Frontal White Matter Changes Research Articles

Frontal White Matter Changes and Craving Recovery in Inpatients With Heroin Use Disorder.

Amidst an unprecedented opioid epidemic, identifying neurobiological correlates of change with medication-assisted treatment of heroin use disorder is imperative. White matter impairments in individuals with heroin use disorder (HUD) have been associated with drug craving, a reliable predictor of treatment outcomes; however, little is known about structural connectivity changes with inpatient treatment and abstinence in individuals with HUD. To assess white matter microstructure and associations with drug craving changes with inpatient treatment in individuals with HUD (effects of time and rescan compared with controls). This cohort study conducted from December 2020 to September 2022 included individuals recruited from urban inpatient treatment facilities treating HUD and surrounding communities in New York City. Participants with HUD were receiving medication-assisted treatment. Data were analyzed from October 2022 to March 2023. Between scans, inpatient individuals with HUD continued treatment and related clinical interventions. Control participants were scanned at similar time intervals. Changes in white matter diffusion metrics (fractional anisotropy and mean, axial, and radial diffusivities) assessed voxelwise with general linear models in addition to baseline and cue-induced drug craving, and other clinical outcome variables (mood, sleep, affect, perceived stress, and therapy attendance). Thirty-four individuals with HUD (mean [SD] age, 40.5 [11.0] years; 9 women [36%]; 3 Black [9%], 17 White [50%], 14 other race or ethnicity [41%]) and 25 control (mean [SD] age, 42.1 [9.0]; 7 women [21%]; 8 Black [32%], 10 White [40%], 7 other race or ethnicity [28%]) were included. Main voxelwise findings showed HUD-specific white matter microstructure changes (1 - P > .949), including increased fractional anisotropy and decreased mean and radial diffusivities, encompassing mostly frontal major callosal, projection, and association tracts. The increased fractional anisotropy (r = -0.72, P < .001, slope SE = 9.0 × 10-4) and decreased mean diffusivity (r = 0.69, P < .001, slope SE = 1.25 × 10-6) and/or radial diffusivity (r = 0.67, P < .001, slope SE = 1.16 × 10-6) in the genu and body of the corpus callosum and left anterior corona radiata in individuals with HUD correlated with a reduction in baseline craving (voxelwise 1 - P > .949). No other white matter correlations with outcome variables reached significance. This cohort study of inpatients with HUD on medication-assisted treatment found whole-brain normalization of structural connectivity in frontal white matter pathways implicated in emotional regulation and top-down executive control. Observed associations with decreases in baseline craving further support the possibility of recovery, highlighting the relevance of these white matter markers to a major symptom of addiction, with implications for clinical outcome monitoring.

FRONTAL WHITE MATTER CHANGES INDICATE RECOVERY WITH INPATIENT TREATMENT IN HEROIN ADDICTION.

Amidst an unprecedented opioid epidemic, identifying neurobiological correlates of change with medication-assisted treatment of heroin use disorder is imperative. Distributed white matter (WM) impairments in individuals with heroin use disorder (iHUD) have been associated with increased drug craving, a reliable predictor of treatment outcomes. However, little is known about the extent of whole-brain structural connectivity changes with inpatient treatment and abstinence in iHUD. To assess WM microstructure and associations with drug craving changes with inpatient treatment in iHUD (effects of time/re-scan compared to controls; CTL). Longitudinal cohort study (12/2020-09/2022) where iHUD and CTL underwent baseline magnetic resonance imaging (MRI#1) and follow-up (MRI#2) scans, (mean interval of 13.9 weeks in all participants combined). The iHUD and CTL were recruited from urban inpatient treatment facilities and surrounding communities, respectively. Thirty-four iHUD (42.1yo; 7 women), 25 age-/sex-matched CTL (40.5yo; 9 women). Between scans, inpatient iHUD continued their medically-assisted treatment and related clinical interventions. CTL participants were scanned at similar time intervals. Changes in white matter diffusion metrics [fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivities (RD)] in addition to baseline and cue-induced drug craving, and other clinical outcome variables (mood, sleep, affect, perceived stress, and therapy attendance). Main findings showed HUD-specific WM microstructure changes encompassing mostly frontal major callosal, projection, and association tracts, characterized by increased FA (.949<1-p<.986) and decreased MD (.949<1-p<.997) and RD (.949<1-p<.999). The increased FA (r=-0.72, p<.00001) and decreased MD (r=0.69, p<.00001) and RD (r=0.67, p<.0001) in the genu and body of the corpus callosum and the left anterior corona radiata in iHUD were correlated with a reduction in baseline craving (.949<1-p<.999). No other WM correlations with outcome variables reached significance. Our findings suggest whole-brain normalization of structural connectivity with inpatient medically-assisted treatment in iHUD encompassing recovery in frontal WM pathways implicated in emotional regulation and top-down executive control. The association with decreases in baseline craving further supports the relevance of these WM markers to a major symptom in drug addiction, with implications for monitoring clinical outcomes.

