Regional Volume Loss Research Articles

Healthy Aging: An Automatic Analysis of Global and Regional Morphological Alterations of Human Brain

Morphologic changes of the human brain during healthy aging provide useful reference knowledge for age-related brain disorders. The aim of this study was to explore age-related global and regional morphological changes of healthy adult brains. T1-weighted magnetic resonance images covering the entire brain were acquired for 314 subjects. Image processing of registration, segmentation, and surface construction were performed to calculate the volumes of the cerebrum, cerebellum, brain stem, lateral ventricle, and subcortical nuclei, as well as the surface area, mean curvature index, cortical thickness of the cerebral cortex, and subjacent white matter volume using FreeSurfer software. Mean values of each morphologic index were calculated and plotted against age group for sectional analysis. Regression analysis was conducted using SPSS to investigate the age effects on global and regional volumes of human brain. Overall global and regional volume loss was observed for the entire brain during healthy aging. Moderate atrophy was observed in subcortical gray matter structures, including the thalamus (R(2) = 0.476, P < .001), nucleus accumbens (R(2) = 0.525, P < .001), pallidum (R(2)= 0.461, P < .001), and putamen (R(2) = 0.533, P < .001). The volume of hippocampus showed a slight increase by 40 years of age, followed by a relatively faster decline after the age of 50 years (R(2) = 0.486, P < .001). Surface area and mean curvature were less affected by aging relative to cortical thickness and subjacent white matter volume. Significant cortical thinning was mainly found in the parietal (R(2) = 0.553, P < .001) and insula regions (R(2) = 0.405, P < .001). Morphologic alterations of human brain manifested regional heterogeneity in the scenario of general volume loss during healthy aging. The age effect on the hippocampus demonstrated a unique evolution. These findings provide informative reference knowledge that may help in identifying and differentiating pathologic aging and other neurologic disorders.

Longitudinal loss of gray matter volume in patients with first-episode schizophrenia: DARTEL automated analysis and ROI validation

Region of Interest (ROI) longitudinal studies have detected progressive gray matter (GM) volume reductions in patients with first-episode schizophrenia (FESZ). However, there are only a few longitudinal voxel-based morphometry (VBM) studies, and these have been limited in ability to detect relationships between volume loss and symptoms, perhaps because of methodologic issues. Nor have previous studies compared and validated VBM results with manual Region of Interest (ROI) analysis. In the present VBM study, high-dimensional warping and individualized baseline-rescan templates were used to evaluate longitudinal volume changes within subjects and compared with longitudinal manual ROI analysis on the same subjects. VBM evaluated thirty-three FESZ and thirty-six matched healthy control subjects (HC) at baseline (cross-sectionally) and longitudinally evaluated 21 FESZ and 23 HC after an average of 1.5 years from baseline scans. Correlation analyses detected the relationship between changes in regional GM volumes in FESZ and clinical symptoms derived from the Brief Psychiatric Rating Scale, as well as cognitive function as assessed by the Mini-Mental State Examination. At baseline, patients with FESZ had significantly smaller GM volume compared to HC in some regions including the left superior temporal gyrus (STG). On rescan after 1.5 years, patients showed significant GM volume reductions compared with HC in the left STG including Heschl's gyrus, and in widespread brain neocortical regions of frontal, parietal, and limbic regions including the cingulate gyrus. FESZ showed an association of positive symptoms and volume loss in temporal (especially STG) and frontal regions, and negative symptoms and volume loss in STG and frontal regions. Worse cognitive function was linked to widespread volume reduction, in frontal, temporal and parietal regions. The validation VBM analyses showed results similar to our previous ROI findings for STG and cingulate gyrus. We conclude FESZ show widespread, progressive GM volume reductions in many brain regions. Importantly, these reductions are directly associated with a worse clinical course. Congruence with ROI analyses suggests the promise of this longitudinal VBM methodology.

