White Matter Regions Of Interest Research Articles

Microstructural properties in subacute aphasia: concurrent and prospective relationships underpinning recovery.

Few investigations examined the relationship between microstructural white matter integrity and subacute post-stroke linguistic performance or the relationship between microstructural integrity and the recovery of language function. We examined two key questions: (1) How does subacute language performance, measured in single words and discourse, relate to the microstructural integrity of key white matter regions of interest in the language network? and (2) Does the integrity of these regions before treatment predict the improvement or resolution of linguistic symptoms immediately and chronically following treatment? 58 participants within the first three months of stroke were enrolled in a randomized, single-center, double-blind, sham-controlled, study of anodal transcranial direct current stimulation combined with a computer-delivered speech and language naming therapy for subacute aphasia and were asked to complete magnetic resonance imaging at enrollment. Microstructural integrity was evaluated using diffusion tensor imaging processed with atlas-based segmentation. Regression and correlation analyses were conducted. A subset of 22 participants received diffusion tensor imaging. Picture naming accuracy significantly correlated with lower mean diffusivity (higher microstructural integrity) in the left posterior inferior temporal gyrus. Recovery of naming performance was predicted by days since stroke and baseline microstructural integrity of the left posterior middle temporal gyrus, arcuate fasciculus, and superior longitudinal fasciculus. Recovery of discourse efficiency was significantly predicted by the same model. This study demonstrates an association between picture naming and discourse and microstructural integrity of the key regions in the language network for patients with subacute post-stroke aphasia. Baseline microstructural integrity significantly predicts language recovery.

Quantitative cellular pathology of the amygdala in temporal lobe epilepsy and correlation with magnetic resonance imaging volumetry, tissue microstructure, and sudden unexpected death in epilepsy risk factors.

Amygdala enlargement can occur in temporal lobe epilepsy, and increased amygdala volume is also reported in sudden unexpected death in epilepsy (SUDEP). Apnea can be induced by amygdala stimulation, and postconvulsive central apnea (PCCA) and generalized seizures are both known SUDEP risk factors. Neurite orientation dispersion and density imaging (NODDI) has recently provided additional information on altered amygdala microstructure in SUDEP. In a series of 24 surgical temporal lobe epilepsy cases, our aim was to quantify amygdala cellular pathology parameters that could predict enlargement, NODDI changes, and ictal respiratory dysfunction. Using whole slide scanning automated quantitative image analysis methods, parallel evaluation of myelin, axons, dendrites, oligodendroglia, microglia, astroglia, neurons, serotonergic networks, mTOR-pathway activation (pS6) and phosphorylated tau (pTau; AT8, AT100, PHF) in amygdala, periamygdala cortex, and white matter regions of interest were compared with preoperative magnetic resonance imaging data on amygdala size, and in 13 cases with NODDI and evidence of ictal-associated apnea. We observed significantly higher glial labeling (Iba1, glial fibrillary acidic protein, Olig2) in amygdala regions compared to cortex and a strong positive correlation between Olig2 and Iba1 in the amygdala. Larger amygdala volumes correlated with lower microtubule-associated protein (MAP2), whereas higher NODDI orientation dispersion index correlated with lower Olig2 cell densities. In the three cases with recorded PCCA, higher MAP2 and pS6-235 expression was noted than in those without. pTau did not correlate with SUDEP risk factors, including seizure frequency. Histological quantitation of amygdala microstructure can shed light on enlargement and diffusion imaging alterations in epilepsy to explore possible mechanisms of amygdala dysfunction, including mTOR pathway activation, that in turn may increase the risk for SUDEP.

Reduced myelin content in bipolar disorder: A study of inhomogeneous magnetization transfer

