective sleep quality, and diffusion tensor imaging. Using machine learning, we examined whether chronotype or sleep quality (alongside diagnostic and demographic factors) could predict four measures of WM integrity: fractional anisotropy (FA), and radial, axial, and mean diffusivities (RD, AD and MD). We prioritised tracts that showed a univariate association with sleep quality or chronotype and considered predictors identified by ≥80% of machine learning (ML) models as 'important'. The most important predictors of WM integrity were demographics (age, sex and education) and diagnosis (depressive and bipolar disorders). Subjective sleep quality only predicted FA in the perihippocampal cingulum tract, whereas chronotype had limited predictive importance for WM integrity. To further examine links with mood disorders, we conducted a subgroup analysis. In youth with depressive and bipolar disorders, chronotype emerged as an important (often top-ranking) feature, predicting FA in the cingulum (cingulate gyrus), AD in the anterior corona radiata and genu of the corpus callosum, and RD in the corona radiata, anterior corona radiata, and genu of corpus callosum. Subjective quality was not important in this subgroup analysis. In summary, chronotype predicted altered WM integrity in the corona radiata and corpus callosum, whereas subjective sleep quality had a less significant role, suggesting that circadian factors may play a more prominent role in WM integrity in emerging mood disorders.

Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter's microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (n = 24), neurofibromatosis type 1 (n = 28) and age- and sex-matched controls (n = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (d = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; P < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (P < 0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observations from independent cohorts of Noonan syndrome and neurofibromatosis type 1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras-mitogen-activated protein kinase pathway.

BackgroundWe hypothesized that the integrity of white matter might be related to the severity of freezing of gait in age-related white matter changes.MethodsTwenty subjects exhibiting excessive hyperintensities in the periventricular and deep white matter were recruited. The subjects underwent the Freezing of Gait Questionnaire, computerized gait analyses, and diffusion tensor magnetic resonance imaging. Images of axial, radial and mean diffusivity, and fractional anisotropy were calculated as indices of white matter integrity and analyzed with tract-based spatial statistics.ResultsThe fractional anisotropy, mean, axial and radial diffusivity averaged across the whole white matter structure were all significantly correlated with Freezing of Gait Questionnaire scores. Regionally, a negative correlation between Freezing of Gait Questionnaire scores and fractional anisotropy was found in the left superior longitudinal fasciculus beneath the left premotor cortex, right corpus callosum, and left cerebral peduncle. The scores of the Freezing of Gait Questionnaire were positively correlated with mean diffusivity in the left corona radiata and right corpus callosum, and with both axial and radial diffusivity in the left corona radiata. The white matter integrity in these tracts (except the corpus callosum) showed no correlation with cognitive or other gait measures, supporting the specificity of those abnormalities to freezing of gait.ConclusionDivergent pathological lesions involved neural circuits composed of the cerebral cortex, basal ganglia and brainstem, suggesting that freezing of gait has a multifactorial nature.

BackgroundNew daily persistent headache (NDPH) is a rare primary headache disorder characterized by daily and persistent sudden onset headaches. The pathogenesis of NDPH remains unclear, and there are few white matter imaging studies related to NDPH. The purpose of this study was to investigate the micro-structural abnormalities of white matter in NDPH and provided insights into the pathogenesis of this disease based on tract-based spatial statistics (TBSS).MethodsTwenty-one patients with NDPH and 25 healthy controls (HCs) were included in this study. T1 structural and diffusion magnetic resonance imaging (MRI) were acquired from all participants. Differences in the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) between patients with NDPH and HCs were investigated using TBSS analysis.ResultsSignificantly decreased FA, increased MD and RD were found in patients with NDPH compared to HCs. White matter regions overlaid with decreased FA, increased MD and RD were found in 16 white matter tracts from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas and Johns Hopkins University White-Matter Tractography Atlas. Specifically, these white matter regions included the right anterior thalamic radiation (ATR), body of the corpus callosum (BCC), bilateral cingulum, left hippocampal cingulum (CGH), left corticospinal tract (CST), forceps major, fornix, left inferior fronto-occipital fasciculus (IFOF), bilateral inferior longitudinal fasciculus (ILF), left posterior limb of the internal capsule (PLIC), right retrolenticular part of the internal capsule (RPIC), splenium of the corpus callosum (SCC), right superior longitudinal fasciculus (SLF) and left uncinate fasciculus (UF). After Bonferroni correction, there were no correlations between the FA, MD, AD and RD values and the clinical characteristics of patients with NDPH (p > 0.05/96).ConclusionThe results of our research indicated that patients with NDPH might have widespread abnormalities in the white matter of the brain.

