Freezing of gait and white matter changes: a tract-based spatial statistics study

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.

Previous studies have proven that migraine and depression are bidirectionally linked. However, few studies have investigated white matter (WM) integrity affected by depressive symptoms in patients suffering from migraine without aura (MWoA). Forty patients with MWoA were divided into two groups according to their self-rating depression scale (SDS) score in the present study, including 20 in the SDS (+) (SDS > 49) group and 20 in the SDS (-) (SDS ≤ 49) group. Forty healthy participants were also recruited as the control group. Tract-based spatial statistics analyses with multiple diffusion tensor imaging-derived indices [fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)] were employed collectively to investigate WM integrity between all patients with MWoA and all healthy controls, between each subgroup (SDS (-) group and SDS (+) group) and healthy controls, and between the SDS (-) and SDS (+) groups. Compared with healthy controls, decreased AD was shown in several WM tracts of the whole MWoA group, SDS (-) group and SDS (+) group. In addition, compared with the SDS (-) group, the SDS (+) group showed decreased FA and increased MD and RD, with conserved AD, including the genu, body and splenium of the corpus callosum, bilateral superior longitudinal fasciculi, the right anterior corona radiata and some other WM tracts, similar to previous findings in depression disorder. Furthermore, mean FA and RD in some of the above-mentioned WM tracts in the SDS (+) group were correlated significantly with SDS scores, including the genu and splenium of the corpus callosum, the right anterior corona radiata and the superior longitudinal fasciculi. Our results suggest that WM integrity may be affected by both depression symptoms (more sensitive as RD) and migraine (more sensitive as AD). The findings may serve as a sensitive biomarker of depression severity in MWoA.

Patients with classic trigeminal neuralgia (CTN) have abnormalities in white matter integrity of the corpus callosum (CC). However, in CTN patients, it is unclear whether the CC substructure region is affected to varying degrees. A total of 22 patients with CTN and 22 healthy controls (HC) with matching age, gender, and education were selected. All subjects underwent 3.0 T magnetic resonance diffusion tensor imaging and high resolution T1-weighted imaging. The CC was reconstructed by DTI technology, which was divided into three substructure regions: genu, body, and splenium. Group differences in multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD), were compared between CTN patients and HC, and correlations between the white matter change and disease duration and VAS in CTN patients were assessed. Compared with HC group, CTN patients had extensive damage to the CC white matter. The FA of the genu (P = 0.04) and body (P = 001) parts decreased, while RD (P = 0.003; P = 0.02) and MD (P = 0.002; P = 0.04) increased. In addition, the authors observed that the disease duration and VAS of CTN patients were negatively correlated with FA. The corpus callosum substructure region has extensive damage in chronic pain, and the selective microstructural integrity damage was particularly manifested by changes in axons and myelin sheath in the genu and body of corpus callosum.

22q11.2 Deletion Syndrome (22q11DS) is considered to be a promising cohort to explore biomarkers of schizophrenia risk based on a 30% probability of developing schizophrenia in adulthood. In this study, we investigated abnormalities in the microstructure of white matter in adolescents with 22q11DS and their specificity to prodromal symptoms of schizophrenia. Diffusion Magnetic Resonance Imaging (dMRI) data were acquired from 50 subjects with 22q11DS (9 with and 41 without prodromal psychotic symptoms), and 47 matched healthy controls (mean age 18 +/-2years). DMRI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and compared between groups using the Tract Based Spatial Statistics (TBSS) method. Additionally, correlations between dMRI measures and scores on positive symptoms were performed. Reductions in MD, AD and RD (but not FA) were found in the corpus callosum (CC), left and right superior longitudinal fasciculus (SLF), and left and right corona radiata in the entire 22q11DS group. In addition, the 22q11DS subgroup with prodromal symptoms showed reductions in AD and MD, but no changes in RD when compared to the non-prodromal subgroup, in CC, right SLF, right corona radiata and right internal capsule. Finally, AD values in these tracts correlated with the scores on the psychosis subscale. Microstructural abnormalities in brain white matter are present in adolescent subjects with prodromal psychotic symptoms.

Increasing evidence demonstrates that there is marked damage and dysfunction in the white matter in Alzheimer's disease (AD). The present study investigates the nature of white matter damage of patients with Alzheimer's disease with diffusion tensor magnetic resonance imaging (DTI) and analyses the relationship between the white matter damage and the cognition function. DTI, as well as T1 fluid attenuated inversion recovery (FLAIR) and T2-FLAIR, was performed on probable patients of Alzheimer's disease, and sex and age matched healthy volunteers to measure the fractional anisotropy (FA) and mean diffusivity (MD) in the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, and the white matter of frontal, temporal, parietal, and occipital lobes. FA was lower in the splenium of corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimer's disease than in the corresponding region from healthy controls and was strongly positive correlated with MMSE scores, whereas FA appeared no different in the anterior and posterior limbs of internal capsule, occipital lobes white matter, and the genu of corpus callosum between the patients and healthy controls. MD was significantly higher in the splenium of corpus callosum and parietal lobes white matter from patients than in that those from healthy controls and was strongly negative correlated with MMSE scores, whereas MD in the anterior and posterior limbs of internal capsule, as well as in frontal, temporal, occipital lobes white matter and the genu of corpus callosum, was not different between the patients and healthy controls. The most prominent alteration of FA and MD was in the splenium of corpus callosum. Our results suggested that white matter of patients with Alzheimer's disease was selectively impaired and the extent of damage had a strong correlation with the cognitive function, and that selective impairment reflected the cortico-cortical and cortico-subcortical disconnections in the pathomechanism of Alzheimer's disease. The values of FA and MD in white matter, especially in the splenium of corpus callosum in AD patients, might be a more appropriate surrogate marker for monitoring the disease progression.