Global and regional putamen volume loss in patients with heart failure

Heart failure (HF) is accompanied by diminished cognitive, motor, learning, emotional, and planning deficits, which are associated with increased morbidity and mortality. A basal ganglia structure, the putamen, serves many functions that are affected in HF, but its global or localized structural integrity is unknown. Our aim was to evaluate global and regional putamen volume differences in HF over control subjects. We collected two high-resolution T1-weighted scans from 16 HF patients (age, 54.1 ± 8.3 years; 12 males; left ventricular ejection fraction, 27.8 ± 6.8%) and 32 control subjects (52.4 ± 7.3 years; 24 males) using a 3.0 T magnetic resonance imaging scanner. After realigning, averaging, and reorienting the T1-weighted volumes into a common space, the structures were manually outlined, tracings were normalized for head size, volumes calculated, and surface models generated. Demographic data were compared between groups with χ(2) and independent samples t-tests, global putamen volumes were evaluated using independent samples t-tests, and regional differences were examined with surface morphometry. No significant differences in age or sex appeared between groups, but body mass index differed significantly (P = 0.008). Heart failure patients showed significantly lower left (controls vs. HF; 4842.1 ± 740.0 vs. 4224.1 ± 894.4 mm(3), P = 0.014) and right (4769.3 ± 651.9 vs. 4193.7 ± 876.2 mm(3), P = 0.014) global putamen volumes than controls, with localized reductions in bilateral rostral, mid-dorsal, and medial-caudal regions (left, P < 0.003; right, P < 0.0002). Putamen structures showed global and localized volume reductions in HF over controls. The localized volume losses suggest deficits in motor and neuropsychological functions, which are evident in HF subjects, and may be due to hypoxic and ischaemic processes targeting these areas.

Clinical and Genetic High-Risk Paradigms: Converging Paths to Psychosis Meet in the Temporal Lobes

Clinical and Genetic High-Risk Paradigms: Converging Paths to Psychosis Meet in the Temporal Lobes

Cortical Thickness, Surface Area, and Volume of the Brain Reward System in Alcohol Dependence: Relationships to Relapse and Extended Abstinence

At least 60% of those treated for an alcohol use disorder will relapse. Empirical study of the integrity of the brain reward system (BRS) is critical to understanding the mechanisms of relapse as this collection of circuits is implicated in the development and maintenance of all forms of addictive disorders. This study compared thickness, surface area, and volume in neocortical components of the BRS among nonsmoking light-drinking controls (controls), individuals who remained abstinent and those who relapsed after treatment. Seventy-five treatment-seeking alcohol-dependent individuals (abstinent for 7±3 days) and 43 controls completed 1.5T proton magnetic resonance imaging studies. Parcellated morphological data were obtained for following bilateral components of the BRS: rostral and caudal anterior cingulate cortex, insula, medial and lateral orbitofrontal cortex (OFC), rostral and caudal middle and superior frontal gyri, amygdala and hippocampus as well as for 26 other bilateral neocortical regions. Alcohol-dependent participants were followed over 12-months after baseline study and were classified as abstainers (no alcohol consumption; n=24) and relapsers (any alcohol consumption; n=51) at follow-up. Relapsers and abstainers demonstrated lower cortical thickness in the vast majority of BRS regions as well as lower global thickness compared to controls. Relapsers had lower total BRS surface area than both controls and abstainers, but abstainers were not significantly different from controls on any surface area measure. Relapsers demonstrated lower volumes than controls in the majority of regions, while abstainers showed lower volumes than controls in the superior frontal gyrus, insula, amygdala, and hippocampus, bilaterally. Relapsers exhibited smaller volumes than abstainers in the right rostral middle and caudal middle frontal gyri and the lateral OFC, bilaterally. In relapsers, lower baseline volumes and surface areas in multiple regions were associated with a greater magnitude of post-treatment alcohol consumption. Results suggest relapsers demonstrated morphological abnormalities in regions involved in the "top down" regulation/modulation of internal drive states, emotions, reward processing, and behavior, which may impart increased risk for the relapse/remit cycle that afflicts many with an alcohol use disorder. Results also highlight the importance of examining both cortical thickness and surface area to better understand the nature of regional volume loss frequently observed in alcohol use disorders. Results from this report are consistent with previous research implicating plastic neurobiological changes in the BRS in the maintenance of addictive disorders.