Exploring the relationship between white matter integrity, cocaine use and GAD polymorphisms using Bayesian Model Averaging.

Past investigations utilizing diffusion tensor imaging (DTI) have demonstrated that cocaine use disorder (CUD) yields white matter changes, primarily in the corpus callosum. By applying Bayesian model averaging using multiple linear regression in DTI, we demonstrate there may exist relationships between the impaired white matter and glutamic acid decarboxylase (GAD) polymorphisms. This work explored the two-way and three-way interactions between GAD1a (SNP: rs1978340) and GAD1b (SNP: rs769390) polymorphisms and years of cocaine use (YCU). GAD1a was associated with more frontal white matter changes on its own but GAD1b was associated with more midbrain and cerebellar changes as well as a greater increase in white matter changes in the context of chronic cocaine use. The three-way interaction GAD1a|GAD1b|YCU appeared to be roughly an average of the polymorphism two-way interactions GAD1a|YCU and GAD1b|YCU. The three-way interaction demonstrated multiple regions including corpus callosum which featured fewer significant voxel changes, perhaps suggesting a small protective effect of having both polymorphisms on corpus callosum and cerebellar peduncle.

A Cluster of Cyclic Esotropia: White Matter Changes on MRI and Surgical Outcomes.

To report a series of patients with cyclic esotropia, their surgical outcomes, and incidental findings. The medical records of five patients with cyclic esotropia presenting over 17 months were reviewed. Age at onset, ocular and motility examinations, brain magnetic resonance imaging (MRI), acetylcholine receptor antibodies, thyroid hormone levels and antibodies, calendars documenting phases, surgical treatments, postoperative alignment, and fusion were documented. Three boys and two girls presented at 3 to 4 years old in 2015-2016. Typical periodicity followed a 48-hour cycle. Duration of cycling varied from 1 to 9 weeks. Mean maximum deviation was 37 prism diopters (PD) of esotropia (range: 35 to 40 PD of esotropia). All patients had normal laboratory studies. MRIs showed an abnormal white matter signal in the frontal lobes in 2 patients and were normal in the others. Bilateral medial rectus recessions for the maximum angle were successful in 4 patients at a minimum follow-up of 13 months; the other patient required reoperation for a residual esotropia. Fusion was present in 4 patients preoperatively and all postoperatively. Stereopsis was stable or improved in all postoperatively. This is the first report of frontal white matter changes occurring in the setting of cyclic esotropia. MRI with attention to frontal lobe white matter might be considered in the work-up of cyclic esotropia to determine if this is a common finding. Bilateral medial rectus recessions can restore fusion in these patients. [J Pediatr Ophthalmol Strabismus. 2019;56(3):178-182.].

Brain MRI morphometric analysis in Parkinson\u2019s disease patients with sleep disturbances

BackgroundSleep disturbances are common in patients with advanced Parkinson disease (PD). The aim of this study was to evaluate a possible association of cortical thickness, cortical and subcortical volume with sleep disturbances in PD patients.MethodsTwenty-eight PD patients (14 men and 14 women, median age 58 years) were evaluated for sleep disturbances with PDSS and underwent brain MRI. Control group consisted of 28 healthy volunteers who were matched by age and gender. Automated voxel based image analysis was performed with the FreeSurfer software.ResultsPD patients when compared to controls had larger ventricles, smaller volumes of hippocampus and superior cerebellar peduncle, smaller grey matter thickness in the left fusiform, parahipocampal and precentral gyruses, and right caudal anterior cingulate, parahipocampal and precentral hemisphere gyruses, as well as smaller volume of left rostral middle frontal and frontal pole areas, and right entorhinal and transverse temporal areas. According to the Parkinson’s disease Sleep Scale (PDSS), 15 (53.58%) patients had severely disturbed sleep. The most frequent complaints were difficulties staying asleep during the night and nocturia. The least frequent sleep disturbances were distressing hallucinations and urine incontinence due to off symptoms. Patients who fidgeted during the night had thicker white matter in the left caudal middle frontal area and lesser global left hemisphere cortical surface, especially in the lateral orbitofrontal and lateral occipital area, and right hemisphere medial orbitofrontal area. Patients with frequent distressful dreams had white matter reduction in cingulate area, and cortical surface reduction in left paracentral area, inferior frontal gyrus and right postcentral and superior frontal areas. Nocturnal hallucinations were associated with volume reduction in the basal ganglia, nucleus accumbens and putamen bilaterally. Patients with disturbing nocturia had reduction of cortical surface on the left pre- and postcentral areas, total white matter volume decrease bilaterally as well in the pons.ConclusionsPD patients with nocturnal hallucinations had prominent basal ganglia volume reduction. Distressful dreams were associated with limbic system and frontal white matter changes, meanwhile nocturia was mostly associated with global white matter reduction and surface reduction of cortical surface on the left hemisphere pre- and postcentral areas.

