Reduced White Matter Integrity Research Articles

Frontal white and gray matter abnormality in gambling disorder: A multimodal MRI study.

Changes in brain structural connections appear to be important in the pathophysiology of substance use disorders, but their role in behavioral addictions, such as gambling disorder (GD), is unclear. GD also offers a model to study addiction mechanisms without pharmacological confounding factors. Here, we used multimodal MRI data to examine the integrity of white matter connections in individuals with GD. We hypothesized that the affected areas would be in the fronto-striatal-thalamic circuit. Twenty individuals with GD (mean age: 64 years, GD duration: 15.7 years) and 40 age- and sex-matched healthy controls (HCs) underwent detailed clinical examinations together with brain 3T MRI scans (T1, T2, FLAIR and DWI). White matter (WM) analysis involved fractional anisotropy and lesion load, while gray matter (GM) analysis included voxel- and surface-based morphometry. These measures were compared between groups, and correlations with GD-related behavioral characteristics were examined. Individuals with GD showed reduced WM integrity in the left and right frontal parts of the corona radiata and corpus callosum (pFWE < 0.05). WM gambling symptom severity (SOGS score) was negatively associated to WM integrity in these areas within the left hemisphere (p< 0.05). Individuals with GD also exhibited higher WM lesion load in the left anterior corona radiata (pFWE < 0.05). GM volume in the left thalamus and GM thickness in the left orbitofrontal cortex were reduced in the GD group (pFWE < 0.05). Similar to substance addictions, the fronto-striatal-thalamic circuit is also affected in GD, suggesting that this circuitry may have a crucial role in addictions, independent of pharmacological substances.

A Pilot Study Investigating the Use of Serum Glial Fibrillary Acidic Protein to Monitor Changes in Brain White Matter Integrity After Repetitive Head Hits During a Single Collegiate Football Game.

Repetitive head hits (RHHs) in sports and military settings are increasingly recognized as a risk factor for adverse neurological outcomes, but they are not currently tracked. Blood-based biomarkers of concussion have recently been shown to increase after nonconcussive RHHs during a single sporting contest, raising the possibility that they could be used in real time to monitor the brain's early response to repeated asymptomatic head hits. To test this hypothesis, we measured GFAP in serum immediately before (T0), immediately after (T1) and 45 min (T2) after a single collegiate football game in 30 athletes. Glial fibrillary acidic protein (GFAP) changes were correlated with three measures of head impact exposure (number of hits, total linear acceleration, and total rotational acceleration captured by helmet impact sensors) and to changes in brain white matter (WM) integrity, estimated by regional changes in fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging from 24 h before (T1) to 48 h after (T3) the game. To account for the potentially confounding effects of physical exertion on GFAP, correlations were adjusted for kilocalories of energy expended during the game measured by wearable body sensors. All 30 participants were male with a mean age of 19.5 ± 1.2 years. No participant had a concussion during the index game. We observed a significant increase in GFAP from T0 to T1 (mean 79.69 vs. 91.95 pg/mL, p = 0.008) and from T0 to T2 (mean 79.69 vs. 99.21 pg/mL, p < 0.001). WM integrity decreased in multiple WM regions but was statistically significant in the right fornix (mean % FA change -1.43, 95% confidence interval [CI]: -2.20, -0.66). T0 to T2 increases in GFAP correlated with reduced FA in the left fornix, right fornix, and right medical meniscus and with increased MD in the right fornix (r-values ranged from 0.59 to 0.61). Adjustment for exertion had minimal effect on these correlations. GFAP changes did not correlate to head hit exposure, but after adjustment for exertion, T0 to T2 increases correlated with all three hit metrics (r-values ranged from 0.69 to 0.74). Thus, acute elevations in GFAP after a single collegiate football game of RHHs correlated with in-game head hit exposure and with reduced WM integrity 2 days later. These results suggest that GFAP may be a biologically relevant indicator of the brain's early response to RHHs during a single sporting event. Developing tools to measure the neurological response to RHHs on an individual level has the potential to provide insight into the heterogeneity in adverse outcomes after RHH exposure and for developing effective and personalized countermeasures. Owing to the small sample size, these findings should be considered preliminary; validation in a larger, independent cohort is necessary.