BackgroundPrevious neuroimaging and pathological studies have found myelin-related abnormalities in bipolar disorder (BD), which prompted the use of magnetic resonance (MR) imaging technology sensitive to neuropathological changes to explore its neuropathological basis. We holistically investigated alterations in myelin within BD patients by inhomogeneous magnetization transfer (ihMT), which is sensitive and specific to myelin content. MethodsThirty-one BD and 42 healthy controls (HC) were involved. Four MR metrics, i.e., ihMT ratio (ihMTR), pseudo-quantitative ihMT (qihMT), magnetization transfer ratio and pseudo-quantitative magnetization transfer (qMT), were compared between groups using analysis methods based on whole-brain voxel-level and white matter regions of interest (ROI), respectively. ResultsThe voxel-wise analysis showed significantly inter-group differences of ihMTR and qihMT in the corpus callosum. The ROI-wise analysis showed that ihMTR, qihMT, and qMT values in BD group were significantly lower than that in HC group in the genu and body of corpus callosum, left anterior limb of the internal capsule, left anterior corona radiate, and bilateral cingulum (p < 0.001). And the qihMT in genu of corpus callosum and right cingulum were negatively correlated with depressive symptoms in BD group. LimitationsThis study is based on cross-sectional data and the sample size is limited. ConclusionThese findings suggest the reduced myelin content of anterior midline structure in the bipolar patients, which might be a critical pathophysiological feature of BD.

Global White Matter Changes and Associations with Cognition in Pediatric Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a genetic blood disorder affecting multiple organ systems, particularly the brain (Pinto, V.M. et al 2019). Neurocognitive deficits can occur in the presence or absence of overt brain injury, such as stroke or silent cerebral infarction (SCI). Using diffusion tensor imaging (DTI) metrics, multiple studies have identified widespread white matter alterations in individuals with SCD. DTI abnormalities, such as decreased fractional anisotropy (FA) and increased mean diffusivity (MD), have been associated with decreased processing speed in this population (Stotesbury et al. 2018). The goals of this study are to 1) define developmental differences in diffuse (brain-wide) white matter microstructure between SCD and control pediatric participants and 2) determine medical and neurocognitive characteristics of pediatric participants with SCD and abnormal DTI metrics. Methods: Thirty-eight participants between 8 to 12 years of age with no prior known history of stroke, SCI, or seizures were recruited for a prospective longitudinal study. Study groups consisted of 28 participants with SCD and 10 sibling or unrelated control participants. This study was a cross-sectional analysis of participants who completed DTI scans and neuropsychological testing at study entry (n=35). DTI was obtained on a 3T Philips research scanner 2.2mm nominal isotropic resolution; 32 diffusion directions obtained at b=700 s/mm 2. Preprocessing, tensor estimation, and calculation of FA and MD maps were performed using DTI Studio/MRICloud and its pediatric DTI atlas. Neurocognitive evaluation was performed and interpreted by a trained psychology associate with supervision from a board-certified neuropsychologist and included intelligence testing (Weschler Intelligence Scale for Children, WISC-5). Statistical analyses were performed using STATA 18 and MATLAB 2022a. We examined cohort-level demographics using chi-square tests, T-tests, and Wilcoxon rank sum tests (Table 1). To examine diffuse differences in white matter microstructure development, we used 19 bilateral white matter regions of interest [ROIs] shown in prior research to be important in patients with SCD with and without SCI. We examined MD and FA values within ANOVA models (each in terms of Group*Age + ROI) to assess group-level differences (SCD vs. control) and group x age interactions. We used ANOVA loadings to compute global MD and FA scores and computed 95% prediction intervals by age based on control participants. We identified participants with SCD with global scores suggestive of white matter microstructural differences (high MD and/or low FA) and compared their overall neurocognitive profiles. Results: The SCD and control participants were similar with regards to age, sex, and full-scale IQ. SCD participants had significantly lower median hemoglobin levels than control participants. There was one control participant who met criteria for SCI. SCD vs. control group status, age, and group x age interactions all significantly impacted our MD model (explaining 0.8%, 1.1%, and 0.8% of total variance, respectively; all p&amp;lt;0.001). MD decreased with age in the combined cohort (β=-9.3±1.6e-7/month) with significant flattening of this trend in children with SCD (group x age interaction: β=+7.9±2.0e-7/month). In contrast, only age significantly impacted our FA model (p&amp;lt;0.001, explaining 1.1% of variance); group status and group x age interactions each explained &amp;lt;0.2% of variance in FA. Four children with SCD had global DTI metrics suggestive of white matter injury (one with high MD and low FA; two with high MD only; one with low FA only). All 4 participants with abnormal DTI metrics had abnormal MRIs, three of whom had SCI and one of whom had lesions that did not meet the size criteria for SCI. Three participants had full scale IQs 1 standard deviation below the expected mean of 100 (&amp;lt;85). Conclusion: We identified differences in global white matter microstructural indices between SCD and control participants with an apparent blunting of expected decreases in mean diffusivity with age. Our continuing longitudinal study will explicitly assess DTI trajectories and implications for neurocognitive functioning in children with SCD.