Neocortical and hippocampal volume loss in a human ciliopathy: A quantitative MRI study in Bardet–Biedl syndrome

Cilia are ubiquitous cell surface organelles with diverse roles from embryogenesis to adult life. The neurodevelopmental functions of the cilium are currently under investigation in animal systems, but relevance to human brain development remains uncertain. We present the first systematic investigation of structural neuroanatomy in a ciliopathy-Bardet-Biedl syndrome (BBS). Qualitative and quantitative aspects of brain structure were evaluated via magnetic resonance imaging in 10 patients with BBS (ages 14-28 years). In comparison to age and gender-matched healthy controls, BBS patients had significantly reduced total gray matter (GM) volume but no total white matter (WM) or cerebrospinal fluid volume changes. Voxel-based morphometric analysis indicated regional GM volume loss bilaterally in the anterior temporal lobes and in the medial orbitofrontal cortex, and WM volume loss in the right inferior longitudinal fasciculus. Region-of-interest measurements revealed reduced volume of the hippocampus. Two patients were found to have ventriculomegaly. Global GM reduction and regional volume reductions in the temporal lobe may underlie the learning disabilities and behavioral problems experienced by some patients with BBS. These findings are consistent with previous observations in mouse models of BBS, and further implicate the cilium in neurodevelopmental processes relevant to human cognitive function.

Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms

First-generation antipsychotics have been associated with striatal volume increases. The effects of second-generation antipsychotics (SGAs) on the striatum are unclear. Moreover, SGAs may have neuroprotective effects on the hippocampus. Dose-dependent volumetric effects of individual SGAs have scarcely been investigated. Here we investigated structural brain changes in antipsychotic-naive, first-episode schizophrenia patients after 6 months treatment with the SGA, quetiapine. We have recently reported on baseline volume reductions in the caudate nucleus and hippocampus. Baseline and follow-up T1-weighted images (3 T) from 22 patients and 28 matched healthy controls were analysed using tensor-based morphometry. Non-parametric voxel-wise group comparisons were performed. Small volume correction was employed for striatum, hippocampus and ventricles. Dose-dependent medication effects and associations with psychopathology were assessed. Patients had significant bilateral striatal and hippocampal loss over the 6-month treatment period. When compared to controls the striatal volume loss was most pronounced with low quetiapine doses and less apparent with high doses. Post-hoc analyses revealed that the striatal volume loss was most pronounced in the caudate and putamen, but not in accumbens. Conversely, hippocampal volume loss appeared more pronounced with high quetiapine doses than with low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal loss over time. Although patients' ventricles did not change significantly, ventricular increases correlated with less improvement of negative symptoms. Progressive regional volume loss in quetiapine-treated, first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further research.

Regionally Selective Atrophy After Traumatic Axonal Injury

To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome. Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging-based morphometric analysis. Inpatient traumatic brain injury unit. Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls. Changes in global and regional brain volumes between initial and follow-up magnetic resonance imaging were used to assess the spatial distribution of posttraumatic volume loss. The Glasgow Outcome Scale-Extended score was the primary measure of functional outcome. Patients underwent substantial global atrophy with mean whole-brain parenchymal volume loss of 4.5% (95% confidence interval, 2.7%-6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole-brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus. Traumatic axonal injury leads to substantial posttraumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.