Androgen Deprivation Therapy for Prostate Cancer: Focus on Cognitive Function and Mood.

Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.

Effect of the duration of hypertension on white matter structure and its link with cognition

The relation between hypertension (HTN) and cognition has been reported inclusive results, which may be affected by disease duration. Our study aimed to examine the influence of HTN duration on cognition and its underlying white matter (WM) changes including macrostructural WM hyperintensities (WMH) and microstructural WM integrity. A total of 1218 patients aged ≥55 years with neuropsychological assessment and a subgroup of 233 people with imaging data were recruited and divided into 3 groups (short duration: <5 years, medium duration: 5–20 years, long duration: >20 years). We found that greater HTN duration was preferentially related to worse executive function (EF), processing speed (PS), and more severe WMH, which became more significant during long duration stage. The reductions in WM integrity were evident at the early stage especially in long-range association fibers and then scattered through the whole brain. Increasing WMH and decreasing integrity of specific tracts consistently undermined EF. Furthermore, free water imaging method greatly enhanced the sensitivity in detecting HTN-related WM alterations. These findings supported that the neurological damaging effects of HTN is cumulative and neuroimaging markers of WM at macro- and microstructural level underlie the progressive effect of HTN on cognition.

Sleep disorders and white matter integrity in patients with sporadic amyotrophic lateral sclerosis

This study aimed to explore the characteristics of sleep disorders and their relationship with abnormal white-matter integrity in patients with sporadic amyotrophic lateral sclerosis. One hundred and thirty-six patients and 80 healthy controls were screened consecutively, and 56 patients and 43 healthy controls were ultimately analyzed. Sleep disorders were confirmed using the Pittsburgh sleep quality index, the Epworth sleepiness scale, and polysomnography; patients were classified into those with poor and good sleep quality. White-matter integrity was assessed using diffusion tensor imaging and compared between groups to identify the white-matter tracts associated with sleep disorders. The relationship between scores on the Pittsburgh sleep quality index and impaired white-matter tracts was analyzed using multiple regression. Poor sleep quality was more common in patients (adjusted odds ratio, 4.26; p = 0.005). Compared to patients with good sleep quality (n = 30), patients with poor sleep quality (n = 26; 46.4%) showed decreased fractional anisotropy, increased mean diffusivity, and increased radial diffusivity of projection and commissural fibers, and increased radial diffusivity of the right thalamus. The Pittsburgh score showed the best fit with the mean fractional anisotropy of the right anterior limb of the internal capsule (r = - 0.355, p = 0.011) and the mean radial diffusivity of the right thalamus (r = 0.309, p = 0.028). We conclude that sleep disorders are common in patients with sporadic amyotrophic lateral sclerosis and are associated with reduced white-matter integrity. The pathophysiology of amyotrophic lateral sclerosis may contribute directly to sleep disorders.

White matter microstructural abnormalities in individuals with attenuated positive symptom syndromes

White matter (WM) microstructural alterations have been extensively studied in patients with psychosis, but research on the microstructure of WM in individuals with attenuated positive symptom syndrome (APSS) is currently limited. To improve the understanding of the neuropathology in APSS, this study investigated the WM of individuals with APSS using diffusion tensor and T1-weighted imaging. Automated fiber quantification was used to calculate the diffusion index values along the trajectories of 20 major fiber tracts in 42 individuals with APSS and 51 age-and sex-matched healthy control (HC) individuals. The diffusion index values in each of fiber tracts were compared node-by-node between the 2 groups. Compared with the HC group, the APSS group showed differences in the diffusion index values in partial segments of the callosum forceps minor, left and right cingulum cingulate, inferior fronto-occipital fasciculus, right corticospinal tract, left superior longitudinal fasciculus, and arcuate fasciculus. Notably, in the APSS group positive associations were found between the axial diffusivity values of the partial nodes of the left and right cingulum cingulate and the current Global Assessment of Functioning scores, as well as between the axial diffusivity values of the partial nodes of the right corticospinal tract and negative symptoms scores and reasoning and problem-solving scores. These findings suggest that individuals with APSS exhibit reduced WM integrity or possible impaired myelin in certain segments of WM tracts involved in the frontal- and limbic-cortical connections. Additionally, abnormal WM tracts appear to be associated with impaired general function and neurocognitive function. This study provides important new insights into the neurobiology of APSS and highlights potential targets for future intervention and treatment.

