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1.  Augmented neural activity during executive control processing following diffuse axonal injury 
Neurology  2008;71(11):812-818.
Deficits in working memory are commonly observed after traumatic brain injury (TBI), with executive control processes preferentially impacted relative to storage and rehearsal. Previous activation functional neuroimaging investigations of working memory in patients with TBI have reported altered functional recruitment, but methodologic issues including sample heterogeneity (e.g., variability in injury mechanism, severity, neuropathology or chronicity), underspecified definitions of “working memory,” and behavioral differences between TBI and control groups have hindered interpretation of these changes.
Executive control processing in working memory was explicitly engaged during fMRI in a sample of carefully selected chronic-stage, moderate-to-severe TBI patients with diffuse axonal injury (DAI) but without focal lesions.
Despite equivalent task performance, we observed a pattern of greater recruitment of interhemispheric and intrahemispheric regions of prefrontal cortex (PFC) and posterior cortices in our DAI sample. Enhanced activations were recorded in the left dorsolateral PFC (middle frontal gyrus), right ventrolateral PFC (inferior frontal gyrus), bilateral posterior parietal cortices, and left temporo-occipital junction. Region-of-interest analyses confirmed that these effects were robust across individual patients and could not be attributed to load factors or slowed speed of processing.
Augmented functional recruitment in the context of normal behavioral performance may be a neural marker of capacity or efficiency limits that can affect functional outcome after traumatic brain injury with diffuse injury.
= Brodmann area;
= blood oxygen level–dependent;
= diffuse axonal injury;
= dorsolateral prefrontal function;
= Glasgow Coma Scale;
= inferior frontal gyrus;
= intertrial interval;
= middle frontal gyrus;
= not applicable;
= not significant;
= prefrontal cortex;
= region of interest;
= traumatic brain injury.
PMCID: PMC2676953  PMID: 18779509
2.  Assessing Spatial Relationships between Axonal Integrity, Regional Brain Volumes, and Neuropsychological Outcomes after Traumatic Axonal Injury 
Journal of Neurotrauma  2010;27(12):2121-2130.
Diffuse traumatic axonal injury (TAI) is a type of traumatic brain injury (TBI) characterized predominantly by white matter damage. While TAI is associated with cerebral atrophy, the relationship between gray matter volumes and TAI of afferent or efferent axonal pathways remains unknown. Moreover, it is unclear if deficits in cognition are associated with post-traumatic brain volumes in particular regions. The goal of this study was to determine the relationship between markers of TAI and volumes of cortical and subcortical structures, while also assessing the relationship between cognitive outcomes and regional brain volumes. High-resolution magnetic resonance imaging scans were performed in 24 patients with TAI within 1 week of injury and were repeated 8 months later. Diffusion tensor imaging (DTI) tractography was used to reconstruct prominent white matter tracts and calculate their fractional anisotropy (FA) and mean diffusivity (MD) values. Regional brain volumes were computed using semi-automated morphometric analysis. Pearson's correlation coefficients were used to assess associations between brain volumes, white matter integrity (i.e., FA and MD), and neuropsychological outcomes. Post-traumatic volumes of many gray matter structures were associated with chronic damage to related white matter tracts, and less strongly associated with measures of white matter integrity in the acute scans. For example, left and right hippocampal volumes correlated with FA in the fornix body (r = 0.600, p = 0.001; r = 0.714, p < 0.001, respectively). In addition, regional brain volumes were associated with deficits in corresponding neuropsychological domains. Our results suggest that TAI may be a primary mechanism of post-traumatic atrophy, and provide support for regional morphometry as a biomarker for cognitive outcome after injury.
PMCID: PMC2996819  PMID: 20874032
atrophy; diffuse axonal injury; diffusion tensor imaging; traumatic brain injury; volumetric magnetic resonance imaging
3.  Cerebral Atrophy after Traumatic White Matter Injury: Correlation with Acute Neuroimaging and Outcome 
Journal of Neurotrauma  2008;25(12):1433-1440.