BackgroundDisrupted white matter (WM) microstructure has been commonly identified in youth at clinical high risk (CHR) for psychosis. Several lines of evidence suggest that fatty acids, especially unsaturated fatty acids...

Patients with the postural instability and gait difficulty (PIGD) subtype of Parkinson disease (PD) are at a higher risk of dysfunction and are less responsive to dopamine replacement therapy. The PIGD subtype was found to largely associate with white matter lesions, but details of the diffusion changes within these lesions have not been fully investigated. Voxel-based analysis for diffusion tensor imaging data is one of the preferred measures to compare diffusion changes in each voxel in any part of the brain. PD patients with the PIGD (n=12) and non-PIGD subtypes (n=12) were recruited to compare diffusion differences in fractional anisotropy, axial diffusivity, and radial diffusivity with voxel-based analysis. Significantly reduced fractional anisotropy in bilateral superior longitudinal fasciculus, bilateral anterior corona radiata, and the left genu of the corpus callosum were shown in the PIGD subtype compared with the non-PIGD subtype. Increased radial diffusivity in the left superior longitudinal fasciculus was found in the PIGD subtype with no statistical differences in axial diffusivity found. Our study confirms previous findings that white matter abnormalities were greater in the PIGD subtype than in the non-PIGD subtype. Additionally, our findings suggested: (1) compared with the non-PIGD subtype, loss of white matter integrity was greater in the PIGD subtype; (2) bilateral superior longitudinal fasciculus may play a critical role in microstructural white matter abnormalities in the PIGD subtype; and (3) reduced white matter integrity in the PIGD subtype could be mainly attributed to demyelination rather than axonal loss.

Differences in white matter structure between seizure prone (FAST) and seizure resistant (SLOW) rat strains

BackgroundEarly adverse experiences, especially those involving disruption of the mother-infant relationship, are detrimental for proper socioemotional development in primates. Humans with histories of childhood maltreatment are at high risk for developing psychopathologies including depression, anxiety, substance abuse, and behavioral disorders. However, the underlying neurodevelopmental alterations are not well understood. Here we used a nonhuman primate animal model of infant maltreatment to study the long-term effects of this early life stress on brain white matter integrity during adolescence, its behavioral correlates, and the relationship with early levels of stress hormones.MethodsDiffusion tensor imaging and tract based spatial statistics were used to investigate white matter integrity in 9 maltreated and 10 control animals during adolescence. Basal plasma cortisol levels collected at one month of age (when abuse rates were highest) were correlated with white matter integrity in regions with group differences. Total aggression was also measured and correlated with white matter integrity.ResultsWe found significant reductions in white matter structural integrity (measured as fractional anisotropy) in the corpus callosum, occipital white matter, external medullary lamina, as well as in the brainstem of adolescent rhesus monkeys that experienced maternal infant maltreatment. In most regions showing fractional anisotropy reductions, opposite effects were detected in radial diffusivity, without changes in axial diffusivity, suggesting that the alterations in tract integrity likely involve reduced myelin. Moreover, in most regions showing reduced white matter integrity, this was associated with elevated plasma cortisol levels early in life, which was significantly higher in maltreated than in control infants. Reduced fractional anisotropy in occipital white matter was also associated with increased social aggression.ConclusionsThese findings highlight the long-term impact of infant maltreatment on brain white matter structural integrity, particularly in tracts involved in visual processing, emotional regulation, and somatosensory and motor integration. They also suggest a relationship between elevations in stress hormones detected in maltreated animals during infancy and long-term brain white matter structural effects.