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

Microstructural changes and atrophy in brain white matter tracts with aging

BackgroundDespite dietary intervention, individuals with early treated phenylketonuria (ETPKU) could present neurocognitive deficits and white matter (WM) abnormalities. The aim of the present study was to evaluate the microstructural integrity of WM pathways across the whole brain in a cohort of paediatric ETPKU patients compared with healthy controls (HCs), by collecting DTI-MRI (diffusion tensor magnetic resonance imaging) data and diffusion values (mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA)).MethodsDTI-MRI data and diffusion values (MD, RD, FA) from WM tracts across the whole brain were analized using Tract Based Spatial Statistics (TBSS), in 15 paediatrics TPKU patients (median age: 12 years) and compared with 11 HCs. Areas showing abnormal values in the patient group were correlated (Pearson) with age, lifetime Phe values, last year median and mean Phe, concurrent Phe values in plasma, urine neurotransmitters status biomarkers, and with a processing speed task.ResultsETPKU showed bilaterally decreased MD values compared with HCs in the body and splenium of the corpus callosum, superior longitudinal fasciculus, corona radiata and in the posterior limb of the internal capsule. RD values followed a similar pattern, although decreased RD values in PKU patients were also found in the anterior limb of the internal capsule and in the cerebral peduncle. Decreased MD and RD values within the aforementioned regions had significant negative correlations with age, last year median and mean Phe and concurrent Phe values. No correlations were found with monoamines in urine or processing speed task.ConclusionsETPKU patients showed MD and RD values significantly decreased across the whole brain when compared with HCs, and this damage was associated with high Phe values and the age of patients. Despite this microstructural damage, no affectation in processing speed was observed in patients with good metabolic control. DTI-MRI sequences could be used as a technique to quantify WM damage that is difficult to be detect in T1 or T2-weighted images, but also to quantify damage of WM through the follow up of patients with poor metabolic control in prospective studies.

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.

Cognitive decline in survivors of medulloblastoma is commonly attributed to radiation- and chemotherapy-induced brain microstructural alterations. Factors preceding this adjuvant therapy, such as disrupted brain development or resection surgery, may affect brain microstructure but have not been thoroughly explored in medulloblastoma. The aim of this study was to assess cortical thickness and microstructural integrity of the cerebrum prior to adjuvant therapy in medulloblastoma patients. Cross-sectional image data were acquired of medulloblastoma patients (n = 30) after surgery but before adjuvant therapy and compared with data from healthy controls (n = 35) matched for age range (12-22 years). Biomarkers of microstructural integrity include fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity. Thickness, surface area and volume were estimated for parcels of neocortex to evaluate potential morphology differences. Participants with medulloblastoma showed increased diffusivity parameters (mean, axial and radial diffusivity) and decreased fractional anisotropy, within nearly all white and grey matter parcels of the cerebrum, compared with healthy controls. Medulloblastoma participants additionally showed decreased cortical thickness in sub-regions of frontal, parietal, temporal and paracentral cortex. Broad cerebral microstructural alterations in medulloblastoma patients following surgery but before initiation of radiation or chemotherapy suggest that cerebellar insult, by tumour development or tumour resection, likely contributes to compromised integrity of cerebral grey and white matter. Locations of cortical thinning suggest that cerebellar insult may impair normal growth in cerebral regions responsible for executive function, language and attention-cognitive domains typically affected in medulloblastoma survivors.

This study aimed to characterize age-related white matter changes by evaluating patterns of overlap between the linear association of age with fractional anisotropy (FA) with mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Specifically, we assessed patterns of overlap between diffusion measures of normal appearing white matter by covarying for white matter hyperintensity (WMH) load, as WMHs are thought to increase with age and impact diffusion measures. Seventy-nine healthy adults aged between 18 and 75 years took part in the study. Diffusion tensor imaging (DTI) data were based on 61 directions acquired with a b-value of 2,000. We found five main patterns of overlap: FA alone (15.95%); FA and RD (31.90%); FA and AD (12.99%); FA, RD, and AD (27.93%); and FA, RD, and MD (8.79%). We showed that cognitively healthy aging adults had low WMH load, which subsequently had minimal effect on diffusion measures. We discuss how patterns of overlap may reflect underlying biological changes observed with aging such as loss of myelination, axonal damage, as well as mild microstructural and chronic white matter impairments. This study contributes to understanding the underlying causes of degeneration in specific regions of the brain and highlights the importance of considering the impact of WMHs in aging studies of white matter.