Assessing the structure of the posterior visual pathway in bilateral macular degeneration

Macular degeneration (MD) embodies a collection of disorders causing a progressive loss of central vision. Cross-sectional MRI studies have revealed structural changes in the grey and white matter in the posterior visual pathway in MD but there remains a need to understand how such changes progress over time. To that end we assessed the posterior pathway, characterising the visual cortex and optic radiations over a ~ 2-year period in MD patients and controls. We performed cross-sectional and longitudinal analysis of the former. Reduced cortical thickness and white matter integrity were observed in patients compared to controls, replicating previous findings. While faster, neither the rate of thinning in visual cortex nor the reduction in white matter integrity during the ~ 2-year period reached significance. We also measured cortical myelin density; cross-sectional data showed this was higher in patients than controls, likely as a result of greater thinning of non-myelinated tissue in patients. However, we also found evidence of a greater rate of loss of myelin density in the occipital pole in the patient group indicating that the posterior visual pathway is at risk in established MD. Taken together, our results revealed a broad decline in grey and white matter in the posterior visual pathway in bilateral MD; cortical thickness and fractional anisotropy show hints of an accelerated rate of loss also, with larger effects emerging in the occipital pole.

Alterations in white matter integrity and network topological properties are associated with a decrease in global motion perception in older adults.

Previous studies have mainly explored the effects of structural and functional aging of cortical regions on global motion sensitivity in older adults, but none have explored the structural white matter (WM) substrates underlying the age-related decrease in global motion perception (GMP). In this study, random dot kinematogram and diffusion tensor imaging were used to investigate the effects of age-related reductions in WM fiber integrity and connectivity across various regions on GMP. We recruited 106 younger adults and 94 older adults and utilized both tract-based spatial statistics analysis and graph theoretical analysis to comprehensively investigate group differences in WM microstructural and network connections between older and younger adults at the microscopic and macroscopic levels. Moreover, partial correlation analysis was used to explore the relationship between alterations in WM and the age-related decrease in GMP. The results showed that decreased GMP in older adults was related to decreased fractional anisotropy (FA) of the inferior frontal-occipital fasciculus, inferior longitudinal fasciculus, anterior thalamic radiation, superior longitudinal fasciculus, and cingulum cingulate gyrus. Decreased global efficiency of the WM structural network and increased characteristic path length were closely associated with decreased global motion sensitivity. These results suggest that the reduced GMP in older adults may stem from reduced WM integrity in specific regions of WM fiber tracts as well as decreased efficiency of information integration and communication between distant cortical regions, supporting the "disconnection hypothesis" of cognitive aging.

Cognitive intraindividual variability as a potential biomarker for early detection of cognitive and functional decline.

Intraindividual variability (IIV) in cognitive performance has been associated with cognitive decline and reductions in white matter integrity, but the predictive utility of IIV-between versus IIV-within domains is unknown. The present study aimed to determine if IIV-within a "frontal-subcortical" domain may be a more robust predictor of changes in general cognitive status and functional independence over time than IIV-between cognitive domains. Mixed linear modeling was used to analyze the relationship between cognitive IIV and cognitive and functional status in 651 controls, 211 people with mild cognitive impairment, and 218 people with Alzheimer's disease over a 5-year period. Both IIV-between and IIV-within a frontal-subcortical domain improved prediction of cognitive and functional declines beyond demographic characteristics, genetic risk, and vascular integrity. IIV-between showed the greatest effect over time and was driven primarily by increases in IIV-within. Cognitive IIV, especially between cognitive domains, may be useful for identifying individuals at risk for cognitive and functional decline. Findings may facilitate investigations into mechanisms underlying declines in global cerebral integrity and aid clinical trials aimed at early detection and treatment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neurobiological mechanisms of psychosis in epilepsy: Findings from neuroimaging studies.