Traumatic brain injury (TBI) is a pathologically heterogeneous disease, including injury to both neuronal cell bodies and axonal processes. Global atrophy of both gray and white matter is common after TBI. This study was designed to determine the relationship between neuroimaging markers of acute diffuse axonal injury (DAI) and cerebral atrophy months later. We performed high-resolution magnetic resonance imaging (MRI) at 3 Tesla (T) in 20 patients who suffered non-penetrating TBI, during the acute (within 1 month after the injury) and chronic stage (at least 6 months after the injury). Volume of abnormal fluid-attenuated inversion-recovery (FLAIR) signal seen in white matter in both acute and follow-up scans was quantified. White and gray matter volumes were also quantified. Functional outcome was measured using the Functional Status Examination (FSE) at the time of the chronic scan. Change in brain volumes, including whole brain volume (WBV), white matter volume (WMV), and gray matter volume (GMV), correlates significantly with acute DAI volume (r = −0.69, −0.59, −0.58, respectively; p < 0.01 for all). Volume of acute FLAIR hyperintensities correlates with volume of decreased FLAIR signal in the follow-up scans (r = −0.86, p < 0.001). FSE performance correlates with acute hyperintensity volume and chronic cerebral atrophy (r = 0.53, p = 0.02; r = −0.45, p = 0.03, respectively). Acute axonal lesions measured by FLAIR imaging are strongly predictive of post-traumatic cerebral atrophy. Our findings suggest that axonal pathology measured as white matter lesions following TBI can be identified using MRI, and may be a useful measure for DAI-directed therapies.
PMCID: PMC2858299  PMID: 19072588
MR imaging; post-traumatic atrophy; TBI
4.  MRI investigation of the sensorimotor cortex and the corticospinal tract after acute spinal cord injury: a prospective longitudinal study 
Lancet Neurology  2013;12(9):873-881.
In patients with chronic spinal cord injury, imaging of the spinal cord and brain above the level of the lesion provides evidence of neural degeneration; however, the spatial and temporal patterns of progression and their relation to clinical outcomes are uncertain. New interventions targeting acute spinal cord injury have entered clinical trials but neuroimaging outcomes as responsive markers of treatment have yet to be established. We aimed to use MRI to assess neuronal degeneration above the level of the lesion after acute spinal cord injury.
In our prospective longitudinal study, we enrolled patients with acute traumatic spinal cord injury and healthy controls. We assessed patients clinically and by MRI at baseline, 2 months, 6 months, and 12 months, and controls by MRI at the same timepoints. We assessed atrophy in white matter in the cranial corticospinal tracts and grey matter in sensorimotor cortices by tensor-based analyses of T1-weighted MRI data. We used cross-sectional spinal cord area measurements to assess atrophy at cervical level C2/C3. We used myelin-sensitive magnetisation transfer (MT) and longitudinal relaxation rate (R1) maps to assess microstructural changes associated with myelin. We also assessed associations between MRI parameters and clinical improvement. All analyses of brain scans done with statistical parametric mapping were corrected for family-wise error.
Between Sept 17, 2010, and Dec 31, 2012, we recruited 13 patients and 18 controls. In the 12 months from baseline, patients recovered by a mean of 5·27 points per log month (95% CI 1·91–8·63) on the international standards for the neurological classification of spinal cord injury (ISNCSCI) motor score (p=0·002) and by 10·93 points per log month (6·20–15·66) on the spinal cord independence measure (SCIM) score (p<0·0001). Compared with controls, patients showed a rapid decline in cross-sectional spinal cord area (patients declined by 0·46 mm per month compared with a stable cord area in controls; p<0·0001). Patients had faster rates than controls of volume decline of white matter in the cranial corticospinal tracts at the level of the internal capsule (right Z score 5·21, p=0·0081; left Z score 4·12, p=0·0004) and right cerebral peduncle (Z score 3·89, p=0·0302) and of grey matter in the left primary motor cortex (Z score 4·23, p=0·041). Volume changes were paralleled by significant reductions of MT and R1 in the same areas and beyond. Improvements in SCIM scores at 12 months were associated with a reduced loss in cross-sectional spinal cord area over 12 months (Pearson's correlation 0·77, p=0·004) and reduced white matter volume of the corticospinal tracts at the level of the right internal capsule (Z score 4·30, p=0·0021), the left internal capsule (Z score 4·27, p=0·0278), and left cerebral peduncle (Z score 4·05, p=0·0316). Improvements in ISNCSCI motor scores were associated with less white matter volume change encompassing the corticospinal tract at the level of the right internal capsule (Z score 4·01, p<0·0001).
Extensive upstream atrophic and microstructural changes of corticospinal axons and sensorimotor cortical areas occur in the first months after spinal cord injury, with faster degenerative changes relating to poorer recovery. Structural volumetric and microstructural MRI protocols remote from the site of spinal cord injury could serve as neuroimaging biomarkers in acute spinal cord injury.