Objective To explore the differences of macrostructural and microstructural and their correlations in brain white matter (WM) between left- and right-handed adults. Methods Structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) were performed on twenty-three left-handed (LH) and thirty-two right-handed (RH) healthy subjects. The WM volume, fractional anisotropy (FA) and mean diffusivity (MD) were mearsured and compared between the two groups by using the voxel-based morphometry (VBM) and voxel-based analysis (VBA) methods. Results (1) LH adults showed lower WM volume than RH adults in bilateral splenium of corpus callosum (SC) (Left: x=-15, y=-57, z=13.5, t=-5.160; Right: x=18, y=-42, z=12, t=-3.654; P<0.001). Compared with the RH adults, the FA values in WM of the left postcentral gyrus (PoCG) (x=-24, y=-46, z=54) and the above left insula (INS) (x=-36, y=-12, z=20) increased(P<0.001), as well as the average FA values, the average length and number of streamlines in WM tracts increased (P<0.05) in LH adults.Compared with the RH adults, the MD values in the right HIP (x=24, y=-34, z=-2) decreased(P<0.001), as well as the average MD values decreased, and the average length in WM tracts increased(P<0.05) in LH adults.(2)There was positive correlation between FA and the volume of right splenium of corpus callosum in LH and RH adults (LH: r=0.716, RH: r=0.471, P<0.05). There was negative correlation between FA and MD in the left PoCG (LH : r=-0.769, RH: r=-0.841), left INS (LH: r=-0.775, RH : r=-0.744) and right HIP (LH: r=-0.842, RH: r=-0.742) in LH and RH adults (all P<0.05). Conclusion There are differences in both macrostructure and microstructure of white matter in several brain regions and WM tracts between left-handed and right-handed people, and correlations between these measures were also observed. Key words: Handedness; Structural magnetic resonance imaging (sMRI); Diffusion tensor imaging (DTI); White matter; Fiber tracking; Correlation

SummaryObjectiveElucidation of abnormal connections throughout the whole brain is necessary to understand temporal lobe epilepsy (TLE). We examined abnormalities in whole‐brain white matter integrity and their relationship with duration of illness in patients with TLE.MethodsThe subjects were 15 patients with TLE and 17 healthy controls. Mean duration of illness in the TLE group was 21.6 years. Tract‐based spatial statistics (TBSS) were used for diffusion tensor imaging (DTI) analysis. Four diffusion tensor metrics, that is, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and then examined for differences between the TLE and healthy control groups. We also examined for correlations between DTI parameters and duration of illness in the TLE group.ResultsIn the TLE group, compared with the healthy control group, FA was reduced, and MD and RD were increased, not only in the limbic and temporal lobe regions and their directly connecting regions in both hemispheres, but also in remote white matter regions. Duration of illness showed a significant negative correlation with mean whole‐brain FA and a significant positive correlation with both mean whole‐brain MD and RD. Brain regions showing correlation between disease duration and DTI metrics also extended to the limbic area and its connecting regions, and to remote white matter regions.SignificanceThe results of this study suggest that widespread abnormalities in white matter integrity in patients with TLE are associated with long‐term disease.

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.

The aims of this study were to compare, using diffusion tensor imaging (DTI) of the brainstem, microstructural integrity of the white matter in children with achondroplasia and age-matched participants and to correlate the severity of craniocervical junction (CCJ) narrowing and neurological findings with DTI scalars in children with achondroplasia. This study also aimed to assess the potential role of fibroblast growth factor receptor type 3 on white matter microstructure. Diffusion tensor imaging was performed using a 1.5T magnetic resonance scanner and balanced pairs of diffusion gradients along 20 non-collinear directions. Measurements were obtained from regions of interest, sampled in each pontine corticospinal tract (CST), medial lemniscus, and middle cerebellar peduncle, as well as in the lower brainstem and centrum semiovale, for fractional anisotropy and for mean, axial, and radial diffusivity. In addition, a severity score for achondroplasia was assessed by measuring CCJ narrowing. Eight patients with achondroplasia (seven males, one female; mean age 5y 6mo, range 1y 1mo-15y 1mo) and eight age- and sex-matched comparison participants (mean age 5y 2mo, range 1y 1mo-14y 11mo) were included in this study. Fractional anisotropy was lower and mean diffusivity and radial diffusivity were higher in the lower brainstem of patients with achondroplasia than in age-matched comparison participants. The CST and middle cerebellar peduncle of the participants showed increases in mean, axial, and radial diffusivity. Fractional anisotropy in the lower brainstem was negatively correlated with the degree of CCJ narrowing. No differences in the DTI metrics of the centrum semiovale were observed between the two groups. The reduction in fractional anisotropy and increase in diffusivities in the lower brainstem of participants with achondroplasia may reflect secondary encephalomalacic degeneration and cavitation of the affected white matter tracts as shown by histology. In children with achondroplasia, DTI may serve as a potential biomarker for brainstem white matter injury and aid in the care and management of these patients.