Noncognitive Behavioral Changes Associated With Alzheimer's Disease: Implications of Neuroimaging Findings.

Alzheimer's disease (AD) is commonly associated with noncognitive behavioral changes (NCBCs). The authors systematically reviewed whether neuroimaging has helped with understanding the pathophysiology, diagnosis, or management of NCBCs associated with AD, including depression, aggression or agitation, anxiety, apathy, psychosis, and sleep disorder. The authors identified dissociable neural substrates with multimodal imaging: depression implicates the lateral and superior prefrontal cortex; apathy and agitation implicate the dorsal anterior cingulate; psychosis implicates right lateralized frontal and medial temporal areas; and anxiety implicates mesial temporal regions. Frontal white matter changes appear to underlie many NCBCs, emphasizing the preventative management of vascular risk factors. Further delineation of underlying neurocircuitry and pathophysiology in larger data sets might lead to biomarker identification for diagnosis and optimizing treatment targets.

Frontal white matter changes and aggression in methamphetamine dependence.

Chronic methamphetamine (MA) use can lead to white matter (WM) changes and increased levels of aggression. While previous studies have examined WM abnormalities relating to cognitive impairment, associations between WM integrity and aggression in MA dependence remain unclear. Diffusion Tensor Imaging (DTI) was used to investigate WM changes in 40 individuals with MA dependence and 40 matched healthy controls. A region of interest (ROI) approach using tract based spatial statistics (TBSS) in FSL was performed. We compared fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (λ║) and perpendicular diffusivity (λ┴) in WM tracts of the frontal brain. A relationship of WM with aggression scores from the Buss & Perry Questionnaire was investigated. Mean scores for anger (p < 0.001), physical aggression (p = 0.032) and total aggression (p = 0.021) were significantly higher in the MA group relative to controls. ROI analysis showed increased MD (U = 439.5, p = 0.001) and λ┴ (U = 561.5, p = 0.021) values in the genu of the corpus callosum, and increased MD (U = 541.5, p = 0.012) values in the right cingulum in MA dependence. None of the WM changes were significantly associated with aggression scores. This study provides evidence of frontal WM changes and increased levels of aggression in individuals with MA dependence. The lack of significant associations between WM and aggressive behaviour may reflect methodological issues in measuring such behaviour, or may indicate that the neurobiology of aggression is not simply correlated with WM damage but is more complex.

Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia.

White matter hyperintensities as seen on brain T2-weighted magnetic resonance imaging are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the white matter accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of white matter hyperintensities, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal white matter hyperintensities volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the white matter that would distinguish post-stroke demented from post-stroke non-demented subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP+ astrocytes, clasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ALDH1L1) showed cytoplasmic disintegration of the astrocytes. Total GFAP+ cells in both the frontal and temporal white matter were not greater in post-stroke demented versus post-stroke non-demented subjects. However, the percentage of clasmatodendrocytes was increased by >2-fold in subjects with post-stroke demented compared to post-stroke non-demented subjects (P = 0.026) and by 11-fold in older controls versus young controls (P < 0.023) in the frontal white matter. High ratios of clasmotodendrocytes to total astrocytes in the frontal white matter were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in post-stroke demented subjects. Double immunofluorescent staining showed aberrant co-localization of aquaporin 4 (AQP4) in retracted GFAP+ astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood-brain barrier damage, we assessed the co-localization of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of three major vessels supplying blood to the brain. Analysis of the frontal white matter in perfused brains from the animals surviving 1-28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP+ astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the blood-brain barrier in the frontal white matter and cognitive impairment in elderly post-stroke survivors. We propose that clasmatodendrosis is another pathological substrate, linked to white matter hyperintensities and frontal white matter changes, which may contribute to post-stroke or small vessel disease dementia.