Central Nervous System Changes in Pediatric Heart Failure: A Volumetric Study

Autonomic dysfunction, mood disturbances, and memory deficits appear in pediatric and adult heart failure (HF). Brain areas controlling these functions show injury in adult HF patients, many of whom have comorbid cerebrovascular disease. We examined whether similar brain pathology develops in pediatric subjects without such comorbidities. In this study, high-resolution T1 brain magnetic resonance images were collected from seven severe HF subjects age (age 8–18 years [mean 13]; left ventricular shortening 9 to 19% [median 14%]) and seven age-matched healthy controls (age 8–18 years [mean 13]). After segmentation into gray matter (GM), white matter, and cerebrospinal fluid (CSF), regional volume loss between groups was determined by voxel-based morphometry. GM volume loss appeared on all HF scans, but ischemic changes and infarcts were absent. HF subjects showed greater CSF volume than controls (mean ± SD 0.30 ± 0.04 vs. 0.25 ± 0.04 l, P = 0.03), but total intracranial volume was identical (1.39 ± 0.11 vs. 1.39 ± 0.09 l, P = NS). Regional GM volume reduction appeared in the right and left posterior hippocampus, bilateral mid-insulae, and the superior medial frontal gyrus and mid-cingulate cortex of HF subjects (threshold P < 0.001). No volume-loss sites appeared in control brains. We conclude that pediatric HF patients show brain GM loss in areas similar to those of adult HF subjects. Substantial changes emerged in sites that regulate autonomic function as well as mood, personality and short-term memory. In the absence of thromboembolic disease and many comorbid conditions found in adult HF patients, pediatric HF patients show significant, focal GM volume loss, which may coincide with the multiple neurologic and psychological changes observed in patients with HF.

Spatiotemporal distribution pattern of white matter lesion volumes and their association with regional grey matter volume reductions in relapsing‐remitting multiple sclerosis

The association of white matter (WM) lesions and grey matter (GM) atrophy is a feature in relapsing-remitting multiple sclerosis (RRMS). The spatiotemporal distribution pattern of WM lesions, their relations to regional GM changes and the underlying dynamics are unclear. Here we combined parametric and non-parametric voxel-based morphometry (VBM) to clarify these issues. MRI data from RRMS patients with progressive (PLV, n = 45) and non-progressive WM lesion volumes (NPLV, n = 44) followed up for 12 months were analysed. Cross-sectionally, the spatial WM lesion distribution was compared using lesion probability maps (LPMs). Longitudinally, WM lesions and GM volumes were studied using FSL-VBM and SPM5-VBM, respectively. WM lesions clustered around the lateral ventricles and in the centrum semiovale with a more widespread pattern in the PLV than in the NPLV group. The maximum local probabilities were similar in both groups and higher for T2 lesions (PLV: 27%, NPLV: 25%) than for T1 lesions (PLV: 15%, NPLV 14%). Significant WM lesion changes accompanied by cortical GM volume reductions occurred in the corpus callosum and optic radiations (P = 0.01 corrected), and more liberally tested (uncorrected P < 0.01) in the inferior fronto-occipital and longitudinal fasciculi, and corona radiata in the PLV group. Not any WM or GM changes were found in the NPLV group. In the PLV group, WM lesion distribution and development in fibres, was associated with regional GM volume loss. The different spatiotemporal distribution patterns of patients with progressive compared to patients with non-progressive WM lesions suggest differences in the dynamics of pathogenesis.

Kann Sport den Verlust kognitiver Funktionen im Alter verhindern?

Summary Cognitive functions such as cognitive speed, inhibition of irrelevant information, and switching between tasks decline with age. The risk of dementia is strongly associated with age. Considering demographic changes with the projected increase in the number of adults surviving to advanced age and a predicted number of people suffering from dementia of 2 millions in 2040, preventive measures become increasingly important. Although the results are not unequivocal the majority of the studies provide clinical evidence for the benefits of physical activity on slow-down or prevention of cognitive decline and dementia. Physically active elderly develop less often dementia and their cognitive performance is superior to that of sedentary age-matched subjects. Aerobic fitness training has a significant effect on cognitive function with the main benefits occurring in executive control-processes. The effectiveness of the physical intervention seems to be dependent on frequency and intensity of the training. So far, it is still not clarified whether aerobic training has to lead to improved cardiovascular fitness to be effective. Animal and human research suggest that physical activities enhance the plasticity of the brain and prevent brain volume loss in regions of higher order cognitive processes, which show disproportionate structural decline with age.