Despite the high prevalence and clinical importance of comorbid psychosis in epilepsy, its neurobiological mechanisms remain understudied. This narrative mini-review aims to provide an overview of recent updates in in vivo neuroimaging studies on psychosis in epilepsy, including structural and diffusion magnetic resonance imaging (MRI) and functional and molecular imaging, and to discuss future directions in this field. While the conventional morphological analysis of structural MRI has provided relatively inconsistent results, advanced methods, including brain network analysis, hippocampal subregion volumetry, and machine learning models, have recently provided novel findings. Diffusion MRI, for example, has revealed a reduction in white matter integrity mainly in the frontal and temporal lobes, as well as a disruption of brain white matter networks. Functional neuroimaging, such as perfusion single-photon emission computed tomography (SPECT) or fluorodeoxyglucose positron emission tomography (FDG-PET), often identifies hyperactivity in various brain regions. The current limitations of these more recent studies may include small and sometimes heterogeneous samples, insufficient control groups, the effects of psychoactive drugs, and the lack of longitudinal analysis. Further investigations are required to establish novel treatments and identify clinical diagnostic or disease-monitoring biomarkers in psychosis in epilepsy.

Trait-like white matter abnormalities in current and remitted depression

Microstructural alterations to white matter (WM) have been implicated in the onset and recurrence of major depressive disorder (MDD). The present study aimed to identify trait-like WM abnormality in current and remitted depression, as well as changes to WM that could be specifically related to the state of clinical remission. Diffusion tensor imaging data were collected from 60 patients with medication-naive first episode current depression (cMDD), 41 patients with medication-naive remitted depression (rMDD), and 62 demographically-matched healthy control participants (HCs). Tract-based spatial statistics (TBSS) applied to the whole brain were used to detect microstructural differences of WM among the three groups. TBSS analyses showed that, compared with HCs, both the cMDD and rMDD groups exhibited significantly reduced FA values in the genus and body of the corpus callosum, and superior and anterior corona radiata, with no significant differences between the cMDD and rMDD groups. FA values in the corpus callosum were negatively correlated with the duration of illness in the rMDD group. Reduced WM integrity in the corpus callosum and corona radiata might reflect the trait markers of MDD, and could constitute a neuroanatomical marker of MDD.

The Structural and Functional Correlates of Frailty in Persons With Human Immunodeficiency Virus.

Persons with HIV (PWH) are at increased risk of frailty, a clinically recognizable state of increased vulnerability resulting from aging-associated decline in multiple physiologic systems. Frailty is often defined by the Fried criteria, which includes subjective and objective standards concerning health resiliency. However, these frailty metrics do not incorporate cognitive performance or neuroimaging measures. We compared structural (diffusion tensor imaging [DTI]) and functional (cerebral blood flow [CBF]) neuroimaging markers in PWH with frailty and cognitive performance. Virologically controlled PWH were dichotomized as either frail (≥3) or nonfrail (<3) using the Fried criteria. Cognitive Z-scores, both domain (executive, psychomotor speed, language, and memory) and global, were derived from a battery of tests. We identified three regions of reduced CBF, based on a voxel-wise comparison of frail PWH compared with nonfrail PWH. These clusters (bilateral frontal and posterior cingulate) were subsequently used as seed regions of interest (ROIs) for DTI probabilistic white matter tractography. White matter integrity connecting the ROIs was significantly decreased in frail compared with nonfrail PWH. No differences in cognition were observed between frail and nonfrail PWH. However, reductions in white matter integrity among these ROIs was significantly associated with worse psychomotor speed and executive function across the entire cohort. We conclude that frailty in PWH can lead to structural and functional brain changes, including subtle changes that are not detectable by standard neuropsychological tests. Multimodal neuroimaging in conjunction with frailty assessment could identify pathological brain changes observed in PWH.