Applicability of multiple quantitative magnetic resonance methods in genetic brain white matter disorders.

Magnetic resonance imaging (MRI) measures of tissue microstructure are important for monitoring brain white matter (WM) disorders like leukodystrophies and multiple sclerosis. They should be sensitive to underlying pathological changes. Three whole-brain isotropic quantitative methods were applied and compared within a cohort of controls and leukodystrophy patients: two novel myelin water imaging (MWI) techniques (multi-compartment relaxometry diffusion-informed MWI: MCR-DIMWI, and multi-echo T2 relaxation imaging with compressed sensing: METRICS) and neurite orientation dispersion and density imaging (NODDI). For 9 patients with different leukodystrophies (age range 0.4-62.4 years) and 15 control subjects (2.3-61.3 years), T1-weighted MRI, fluid-attenuated inversion recovery, multi-echo gradient echo with variable flip angles, METRICS, and multi-shell diffusion-weighted imaging were acquired on 3 Tesla. MCR-DIMWI, METRICS, NODDI, and quality control measures were extracted to evaluate differences between patients and controls in WM and deep gray matter (GM) regions of interest (ROIs). Pearson correlations, effect size calculations, and multi-level analyses were performed. MCR-DIMWI and METRICS-derived myelin water fractions (MWFs) were lower and relaxation times were higher in patients than in controls. Effect sizes of MWF values and relaxation times were large for both techniques. Differences between patients and controls were more pronounced in WM ROIs than in deep GM. MCR-DIMWI-MWFs were more homogeneous within ROIs and more bilaterally symmetrical than METRICS-MWFs. The neurite density index was more sensitive in detecting differences between patients and controls than fractional anisotropy. Most measures obtained from MCR-DIMWI, METRICS, NODDI, and diffusion tensor imaging correlated strongly with each other. This proof-of-concept study shows that MCR-DIMWI, METRICS, and NODDI are sensitive techniques to detect changes in tissue microstructure in WM disorders.

Neuroimaging of tissue microstructure as a marker of neurodegeneration in the AT(N) framework: defining abnormal neurodegeneration and improving prediction of clinical status

BackgroundAlzheimer’s disease involves accumulating amyloid (A) and tau (T) pathology, and progressive neurodegeneration (N), leading to the development of the AD clinical syndrome. While several markers of N have been proposed, efforts to define normal vs. abnormal neurodegeneration based on neuroimaging have been limited. Sensitive markers that may account for or predict cognitive dysfunction for individuals in early disease stages are critical.MethodsParticipants (n = 296) defined on A and T status and spanning the AD-clinical continuum underwent multi-shell diffusion-weighted magnetic resonance imaging to generate Neurite Orientation Dispersion and Density Imaging (NODDI) metrics, which were tested as markers of N. To better define N, we developed age- and sex-adjusted robust z-score values to quantify normal and AD-associated (abnormal) neurodegeneration in both cortical gray matter and subcortical white matter regions of interest. We used general logistic regression with receiver operating characteristic (ROC) and area under the curve (AUC) analysis to test whether NODDI metrics improved diagnostic accuracy compared to models that only relied on cerebrospinal fluid (CSF) A and T status (alone and in combination).ResultsUsing internal robust norms, we found that NODDI metrics correlate with worsening cognitive status and that NODDI captures early, AD neurodegenerative pathology in the gray matter of cognitively unimpaired, but A/T biomarker-positive, individuals. NODDI metrics utilized together with A and T status improved diagnostic prediction accuracy of AD clinical status, compared with models using CSF A and T status alone.ConclusionUsing a robust norms approach, we show that abnormal AD-related neurodegeneration can be detected among cognitively unimpaired individuals. Metrics derived from diffusion-weighted imaging are potential sensitive markers of N and could be considered for trial enrichment and as outcomes in clinical trials. However, given the small sample sizes, the exploratory nature of the work must be acknowledged.

Sex, myelin, and clinical characteristics of Parkinson's disease.