Gray Matter Deficits, Mismatch Negativity, and Outcomes in Schizophrenia

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients' levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl's gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl's gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

Abnormal motor symptoms of Alzheimer's disease are associated with regional volume loss in frontal lobes and cerebellar hemispheres: A Voxel-Based Morphometric study

Abnormal motor symptoms of Alzheimer's disease are associated with regional volume loss in frontal lobes and cerebellar hemispheres: A Voxel-Based Morphometric study

Abnormal motor symptoms of Alzheimer's disease are associated with regional volume loss in frontal lobes and cerebellar hemispheres; A voxel-based morphometric study

Abnormal motor symptoms of Alzheimer's disease are associated with regional volume loss in frontal lobes and cerebellar hemispheres; A voxel-based morphometric study

Grey matter volume loss in medial and anterior temporal regions may explain excessive lexical semantic decline in MCI APOE e4 carriers

Grey matter volume loss in medial and anterior temporal regions may explain excessive lexical semantic decline in MCI APOE e4 carriers

Longitudinal pattern of regional brain volume change differentiates normal aging from MCI

Neuroimaging measures have potential as surrogate markers of disease through identification of consistent features that occur prior to clinical symptoms. Despite numerous investigations, especially in relation to the transition to clinical impairment, the regional pattern of brain changes in clinically normal older adults has not been established. We predict that the regions that show early pathologic changes in association with Alzheimer disease will show accelerated volume loss in mild cognitive impairment (MCI) compared to normal aging. Through the Baltimore Longitudinal Study of Aging, we prospectively evaluated 138 nondemented individuals (age 64-86 years) annually for up to 10 consecutive years. Eighteen participants were diagnosed with MCI over the course of the study. Mixed-effects regression was used to compare regional brain volume trajectories of clinically normal individuals to those with MCI based on a total of 1,017 observations. All investigated volumes declined with normal aging (p < 0.05). Accelerated change with age was observed for ventricular CSF (vCSF), frontal gray matter, superior, middle, and medial frontal, and superior parietal regions (p < or = 0.04). The MCI group showed accelerated changes compared to normal controls in whole brain volume, vCSF, temporal gray matter, and orbitofrontal and temporal association cortices, including the hippocampus (p < or = 0.04). Although age-related regional volume loss is apparent and widespread in nondemented individuals, mild cognitive impairment is associated with a unique pattern of structural vulnerability reflected in differential volume loss in specific regions. Early identification of patterns of abnormality is of fundamental importance for detecting disease onset and tracking progression.

SU‐DD‐A4‐03: Regional Atrophy in Alzheimer's Disease Measured by Voxel Based Morphometry Compare with PET and MRI

Purpose: Voxel based morphometry (VBM) has been increasingly applied to investigate differences in brain morphology between a group of patients and control subjects. VBM permits comparison of gray matter (GM) volume at voxel‐level from the entire brain, thus is an efficient method for assessing regional differences. The purpose of this study was to assess the regional GM volume loss measured by VBM in Alzheimer's disease (AD) compared to controls, and to measure hippocampal volume using manually delineated volumetry and compare the results to VBM findings. Method and Materials: Twenty‐three AD (mean age 70 ± 8y; m/f= 7/16, Mini‐Mental State Exam [MMSE]= 22.2) and 20 cognitively normal elderly control subjects (mean age 69 ± 4y; m/f= 10/10) were included in this study. The 20 sets of images were first normalized and create the probability maps for segmentation. Normalized hippocampal volume to the intracranial volume was compared between AD and control groups. Results: The AD group had a lower GM %, and a higher CSF% compared to controls. The hippocampal volume of AD patients was significantly lower than that of controls (P&lt;0.001). The region includes parahippocampal gyrus, cingulate, insula, frontal lobe and middle temporal complex. Despite the high significance in manual ROI analysis, hippocampus was not revealed in the VBM. Conclusions: We found that the hippocampal volume in AD was significantly smaller than in controls using ROI‐based volumetry. However, although our VBM results demonstrated that AD patients had a significant atrophy in middle temporal lobe, parahippocampus and insula, the hippocampus was not revealed. While VBM can be applied to assess global atrophy efficiently, manual volumetry is needed to study irregularly‐shaped subcortical structures.