Four-modality imaging of unmedicated subjects with schizophrenia: 18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, and MRI

Diminished prefrontal function, dopaminergic abnormalities in the striatum and thalamus, reductions in white matter integrity and frontotemporal gray matter deficits are the most replicated findings in schizophrenia. We used four imaging modalities (18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, structural MRI) in 19 healthy and 25 schizophrenia subjects to assess the relationship between functional (dopamine D2/D3 receptor binding potential, glucose metabolic rate) and structural (fractional anisotropy, MRI) correlates of schizophrenia and their additive diagnostic prediction potential. Multivariate ANOVA was used to compare structural and functional image sets for identification of schizophrenia. Integration of data from all four modalities yielded better predictive power than less inclusive combinations, specifically in the thalamus, left dorsolateral prefrontal and temporal regions. Among the modalities, fractional anisotropy showed highest discrimination in white matter whereas 18F-fallypride binding showed highest discrimination in gray matter. Structural and functional modalities displayed comparable discriminative power but different topography, with higher sensitivity of structural modalities in the left prefrontal region. Combination of functional and structural imaging modalities with inclusion of both gray and white matter appears most effective in diagnostic discrimination. The highest sensitivity of 18F-fallypride PET to gray matter changes in schizophrenia supports the primacy of dopaminergic abnormalities in its pathophysiology.

Microstructural white matter abnormalities in Lesch-Nyhan disease.

Lesch-Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch-Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch-Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch-Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch-Nyhan disease (n = 5), Lesch-Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch-Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch-Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch-Nyhan disease.

Cognitive intraindividual variability as a biomarker for functional declines in the Texas Alzheimer’s Research and Care Consortium (TARCC) Longitudinal Hispanic Cohort

AbstractBackgroundWhile intraindividual variability (IIV) in cognitive performance has been associated with increased risk for cognitive decline, the relative predictive utility of IIV‐across versus IIV‐within different cognitive domains remains unknown. Given that cognitive IIV has also been linked to age‐related reductions in white matter integrity, the current study aimed to determine if IIV‐within a “frontal‐subcortical” domain may be a more robust predictor of functional declines over time than IIV‐across cognitive domains.MethodsParticipants included 651 controls, 211 MCI and 218 AD patients enrolled in the TARCC Hispanic Longitudinal Cohort. Mixed Linear Modeling was used to examine the fixed effects of static predictors (i.e., age, education, gender, ethnicity, APOE genotype, cognitive status) at baseline, and the fixed and random effects of time‐varying covariates (i.e., depression, pulse pressure, IIV‐across domains, and IIV‐within the frontal‐subcortical domain) on changes in functional independence over 5 years.ResultsAge, education and ethnicity moderated the relationship between APOE genotype, baseline cognitive status and declines in functional independence over time. Overall, greater pulse pressure, IIV‐across domains and IIV‐within the frontal‐subcortical domain were all associated with larger decrements in functional independence over time. Although increases in IIV‐across domains were primarily driven by increases in IIV‐within the frontal‐subcortical domain over time, the former emerged as a stronger predictor of functional independence than the latter. Gender and education significantly influenced individual differences in rates of change over time, while the effects of IIV‐across domains and IIV‐within the frontal‐subcortical domain on functional declines differed from person‐to‐person. The addition of cognitive IIV predictors significantly improved model fit with a 1498.3 reduction in ‐2LL (p &lt; 0.001). The final model accounted for 97.8% of the variance in functional independence over time.ConclusionsResults suggest that IIV‐across domains may be a robust biomarker of subsequent declines in functional independence and changes in this metric are primarily driven by increasing variability across tasks dependent on frontal‐subcortical circuitry. Findings also highlight important considerations for the development of future clinical trials aimed at early prevention and treatment, including the significance of demographic and clinical characteristics in moderating the risk of decline in functional independence over time.