To determine if there are sex differences in myelin in Parkinson's disease, and whether these explain some of the previously-described sex differences in clinical presentation. Thirty-three subjects (23 males, 10 females) with Parkinson's disease underwent myelin water fraction (MWF) imaging, an MRI scanning technique of in vivo myelin content. MWF of 20 white matter regions of interest (ROIs) were assessed. Motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). Principal component analysis, logistic and multiple linear regressions, and t-tests were used to determine which white matter ROIs differed between sexes, the clinical features associated with these myelin changes, and if overall MWF and MWF laterality differed between males and females. Consistent with prior reports, tremor and bradykinesia were more likely seen in females, whereas rigidity and axial symptoms were more likely seen in males in our cohort. MWF of the thalamic radiation, cingulum, cingulum hippocampus, inferior fronto-occipital fasciculi, inferior longitudinal fasciculi, and uncinate were significant in predicting sex. Overall MWF and asymmetry of MWF was greater in males. MWF differences between sexes were associated with tremor symptomatology and asymmetry of motor performance. Sex differences in myelin are associated with tremor and asymmetry of motor presentation. While preliminary, our results suggest that further investigation of the role of biological sex in myelin pathology and clinical presentation in Parkinson's disease is warranted.

Association of Intensive vs Standard Blood Pressure Control With Regional Changes in Cerebral Small Vessel Disease Biomarkers

Little is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers. To investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF). The Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target <120 mm Hg) vs standard control (SBP target <140 mm Hg) among participants aged 50 years or older with hypertension and without diabetes or a history of stroke. The study began randomization on November 8, 2010, and stopped July 1, 2016, with a follow-up duration of approximately 4 years. A total of 670 and 458 participants completed brain magnetic resonance imaging at baseline and follow-up, respectively, and comprise the cohort for this post hoc analysis. Statistical analyses for this post hoc analysis were performed between August 2020 and October 2022. At baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment. The main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest). At baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]). This study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control. ClinicalTrials.gov Identifier: NCT01206062.

Posterior white matter integrity and self-reported posterior cortical symptoms using the Colorado Posterior Cortical Questionnaire.

The Colorado Posterior Cortical Questionnaire (CPC-Q) is a self-report, 15-item screening questionnaire for posterior cortical symptoms, including visuospatial and visuoperceptual difficulties. Changes in white matter connectivity may precede obvious gray matter atrophy in neurodegenerative conditions, especially posterior cortical atrophy. Integration of CPC-Q scores and measures of white matter integrity could contribute to earlier detection of posterior cortical syndromes. We investigated the relationships between posterior cortical symptoms as captured by the CPC-Q and diffusion tensor imaging fractional anisotropy (DTI FA) of white matter regions of interest localized to posterior brain regions (posterior thalamic radiations, splenium of corpus callosum, tapetum). Comparisons were also made by diagnostic group [healthy older adult (n = 31), amnestic Alzheimer's disease (AD, n = 18), and posterior cortical atrophy (PCA, n = 9)] and by SENAS battery visuospatial composite score quartile. Exploratory comparisons of all available individual white matter region DTI FA to CPC-Q, as well as comparisons of DTI FA between diagnostic groups and visuospatial quartiles, were also made. CPC-Q score was correlated with the average DTI FA for the averaged posterior white matter regions of interest (r = -0.31, p = 0.02). Posterior thalamic radiation DTI FA was most strongly associated with CPC-Q (r = -0.34, p = 0.01) and visuospatial composite (r = 0.58, p < 0.01) scores and differed between the PCA and AD groups and the lower and higher visuospatial quartiles. The DTI FA of body and splenium of the corpus callosum also demonstrated this pattern but not the DTI FA of the tapetum. The integrity of posterior white matter tracts is associated with scores on the CPC-Q, adding to the validation evidence for this new questionnaire. White matter regions that may be related to posterior cortical symptoms detected by the CPC-Q, and distinct from those affected in amnestic syndromes, include the posterior thalamic radiations and body and splenium of the corpus callosum. These findings are in line with previous neuroimaging studies of PCA and support continued research on white matter in posterior cortical dysfunction.