The neurobiological mechanism underlying adolescent borderline personality disorder (BPD) remains unclear. This study aimed to assess white matter (WM) microstructural abnormalities associated with emotional dysfunction and childhood trauma in adolescents with BPD. This study enrolled 53 adolescents aged 12-17 years with BPD and 39 healthy controls (HC). Radial diffusivity (RD) and axial diffusivity (AD) were generated using Tract-Based Spatial Statistics (TBSS) analysis of the diffusion tensor imaging (DTI) data. Correlation analysis was conducted to assess the relationship of the DTI parameters with non-suicidal self-injurious behavior (NSSI) and childhood trauma in adolescents with BPD. Adolescents with BPD had lower AD values in the splenium of the corpus callosum, left anterior corona radiata and left external capsule, but higher RD values in the genu of the corpus callosum, body of the corpus callosum, right anterior corona radiata, and right uncinate fasciculus as compared to the HC group (p < 0.05, 5000 permutations). Increased RD values in the body of corpus callosum and right uncinate fasciculus were positively correlated with the NSSI score (p < 0.05). Increased RD value in the right anterior corona radiata was positively correlated with childhood trauma (p < 0.05). This study identified alterations within the cortical-limbic system in adolescents with BPD, which was correlated with NSSI and childhood trauma. WM diffusivity parameters may serve as potential neuroimaging biomarkers in adolescents with BPD.

Background: Schizophrenia (SZ) is a severe mental disorder with heritability estimated at ~80%. Genetic variants in contactin-associated protein-like 2 (CNTNAP2) have been reported in SZ. This gene is critically involved in normal neuronal synchronization and myelin production. Deletions in this gene would therefore be expected to impact white matter (WM) integrity. Compromised WM integrity has been implicated in SZ and may also be a heritable biomarker. In order to help characterize the genetic components of WM changes in SZ, we examined 2 carriers of a large heterozygous deletion in CNTNAP2 with discordant clinical phenotypes. Methods: A 59-year-old female proband who met DSM-IV criteria for a diagnosis of schizoaffective disorder (depressed subtype), her clinically unaffected 90-year-old father, and 4 unrelated nonpsychiatric controls completed a diffusion kurtosis imaging protocol on a Siemens 3T system. Human-induced pluripotent stem cell (hiPSC) lines from skin biopsies of both carriers were generated and differentiated in vitro to oligodendrocytes. Results: The fractional anisotropy (FA) and radial kurtosis (RK) were reduced, and the radial diffusivity (RD) was increased in the corona radiata and the genu of the corpus callosum (CC) in the proband compared with the father and controls. The clinically unaffected father closely resembled the controls in the genu of CC but differed from them in the uncinate fasciculus and internal capsule. In the whole-brain WM analysis, the FA and RK were reduced, and the RD was increased, in both the proband and the father compared with the controls, more substantially in the proband than in the father. Preliminary results from the in vitro differentiation suggest defective differentiation of patient-derived hiPSCs to oligodendrocyte precursor cells in the proband only. Conclusion: These preliminary data suggest that WM integrity is compromised in both carriers, possibly due to a demyelinating process that may be associated with this specific mutation. More severe and widespread demyelination is present in the clinically affected proband than in the unaffected carrier father, suggesting that additional WM changes may be associated with SZ, possibly independent of this mutation. These findings complement the molecular and cellular phenotypes of the hiPSC neural cells derived from these carriers and support the role of brain imaging in helping to elucidate objectively measurable neuroanatomic phenotypic consequences of genetic variant susceptibility. This is one of the first studies to combine neuroimaging and hiPSC-based observations in carriers of the same mutation with discordant phenotypes, demonstrating the utility of both approaches in understanding pleiotropic clinical effects.

Association of brain-derived neurotrophic factor DNA methylation and reduced white matter integrity in the anterior corona radiata in major depression

To evaluate the relationship between (a) pathologic levels of cerebrospinal fluid (CSF) total tau as an index of the intensity of ongoing neuronal degeneration and (b) longitudinal changes in white matter (WM) integrity in patients with mild cognitive impairment (MCI). Participants gave written informed consent, and the Norwegian committee for medical research ethics approved the study. Thirty patients with MCI and nonpathologic CSF total tau levels, nine patients with MCI and pathologic CSF total tau levels, and 16 age-matched healthy control subjects underwent diffusion-tensor imaging at baseline and after a mean follow-up of 2.6 years ± 0.54 (standard deviation), with range of 1.58-3.98 years. The effect of diagnosis (MCI vs no MCI) at baseline and CSF tau levels at fractional anisotropy (FA), mean diffusivity, radial diffusivity (D(R)), and axial diffusivity were tested with tract-based spatial statistics. Differences in WM integrity at baseline and follow-up and change over time were compared among patients with pathologic CSF total tau levels (MCI high tau), patients with normal CSF total tau levels (MCI low tau), and healthy control subjects. Linear mixed-model between-group within-subject analyses were conducted to examine differences in rate of change over time in FA and D(R). Longitudinal analysis of regional WM change revealed significant decrease in FA (P = .038) and increase in D(R) (P = .018) in the MCI high-tau group relative to control subjects. For D(R), the changes were regionally specific to the right cingulum and the right superior and inferior longitudinal fasciculi. Reduction in WM integrity was greater in patients with MCI who had the most intense neuronal degeneration as indexed by using CSF total tau, suggesting that these patients might represent a subgroup of MCI with more intense WM degeneration who are possibly at greater risk of developing Alzheimer disease.