Basal forebrain integrity and cognitive memory profile in healthy aging

Age-related dysfunctions in cholinergic and dopaminergic neuromodulation are assumed to contribute to age-associated impairment of explicit memory. Both neurotransmitters also modulate attention, working memory, and processing speed. To date, in vivo evidence linking structural age-related changes in these neuromodulatory systems to dysfunction within or across these cognitive domains remains scarce. Using a factor analytical approach in a cross-sectional study including 86 healthy older (aged 55 to 83 years) and 24 young (aged 18 to 30 years) adults, we assessed the relationship between structural integrity—as measured by magnetization transfer ratio (MTR)—of the substantia nigra/ventral tegmental area (SN/VTA), main origin of dopaminergic projections, basal forebrain (major origin of cortical cholinergic projections), frontal white matter (FWM), and hippocampus to neuropsychological and psychosocial scores. Basal forebrain MTR and FWM changes correlated with a factor combining verbal learning and memory and working memory and, as indicated by measures of diffusion, were most likely due to vascular pathology. These findings suggest that frontal white matter integrity and cholinergic neuromodulation provide clues as to why age-related cognitive decline is often correlated across cognitive domains.

Alzheimer's disease (AD) and executive dysfunction. A case-control study on the significance of frontal white matter changes detected by diffusion tensor imaging (DTI)

White matter (WM) changes are frequently seen on structural imaging in AD but the clinical relevance of these changes is uncertain. Frontal WM pathology is often observed upon neuropathological examination in AD. Since frontal cortical/sub-cortical pathology is known to relate to executive dysfunction, the aim was to elucidate if frontal WM changes in AD correlated with executive dysfunction. In all, 15 AD patients and 15 age-matched control cases were investigated in the study, which covered conventional magnetic resonance imaging (MRI), DTI, neuropsychiatric and neuropsychological examinations. Reduced performance on neuropsychological testing of executive function correlated significantly with an increasing degree of frontal WM changes detected by DTI in the AD group, while no such correlation was observed for the controls. Conventional semi-quantitative MRI assessment did not correlate with results on neuropsychological testing of executive function in any of the groups. The structural correlate to certain dimensions of executive dysfunction in AD patients could be related to changes in the deep frontal WM. DTI appears to be more sensitive in the detection of clinically significant WM alterations than conventional semi-quantitative MRI.

A close relationship between verbal memory and SN/VTA integrity in young and older adults

Age-related dysfunction in dopaminergic neuromodulation is assumed to contribute to age-associated memory impairment. However, to date there are no in vivo data on how structural parameters of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic projections, relate to memory performance in healthy young and older adults. We investigated this relationship in a cross-sectional study including data from the hippocampus and frontal white matter (FWM) and also assessing working memory span and attention. In groups of young and older adults matched for the variance of their age distribution, gender and body mass index, we observed a robust positive correlation between Magnetization Transfer Ratio (MTR) – a measure of structural integrity – of the SN/VTA and FWM with verbal learning and memory performance among older adults, while there was a negative correlation in the young. Two additional imaging parameters, anisotropy of diffusion and diffusion coefficient, suggested that in older adults FWM changes reflected vascular pathology while SN/VTA changes pointed towards neuronal loss and loss of water content. The negative correlation in the young possibly reflected maturational changes. Multiple regression analyses indicated that in both young and older adults, SN/VTA MTR explained more variance of verbal learning and memory than FWM MTR or hippocampal MTR, and contributed less to explaining variance of working memory span. Together these findings indicate that structural integrity in the SN/VTA has a relatively selective impact on verbal learning and memory and undergoes specific changes from young adulthood to older age that qualitatively differ from changes in the FWM and hippocampus.

Familial Presenile Dementia with Bitemporal Atrophy

This study describes the clinical, neuropsychological, neuroimaging and genetic characteristics in two generations of a Swedish family affected by presenile dementia. The pedigree includes 5 cases (mother and 4 of 5 children) of progressive dementia with onset between 54 and 62 years. The clinical picture is characterized by insidious onset and progressive decline in episodic memory without spatial impairment or dyspraxia, followed by changes in personality and behaviour, with signs of disinhibition, irritability, impulsivity and loss of social awareness. Three siblings, examined after 10 years of duration, showed moderate language deficits but preserved spatial function and praxis. CT and MRI showed progressive bilateral temporal atrophy and moderate frontal white matter changes. Regional cerebral blood flow measurements showed hypoperfusion in temporal areas bilaterally. Quantitative EEG was normal within 5 years after symptom onset and thereafter showed a moderate increase in relative theta power. Sequencing of the tau gene (chromosome 17) revealed the previously described R406W mutation in exon 13 as a likely cause of the disease. This mutation was identified in all affected cases. The clinical picture of this family shows striking similarities not only to frontotemporal dementia but also to Alzheimer’s disease.