An Investigation of Differences in White Matter Tract Patterns in Alcohol Use Disorder: Standard Statistical and Covariance Analyses

Background: Magnetic resonance imaging (MRI) studies have been used to demonstrate differences in white matter (WM) in the brains of individuals with alcohol use disorder (AUD). Alcohol use is known to be deleterious on WM integrity, and there are reports of an inverse relationship between WM fractional anisotropy (FA) and self-reported alcohol consumption. Still, the specific WM tracts which are affected remain unclear. This study sought to determine whether alcohol use differentially alters FA and neurite microstructure in WM regions of interest (ROIs). We used diffusion weighted MRI to compare metrics of WM integrity between non- treatment seeking individuals with AUD and social drinkers (SD).&#x0D; Methods: Thirteen subjects with AUD and 21 SD underwent hybrid diffusion imaging (HYDI) on a 3T Siemens MRI scanner. HYDI data were processed with diffusion tensor imaging and Neurite Orientation Dispersion and Density Index (NODDI) modeling to produce parametric images of outcome metrics. All parametric images were converted to standard space before extraction of average parameter values from regions of interest defined by the John Hopkins University 1 mm WM atlas. For each metric, independent t-tests were used to test for group differences. Covariance analyses will be used to examine differences in covariance matrix structure between groups.&#x0D; Results: Compared to social drinkers, participants with AUD had significantly lower FA, higher radial diffusivity, and higher orientation dispersion (OD) in subregions of the corpus callosum (p&lt;0.05). AUD was also associated with higher OD in the cingulate gyri (p&lt;0.01).&#x0D; Conclusion: Individuals with AUD had significantly altered WM metrics in multiple tracts, consistent with previous research. This is also the first report of NODDI metrics in AUD; the higher OD may reflect WM disorganization. Ultimately, understanding the anatomic variance between groups will help to elucidate connectivity differences that may either predispose individuals to AUD and/or which are disrupted by chronic alcohol consumption.

In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen’s d = 0.37), posterior corona radiata (d = 0.32), and superior fronto‐occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

White matter microstructure and sleep-wake disturbances in individuals at ultra-high risk of psychosis.

White matter changes in individuals at ultra-high risk for psychosis (UHR) may be involved in the transition to psychosis. Sleep-wake disturbances commonly precede the first psychotic episode and predict development of psychosis. We examined associations between white matter microstructure and sleep-wake disturbances in UHR individuals compared to healthy controls (HC), as well as explored the confounding effect of medication, substance use, and level of psychopathology. Sixty-four UHR individuals and 35 HC underwent clinical interviews and diffusion weighted imaging. Group differences on global and callosal mean fractional anisotropy (FA) was tested using general linear modeling. Sleep-wake disturbances were evaluated using the subjective measures disturbed sleep index (DSI) and disturbed awakening index (AWI) from the Karolinska Sleep Questionnaire, supported by objective sleep measures from one-night actigraphy. The primary analyses comprised partial correlation analyses between global FA/callosal FA and sleep-wake measures. Secondary analyses investigated multivariate patterns of covariance between measures of sleep-wake disturbances and FA in 48 white matter regions of interest using partial least square correlations. Ultra-high risk for psychosis individuals displayed lower global FA (F = 14.56, p < 0.001) and lower callosal FA (F = 11.34, p = 0.001) compared to HC. Subjective sleep-wake disturbances were significantly higher among the UHR individuals (DSI: F = 27.59, p < 0.001, AWI: F = 36.42, p < 0.001). Lower callosal FA was correlated with increased wake after sleep onset (r = -0.34, p = 0.011) and increased sleep fragmentation index (r = -0.31, p = 0.019) in UHR individuals. Multivariate analyses identified a pattern of covariance in regional FA which were associated with DSI and AWI in UHR individuals (p = 0.028), but not in HC. Substance use, sleep medication and antipsychotic medication did not significantly confound these associations. The association with objective sleep-wake measures was sustained when controlling for level of depressive and UHR symptoms, but symptom level confounded the covariation between FA and subjective sleep-wake measures in the multivariate analyses. Compromised callosal microstructure in UHR individuals was related to objectively observed disruptions in sleep-wake functioning. Lower FA in ventrally located regions was associated with subjectively measured sleep-wake disturbances and was partly explained by psychopathology. These findings call for further investigation of sleep disturbances as a potential treatment target.