Differences in white matter integrity and hippocampal volumetrics across APOE genotype mice: A blinded preliminary study

AbstractBackgroundGenome‐wide association studies have identified Apolipoprotein (APOE) as one of the strongest risk factors associated with Late‐Onset Alzheimer’s disease (LOAD) with females exhibiting a two‐fold higher incidence as compared to males. MRI studies of patients with LOAD link APOE‐e4 gene load with increased hippocampal volume loss as well as reduction in white matter integrity (WMI) in the limbic and medial temporal regions (Bagepally, 2012). However, there are few translational LOAD mouse model studies utilizing imaging. We hypothesized that hippocampal volume and WMI would be reduced in females and APOE e4 carriers in our humanized APOE (hAPOE) LOAD mouse model.MethodSix cohorts of APOE e3 and e4 genotype (M/F; N=53; mean age = 17.95 month) skull‐extracted ex‐vivo mouse brains were imaged (7T Bruker Biospec MRI scanner). Imaging included structural and diffusion weighted imaging. Bilateral hippocampal volumes, as well as total brain volume (TBV), were extracted using a well‐validated mouse brain atlas (Dorr, 2008). Fractional anisotropy (FA) was used to quantify WMI and between‐group comparisons were made using a groupwise connectometry approach (Yeh, 2013; Yeh, 2016).ResultMRI image analysis indicated genotypic differences in white matter FA where APOE‐e4 carriers exhibited lower FA values (mean tractography FA = 0.263 ± 0.043) compared to APOE‐e3/3 (mean tractography FA = 0.311 ± 0.067) in a total of 10657 tracts (FDR corrected p &lt; 0.003; Figure 1). No statistically significant differences were identified across genotypes for left or right hippocampal volumes. However, right hippocampal volume was significantly greater in males as compared to females (p = 0.007) whereas no effect was observed between sexes for left hippocampus.ConclusionOutcomes of MRI analyses indicate a significant reduction in FA values and reduced white matter integrity across the brain in APOE e4 carriers, irrespective of sex. Contrary to human literature, no significant volumetric differences between genotypes were found in this mouse sample. Consistent with sex‐dependent literature, males exhibited greater total brain volume and additionally greater right hippocampal volume compared to females, irrespective of genotype. These findings may provide evidence of deficits in cholesterol or lipid transport manifest in decreased white matter integrity in this hAPOE mouse model.

White Matter Integrity and Nicotine Dependence: Evaluating Vertical and Horizontal Pleiotropy.

Tobacco smoking is an addictive behavior that supports nicotine dependence and is an independent risk factor for cancer and other illnesses. Its neurogenetic mechanisms are not fully understood but may act through alterations in the cerebral white matter (WM). We hypothesized that the vertical pleiotropic pathways, where genetic variants influence a trait that in turn influences another trait, link genetic factors, integrity of cerebral WM, and nicotine addiction. We tested this hypothesis using individual genetic factors, WM integrity measured by fractional anisotropy (FA), and nicotine dependence-related smoking phenotypes, including smoking status (SS) and cigarettes per day (CPDs), in a large epidemiological sample collected by the UK Biobank. We performed a genome-wide association study (GWAS) to identify previously reported loci associated with smoking behavior. Smoking was found to be associated with reduced WM integrity in multiple brain regions. We then evaluated two competing vertical pathways: Genes → WM integrity → Smoking versus Genes → Smoking → WM integrity and a horizontal pleiotropy pathway where genetic factors independently affect both smoking and WM integrity. The causal pathway analysis identified 272 pleiotropic single-nucleotide polymorphisms (SNPs) whose effects on SS were mediated by FA, as well as 22 pleiotropic SNPs whose effects on FA were mediated by CPD. These SNPs were mainly located in important susceptibility genes for smoking-induced diseases NCAM1 and IREB2. Our findings revealed the role of cerebral WM in the maintenance of the complex addiction and provided potential genetic targets for future research in examining how changes in WM integrity contribute to the nicotine effects on the brain.