Background. Deterioration of motor function is one of several clinical manifestations following traumatic brain injury (TBI) in children and adolescents. Objective. To investigate the relationship between white matter (WM) integrity using diffusion tensor imaging (DTI) and motor functioning in young TBI patients. Methods. A group with moderate to severe TBI (n = 24) and a control group (n = 17) were scanned using DTI along with standard anatomical scans. Using ExploreDTI software, WM regions/tracts that carry efferent output (motor) from the brain were evaluated, as well as the corpus callosum, brainstem, internal capsule, and subcortical WM structures. Motor function was assessed using the Movement Assessment Battery for Children (M-ABC), consisting of manual dexterity, ball skills, and static and dynamic balance items. Results. TBI patients were less successful on the M-ABC than the controls and showed lower WM fractional anisotropy (FA) in the corpus callosum, anterior corona radiata, corticospinal tract, and cerebellum. Decreased FA was associated with lower motor performance in the TBI group but not in the control group. Conclusion. This study provides evidence for a structural alteration of motor pathways and regions in children and adolescents with TBI that are correlated with motor functioning. Further studies may be able to identify therapeutic targets and monitor the effects of new interventions.

Increasing evidence suggests that olfactory impairment is associated with an increased risk of conversion from mild cognitive impairment MCI to Alzheimer's disease. This study was to explore how olfactory identification relates to white matter WM integrity, using diffusion tensor imaging DTI in individuals with amnestic MCI. DTI was performed from nineteen individuals with amnestic MCI mean age: 69.95±8.20 years. Olfactory identification was assessed using the Cross-Cultural Smell Identification Test CC-SIT, a widely used test for odor identification involving a scratch and sniff test of 12 micro-encapsulated odorants. Cross-sectional voxel-wise analyses of relationships between CC-SIT scores and DTI indices were performed using Tract-Based Spatial Statistics. Higher CC-SIT scores were associated with lower mean, axial and radial diffusivities in areas such as the body and splenium of corpus callosum, frontal WM lateral orbitofrontal, caudal middle frontal, precentral, left superior frontal, and right pars opercularis, right superior longitudinal fasciculus, anterior and superior corona radiata, and internal and external capsules, while CC-SIT scores were not significantly associated with fractional anisotropy across all MCI participants. In individuals with amnestic MCI, impaired olfactory identification is associated with alterations in WM integrity expressed as a lower diffusivities value. This cross-sectional preliminary study suggests that olfactory impairment contributes to WM microstructural alterations in individuals with amnestic MCI. © 2016 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 26, 270-276, 2016

To use diffusion-tensor (DT) magnetic resonance (MR) imaging to explore the integrity and connectivity of brain white matter in patients with obsessive-compulsive disorder (OCD) and to correlate DT parameters with clinical measures. This study was approved by the local ethical committee, and written informed consent was obtained from all participants. DT imaging was performed by using a 3.0-T MR imager in 23 patients with OCD and 23 healthy control subjects matched for age, sex, education level, and handedness. By using voxel-based analysis, fractional anisotropy (FA) and axial and radial diffusivities were compared between patients and control subjects with a two-sample t test and were tested for correlation with symptom severity, as measured by using the Yale-Brown Obsessive-Compulsive Scale and obsessive-compulsive subscale scores, and with illness duration, as measured by using simple regression in statistical parametric mapping program. Compared with control subjects, OCD patients demonstrated significantly increased FA in the genu and body of corpus callosum and white matter of right superior frontal gyrus and corpus callosum; no areas of significantly decreased FA were found. For areas of increased FA, axial diffusivity was higher than that in control subjects, while radial diffusivity was not significantly different. The FA values in the white matter of left middle temporal gyrus in OCD patients correlated positively with clinical measures (r = 0.542, P < .001). OCD is associated with axonal microstructural abnormalities within the white matter, which may indicate impaired axonal integrity and increased connectivity. The positive correlation between DT abnormalities and symptom severity suggests that DT imaging may be of clinical value in measuring and following disability in OCD patients.