Beyond the Hippocampus: White Matter Memory Network Implicated in Post-Radiation Memory Decline in Primary Brain Tumor Patients

<h3>Purpose/Objective(s)</h3> Memory deficits after brain RT are common. Critical white matter tracts including the fornix, cingulum, and parahippocampal cingulum (PHC) connect with the hippocampus, comprising the memory network. We analyzed quantitative neuroimaging biomarkers of microstructural injury to these white matter regions of interest (ROI) and hippocampus, to understand the impact these changes have on post-RT verbal and visuospatial memory performance in brain tumor patients. <h3>Materials/Methods</h3> Primary brain tumor patients on a prospective trial receiving fractionated brain RT (n=56) underwent volumetric brain MRI, diffusion tensor imaging, and prospective memory assessments (Hopkins Verbal Learning Test-Revised [HVLT-R] Total and Delayed Recall and Brief Visuospatial Memory Test [BVMT] Total and Delayed Recall) at baseline and 3, 6, and 12 months post-RT. Bilateral hippocampi, fornix, cingulum, and parahippocampal cingulum (PHC) were autosegmented; tumor, surgical bed, and edema were censored to avoid confounding. Volume was measured in each ROI, and diffusion biomarkers also analyzed in white matter ROIs (fractional anisotropy, FA; mean diffusivity, MD). Increase in MD and decrease in FA indicate WM injury. Multivariable linear mixed-effects models assessed associations of biomarkers with time and RT dose, and as longitudinal predictors of memory scores, controlling for time and subject-specific effects. P-values were corrected for multiple comparisons. <h3>Results</h3> Volumes of all ROIs significantly decreased after 6 months (p<0.05). Over time, FA decreased in right and left fornix and cingulum (p<0.05) and MD increased in left fornix (p=0.005). Higher RT dose was associated with: atrophy in left and right hippocampi (p<0.001) and right fornix (p=0.024), decreased FA in right fornix (p=0.046) and right PHC (p=0.042), and increased MD in right PHC (p=0.03). Atrophy of right fornix was associated with worse performance on BVMT Total (p=0.019) and decreased volume of left PHC with worse performance on BVMT Delayed (p=0.039). Volume of either hippocampus was not associated with memory scores. Reduced FA in the left (p=0.010) and right (p=0.019) fornix was associated with worse performance on BVMT Total. Lower FA in the left cingulum (p=0.038) was associated with worse performance on HVLT Total while lower FA in the right PHC was associated with worse performance on HVLT Delayed. Higher MD in the left (p=0.010) and right (p=0.007) fornix and the right PHC (p=0.011) correlated with poorer BVMT Total scores, while higher MD in the right PHC (p=0.046) was correlated with poorer HVLT Total scores. <h3>Conclusion</h3> Microstructural injury in the fornix, cingulum, and PHC predicted for worse verbal and visuospatial memory post-RT, while injury to the hippocampus did not. RT dose avoidance to these white matter regions should be explored to better preserve memory in brain tumor patients.

Diffusion tensor imaging correlates of depressive symptoms in Parkinson disease.

Depression is a heterogeneous clinical syndrome prevalent in patients with Parkinson disease (PD) that remains incompletely understood. Further, the differences in biomarkers of depression in PD and in non-PD patients are unclear. The subcallosal cingulate cortex (SCC) and its connections have been implicated in the pathophysiology of major depressive disorder (MDD). Diffusion tensor imaging (DTI) provides a tool to quantify MDD-related structural abnormalities underlying depressive symptoms in PD. Diffusion-weighted magnetic resonance imaging data were collected from 31 patients with PD. Depression symptom severity was measured using the Beck Depression Inventory (BDI-II), and assessed using three subscales: dysphoric mood, loss of interest/pleasure, and somatic symptoms. Probabilistic tractography methods were used to quantify the SCC connectivity to target regions in cortico-limbic-striatal network (ventral striatum, medial prefrontal cortex [mPFC], dorsal anterior cingulate cortex, and uncinate fasciculus), while fractional anisotropy (FA) was calculated in predefined white matter regions of interest. DTI data were correlated with severity of depression across three domains. SCC-mPFC connectivity in the left hemisphere was positively correlated with severity of dysphoric mood (Benjamini-Hochberg adjusted p=.02). Region of interest-based analyses demonstrated a significant and distinct topographic association between FA and dysphoric mood, loss of interest/pleasure, and somatic symptom severity, although these findings did not maintain significance after applying the false discovery rate correction. Abnormal SCC connectivity underlies depressive symptoms in both PD and MDD, suggesting that interventions used for MDD should be explored in treating depressive symptoms in PD, particularly depression dominated by dysphoric mood.

Brain White Matter Development Over the First 13 Years in Very Preterm and Typically Developing Children Based on the T 1-w/T 2-w Ratio.