CT Brain Findings in Clinical Dementia Investigation – Underestimation of Mixed Dementia

Dementia has been found to display a more heterogeneous clinical picture than previously recognized. We investigated brain changes on computed tomography (CT) in a clinical dementia population consisting of 67 cases with Alzheimer’s disease (AD), 13 with mixed dementia (AD and vascular dementia, VaD), 71 with VaD, and 12 cases that were not demented. Temporal cortical atrophy and atrophy around the temporal horns were more common in patients with mixed dementia compared to patients with VaD and the non-demented, respectively. Frontal white matter changes were present in 64% of AD, in 85% of mixed dementia and in 79% of VaD cases, but there were no differences between the dementia groups. Lacunes were present in almost 40% of AD cases and in 80 and 85% of VaD and mixed dementia cases, respectively. Only 14% of the VaD cases had large infarcts on the CT. We conclude that large infarcts were rare, even in VaD cases. The increased incidence of white matter changes and lacunes in AD patients strongly indicates an underestimation of the mixed dementia diagnosis. More distinct criteria for this diagnostic category are warranted.

Magnetic Resonance Imaging and Histopathology in Dementia, Clinically of Frontotemporal Type

The magnetic resonance imaging (MRI) and computed tomography findings in 28 patients with the clinical diagnosis of frontotemporal dementia (FTD) were compared with the findings in a control group of 76 individuals without dementia or stroke. A pattern of frontal and temporal atrophy with predominantly frontal white matter changes was found in the FTD patients, and this was significantly different from the radiological findings in the control group. Six of the FTD patients have undergone autopsy. Histopathological evaluation showed a primary cortical degenerative disease (frontal lobe degeneration of non-Alzheimer type) in 3 of them, and primary white matter disorder, mainly frontal, of basically ischemic type (selective incomplete white matter infarction) in 3 of them. MRI could be a helpful tool to support the clinical diagnosis FTD, especially in young patients. MRI may also be helpful for the differentiation of a primary neurodegenerative from a mainly ischemic-vascular type of dementia.

Delusions and dementia: clinical and CT correlates

Delusions occur frequently during the course of Alzheimer's disease (AD) and multi-infarct dementia (MID). Their clinical significance and their relationship with progression of disease and involvement of selected cerebral areas are still unclear. The aim of the study was to determine the clinical and CT correlates of delusions in patients with dementia. A series of 67 probable AD and 32 MID patients, underwent computed tomographic scans, psychometric tests, neurologic and psychiatric examination, and blood and serum tests. Twenty-four patients were found to have delusions during the clinical evaluation. Delusional patients showed a significantly higher age when compared with non-delusional patients. The results of a multiple logistic regression (with stepwise deletion of the redundant variables) of the CT lesions on the presence of delusions, showed that only the presence of isolated white matter lesions in the frontal lobes were significantly related to the occurrence of delusions (Exp B = 3.42; Beta = 1.2; S.E. = 0.6; Sig T = 0.04). Frontal white matter changes were significantly related to delusions when a multiple regression analysis, entering age and total number of lesions at CT scans, was carried out. We found that focal lesions in the frontal areas were the only variable that appeared to be significantly and independently associated with delusional disorders.

健常高齢者の大脳白質障害と知的機能，血圧の関連について

The authors examined the relationship between cerebral white matter changes and mental function, blood pressure in 39 neurologically normal aged (21 males, 18 females, mean age 75.0 years) who had no latent lesions on MRI images. The severity of cerebral white matter changes was estimated by T1 value images on MRI and was measured in the bilateral frontal lobe on an axial slice at the level of the basal ganglia and in the bilateral anterior, middle, and posterior portions on axial slices at the level of the body of the lateral ventricle. Mental function was measured by the Hasegawa's dementia rating scale (HDS) and Kohs' block design test (Kohs' test). The severity of cerebral frontal white matter changes increased significantly with age (p less than 0.05). However there was no significant correlation between the severity of cerebral white matter changes and HDS, Kohs' test. The severity of frontal white matter changes correlated with the mean arterial blood pressure (p less than 0.02). These results suggest that the severity of cerebral white matter changes is not related with mental function in the normal elderly, and that the severity of frontal white matter lesions is related with mean arterial blood pressure.