Splenial white matter integrity is associated with memory impairments in posterior cortical atrophy.

Posterior cortical atrophy is an atypical form of Alzheimer’s disease characterized by visuospatial impairments and predominant tissue loss in the posterior parieto-occipital and temporo-occipital cortex. Whilst episodic memory is traditionally thought to be relatively preserved in posterior cortical atrophy, recent work indicates that memory impairments form a common clinical symptom in the early stages of the disease. Neuroimaging studies suggest that memory dysfunction in posterior cortical atrophy may originate from atrophy and functional hypoconnectivity of parietal cortex. The structural connectivity patterns underpinning these memory impairments, however, have not been investigated. This line of inquiry is of particular interest, as changes in white matter tracts of posterior cortical atrophy patients have been shown to be more extensive than expected based on posterior atrophy of grey matter. In this cross-sectional diffusion tensor imaging MRI study, we examine the relationship between white matter microstructure and verbal episodic memory in posterior cortical atrophy. We assessed episodic memory performance in a group of posterior cortical atrophy patients (n = 14) and a group of matched healthy control participants (n = 19) using the Free and Cued Selective Reminding Test with Immediate Recall. Diffusion tensor imaging measures were obtained for 13 of the posterior cortical atrophy patients and a second control group of 18 healthy adults. Patients and healthy controls demonstrated similar memory encoding performance, indicating that learning of verbal information was preserved in posterior cortical atrophy. However, retrieval of verbal items was significantly impaired in the patient group compared with control participants. As expected, tract-based spatial statistics analyses showed widespread reductions of white matter integrity in posterior cortical regions of patients compared with healthy adults. Correlation analyses indicated that poor verbal retrieval in the patient group was specifically associated with microstructural damage of the splenium of the corpus callosum. Post-hoc tractography analyses in healthy controls demonstrated that this splenial region was connected to thalamic radiations and the retrolenticular part of the internal capsule. These results provide insight into the brain circuits that underlie memory impairments in posterior cortical atrophy. From a cognitive perspective, we propose that the association between splenial integrity and memory dysfunction could arise indirectly via disruption of attentional processes. We discuss implications for the clinical phenotype and development of therapeutic aids for cognitive impairment in posterior cortical atrophy.

Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making.

Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.

White Matter Matters: Unraveling Violence in Psychosis and Psychopathy

Abstract Individuals with psychotic disorders have an increased risk of committing acts of violence. Neurobiological support for the extent to which violence in psychosis is driven by psychotic symptoms and/or antisocial traits could have clinical and legal implications. Neuroimaging studies have reported white matter (WM) abnormalities in individuals with psychosis and in those with antisocial traits. However, it is unknown whether WM abnormalities in psychosis patients with a history of violence (violent-PSY) resemble those found in nonviolent psychosis patients (nonviolent PSY), violent nonpsychotic individuals (violent non-PSY), or both. Diffusion tensor imaging scans from 301 males including violent-PSY (n = 28), violent non-PSY (n = 20), nonviolent PSY (n = 58), and healthy controls (HC, n = 195) were analyzed with tract-based spatial statistics. Fractional anisotropy (FA), mean, axial and radial (RD) diffusivity were compared between groups. Psychopathic traits in the violent groups were measured with Psychopathy Checklist-revisited (PCL-R). Violent-PSY had globally lower FA and higher RD, compared with nonviolent PSY. Both psychosis groups and violent non-PSY group had widespread disruptions in WM compared with HC. There were no significant WM differences between violent-PSY and violent non-PSY. PCL-R scores did not differ between the violence groups and were associated with higher RD in corpus callosum. Here we demonstrate a widespread pattern of reduced WM integrity in violent-PSY compared with nonviolent PSY. The lack of significant WM and PCL-R differences between the violence groups, together with the positive association between PCL-R and WM deficits in violent-PSY and violent non-PSY may indicate shared neurobiological underpinnings of trait violence.