To investigate brain regional white matter development in full-term (FT) and very preterm (VP) children at term equivalent and 7 and 13 years of age based on the ratio of T 1- and T 2-weighted MRI (T 1-w/T 2-w), including (1) whether longitudinal changes differ between birth groups or sexes, (2) associations with perinatal risk factors in VP children, and (3) relationships with neurodevelopmental outcomes at 13 years. Prospective longitudinal cohort study of VP (born <30 weeks' gestation or <1,250 g) and FT infants born between 2001 and 2004 and followed up at term equivalent and 7 and 13 years of age, including MRI studies and neurodevelopmental assessments. T 1-w/T 2-w images were parcellated into 48 white matter regions of interest. Of 224 VP participants and 76 FT participants, 197 VP and 55 FT participants had useable T 1-w/T 2-w data from at least one timepoint. T 1-w/T 2-w values increased between term equivalent and 13 years of age, with little evidence that longitudinal changes varied between birth groups or sexes. VP birth, neonatal brain abnormalities, being small for gestational age, and postnatal infection were associated with reduced regional T 1-w/T 2-w values in childhood and adolescence. Increased T 1-w/T 2-w values across the white matter at 13 years were associated with better motor and working memory function for all children. Within the FT group only, larger increases in T 1-w/T 2-w values from term equivalent to 7 years were associated with poorer attention and executive function, and higher T 1-w/T 2-w values at 7 years were associated with poorer mathematics performance. VP birth and multiple known perinatal risk factors are associated with long-term reductions in the T 1-w/T 2-w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Increased T 1-w/T 2-w ratio at 13 years appeared to be associated with better motor and working memory function and there appeared to be developmental differences between VP and FT children in the associations for attention, executive functioning, and mathematics performance.

Differences in Diffusion Tensor Imaging White Matter Integrity Related to Verbal Fluency Between Young and Old Adults.

Throughout adulthood, the brain undergoes an array of structural and functional changes during the typical aging process. These changes involve decreased brain volume, reduced synaptic density, and alterations in white matter (WM). Although there have been some previous neuroimaging studies that have measured the ability of adult language production and its correlations to brain function, structural gray matter volume, and functional differences between young and old adults, the structural role of WM in adult language production in individuals across the life span remains to be thoroughly elucidated. This study selected 38 young adults and 35 old adults for diffusion tensor imaging (DTI) and performed the Controlled Oral Word Association Test to assess verbal fluency (VF). Tract-Based Spatial Statistics were employed to evaluate the voxel-based group differences of diffusion metrics for the values of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and local diffusion homogeneity (LDH) in 12 WM regions of interest associated with language production. To investigate group differences on each DTI metric, an analysis of covariance (ANCOVA) controlling for sex and education level was performed, and the statistical threshold was considered at p < 0.00083 (0.05/60 labels) after Bonferroni correction for multiple comparisons. Significant differences in DTI metrics identified in the ANCOVA were used to perform correlation analyses with VF scores. Compared to the old adults, the young adults had significantly (1) increased FA values on the bilateral anterior corona radiata (ACR); (2) decreased MD values on the right ACR, but increased MD on the left uncinate fasciculus (UF); and (3) decreased RD on the bilateral ACR. There were no significant differences between the groups for AD or LDH. Moreover, the old adults had only a significant correlation between the VF score and the MD on the left UF. There were no significant correlations between VF score and DTI metrics in the young adults. This study adds to the growing body of research that WM areas involved in language production are sensitive to aging.

TractEM: Evaluation of protocols for deterministic tractography white matter atlas

Reproducible identification of white matter pathways across subjects is essential for the study of structural connectivity of the human brain. One of the key challenges is anatomical differences between subjects and human rater subjectivity in labeling. Labeling white matter regions of interest presents many challenges due to the need to integrate both local and global information. Clearly communicating the manual processes to capture this information is cumbersome, yet essential to lay a solid foundation for comprehensive atlases. Segmentation protocols must be designed so the interpretation of the requested tasks as well as locating structural landmarks is anatomically accurate, intuitive and reproducible. In this work, we quantified the reproducibility of a first iteration of an open/public multi-bundle segmentation protocol. This allowed us to establish a baseline for its reproducibility as well as to identify the limitations for future iterations. The protocol was tested/evaluated on both typical 3 T research acquisition Baltimore Longitudinal Study of Aging (BLSA) and high-acquisition quality Human Connectome Project (HCP) datasets. The results show that a rudimentary protocol can produce acceptable intra-rater and inter-rater reproducibility. However, this work highlights the difficulty in generalizing reproducible results and the importance of reaching consensus on anatomical description of white matter pathways. The protocol has been made available in open source to improve generalizability and reliability in collaboration. The goal is to improve upon the first iteration and initiate a discussion on the anatomical validity (or lack thereof) of some bundle definitions and the importance of reproducibility of tractography segmentation.