Regional atrophy of transcallosal prefrontal connections in cognitively normal APOE ϵ4 carriers

To investigate the possible effect of the APOE epsilon4 allele on age-related regional volume loss within the corpus callosum (CC) in healthy epsilon4 allele carriers compared with noncarriers. A total of 211 subjects, ages 27 to 83 years, 51 epsilon4 carriers and 160 noncarriers underwent T1-weighted MRI scan. All subjects had normal MRI scan and performed within normal range on a neuropsychological battery of tests. CC was segmented into seven functionally relevant regions using a previously published probabilistic map of the CC connectivity. We measured the volumes of the CC and its subregions. We used a regression model (with volumes as dependent and age as independent variables) and compared the slopes between carriers and noncarriers using an analysis of covariance model. We also carried out voxel-based-morphometry analysis to investigate the possible effect of the APOE epsilon4 gene on the gray matter. We found that the volume of the CC and all subregions decreased with increasing age in both groups. The slope was steeper in the APOE epsilon4 carriers compared withthe noncarriers particularly in the prefrontal region (P = 0.02). No gray matter differences were observed between the two groups. APOE epsilon4 polymorphism is associated with accelerated age-related volume loss in the prefrontal callosal tracts without gray matter loss. This result suggests the role of APOE epsilon4 in the brain aging by primarily affecting white matter structures particularly in the frontal lobe.

Early structural changes in individuals at risk of familial Alzheimer’s disease: a volumetry and magnetization transfer MR imaging study

Presenilin 1 (PS1) mutation carriers provide the opportunity to asses early features of neurodegeneration in familial Alzheimer's disease (AD). Gray matter (GM) regional volume loss and decrease of magnetization transfer ratio (MTR) consistent with microstructural changes have been reported in sporadic AD. We performed a regional volumetric and MTR analysis in carriers of PS1 mutations. Six non-demented mutated PS1 carriers (5 with memory deficits) and 14 healthy subjects were examined with high resolution T1-weighted images for volumetry and with T2* weighted images for MTR. Cortical GM volume and MTR values were derived. Compared to healthy controls, the GM volume of the left temporal and inferior parietal cortex and the MTR of the temporal cortex bilaterally were significantly decreased in PS1 gene carriers. In the latter, the temporal lobe MTR showed a trend for correlation with memory and executive function scores. Early neurodegeneration in non-demented subjects at risk for familial AD may be associated with atrophy and decreased MTR in the temporal cortex.

The Toronto traumatic brain injury study

To assess the relationship between regional brain volume changes and traumatic brain injury (TBI) severity in patients with and without focal lesions. Sixty-nine chronic-phase TBI patients spanning the full range of severity were recruited from consecutive hospital admissions. Patients received high-resolution structural MRI a minimum of 1 year after injury. Multivariate statistical analyses assessed covariance patterns between volumes of gray matter, white matter, and sulcal/subdural and ventricular CSF across 38 brain regions and TBI severity as assessed by depth of coma at the time of injury. Patients with diffuse and diffuse plus focal injury were analyzed both separately and together. There was a stepwise, dose-response relationship between parenchymal volume loss and TBI severity. Patients with moderate and severe TBI were differentiated from those with mild TBI, who were in turn differentiated from noninjured control subjects. A spatially extensive pattern of volume loss covaried with TBI severity, with particularly widespread effects in white matter volume and sulcal/subdural CSF. The most reliable effects were observed in the frontal, temporal, and cingulate regions, although effects were observed to varying degrees in nearly every brain region. Focal lesions were associated with greater volume loss in frontal and temporal regions, but volume loss remained marked even when analyses were restricted to patients with diffuse injury. Patterns of parenchymal volumetric changes can differentiate among levels of traumatic brain injury (TBI) severity, even in mild TBI. TBI causes a spatially extensive pattern of volume loss that reflects independent but overlapping contributions of focal and diffuse injury.