The Relations Between Physical Activity Level, Executive Function, and White Matter Microstructure in Older Adults.

The population of older adults is increasing, indicating a need to examine factors that may prevent or mitigate age-related cognitive decline. The current study examined whether microstructural white matter characteristics mediated the relation between physical activity and executive function in older adults without any self-reported psychiatric and neurological disorders or cognitive impairment (N = 43, mean age = 73y). Physical activity was measured by average intensity and number of steps via accelerometry. Diffusion tensor imaging was used to examine microstructural white matter characteristics, and neuropsychological testing was used to examine executive functioning. Parallel mediation models were analyzed using microstructural white matter regions of interest as mediators of the association between physical activity and executive function. Results indicated that average steps was significantly related to executive function (β = 0.0003, t = 2.829, P = .007), while moderate to vigorous physical activity was not (β = 0.0007, t = 1.772, P = .08). White matter metrics did not mediate any associations. This suggests that microstructural white matter characteristics alone may not be the mechanism by which physical activity impacts executive function in aging.

Association between white matter organization and cognitive performance in athletes with a history of sport-related concussion

ABSTRACT Introduction Impairments in cognitive performance after sport-related concussion (SRC) typically resolve within weeks of the injury, whereas alterations to white matter (WM) organization have been found to persist longer into the chronic injury stage. However, longer-term associations between cognition and WM organization following SRC have not been studied. The objective of this study was to compare WM organization and cognitive performance in collegiate athletes an average of almost 4 years post-SRC to athletes with no history of SRC. Method National Collegiate Athletic Association Division III athletes (n = 71, age = 19.3 ± 1.2; 14 with self-reported SRC) completed a neurocognitive assessment and diffusion tensor imaging (DTI). WM organization was assessed by extracting measures of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) from 20 WM regions of interest (ROIs). Multivariate partial least squares analyses were used to compare athletes with and without a history of SRC and assess relationships between DTI-derived metrics of WM organization and cognitive measures. Results Cognitive performance and ROI metrics did not differ between athletes with and without prior SRC. However, among athletes with a history of SRC, better executive function, processing speed, and memory but worse choice reaction time were associated with higher FA and lower MD and RD in several WM tracts. Conclusion Athletes with a history of SRC demonstrated greater associations between cognitive performance and WM organization, but also variability in the domains showing associations. Taken together, the findings demonstrate the importance of examining brain-behavior relationships several years after SRC to better gauge how WM organization supports cognition.

Whole brain atlas-based diffusion kurtosis imaging parameters for evaluation of minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) has no recognizable clinical symptoms, but patients have cognitive and psychomotor deficits. Hyperammonemia along with neuroinflammation lead to microstructural changes in cerebral parenchyma. Changes at conventional imaging are detected usually at the overt clinical stage, but microstructural alterations by advanced magnetic resonance imaging techniques can be detected at an early stage. Whole brain diffusion kurtosis imaging (DKI) data acquired at 3T was analyzed to investigate microstructural parenchymal changes in 15 patients with MHE and compared with 15 age- and sex-matched controls. DKI parametric maps, namely kurtosis fractional anisotropy (kFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK), were evaluated at 64 white matter (WM) and gray matter (GM) regions of interest (ROIs) in the whole brain and correlated with the psychometric hepatic encephalopathy score (PHES). The MHE group showed a decrease in kFA and AK across the whole brain, whereas MK and RK decreased in WM ROIs but increased in several cortical and deep GM ROIs. These alterations were consistent with brain regions involved in cognitive function. Significant moderate to strong correlations (-0.52 to -0.66; 0.56) between RK, MK and kFA kurtosis metrics and PHES were observed. DKI parameters show extensive microstructural brain abnormalities in MHE with minor correlation between the severity of tissue damage and psychometric scores.