SRH Holding, Swiss National Science Foundation, Clinical Research Priority Program “NeuroRehab” University of Zurich, Wellcome Trust.
PMCID: PMC3744750  PMID: 23827394
5.  Prospective longitudinal MRI study of brain volumes and diffusion changes during the first year after moderate to severe traumatic brain injury 
NeuroImage : Clinical  2014;5:128-140.
The objectives of this prospective study in 62 moderate–severe TBI patients were to investigate volume change in cortical gray matter (GM), hippocampus, lenticular nucleus, lobar white matter (WM), brainstem and ventricles using a within subject design and repeated MRI in the early phase (1–26 days) and 3 and 12 months postinjury and to assess changes in GM apparent diffusion coefficient (ADC) in normal appearing tissue in the cortex, hippocampus and brainstem. The impact of Glasgow Coma Scale (GCS) score at admission, duration of post-traumatic amnesia (PTA), and diffusion axonal injury (DAI) grade on brain volumes and ADC values over time was assessed. Lastly, we determined if MRI-derived brain volumes from the 3-month scans provided additional, significant predictive value to 12-month outcome classified with the Glasgow Outcome Scale—Extended after adjusting for GCS, PTA and age.
Cortical GM loss was rapid, largely finished by 3 months, but the volume reduction was unrelated to GCS score, PTA, or presence of DAI. However, cortical GM volume at 3 months was a significant independent predictor of 12-month outcome. Volume loss in the hippocampus and lenticular nucleus was protracted and statistically significant first at 12 months. Slopes of volume reduction over time for the cortical and subcortical GGM were significantly different. Hippocampal volume loss was most pronounced and rapid in individuals with PTA > 2 weeks. The 3-month volumes of the hippocampus and lentiform nucleus were the best independent predictors of 12-month outcome after adjusting for GCS, PTA and age. In the brainstem, volume loss was significant at both 3 and 12 months. Brainstem volume reduction was associated with lower GCS score and the presence of DAI. Lobar WM volume was significantly decreased first after 12 months. Surprisingly DAI grade had no impact on lobar WM volume. Ventricular dilation developed predominantly during the first 3 months, and was strongly associated with volume changes in the brainstem and cortical GM, but not lobar WM volume.
Higher ADC values were detected in the cortex in individuals with severe TBI, DAI and PTA > 2 weeks, from 3 months. There were no associations between ADC values and brain volumes, and ADC values did not predict outcome.
•Longitudinal study of brain volume changes following TBI•3 month MRI derived volumes are independent predictors of outcome at 12 months.•PTA, GCS and DAI have different impacts on different brain volumes.•Subcortical and cortical GM volume losses follow significantly different trajectories.•Significant changes in cortical ADC values develop slowly while volume changes are rapid.
PMCID: PMC4110353  PMID: 25068105
Post-traumatic amnesia; Diffuse axonal injury; Glasgow Coma Scale; ADC; Outcome
6.  Interactive Effects of Chronic Cigarette Smoking and Age on Brain Volumes in Controls and Alcohol Dependent Individuals in Early Abstinence 
Addiction biology  2012;19(1):10.1111/j.1369-1600.2012.00492.x.
Chronic alcohol use disorders (AUD) have been shown to interact with normal age-related volume loss to exacerbate brain atrophy with increasing age. However, chronic cigarette smoking, a highly comorbid condition in AUD, and its influence on age-related brain atrophy has not been evaluated. We performed 1.5T quantitative MRI in non-smoking controls (nsCON; n=54), smoking light drinking controls (sCON, n=34), and 1-week-abstinent, treatment-seeking non-smoking alcohol dependent individuals (nsALC, n=35) and smoking ALC (sALC, n=43), to evaluate the independent and interactive effects of alcohol dependence and chronic smoking on regional cortical and subcortical brain volumes, emphasizing the brain reward/executive oversight system (BREOS),. nsCON and sALC showed greater age-related volume losses than nsALC in the dorsal prefrontal cortex (DPFC), total cortical BREOS, superior parietal lobule and putamen. nsALC and sALC demonstrated smaller volumes than nsCON in most cortical ROIs. sCON had smaller volumes than nsCON in the DPFC, insula, inferior parietal lobule, temporal pole/parahippocampal region and all global cortical measures. nsALC and sALC had smaller volumes than sCON in the DPFC, superior temporal gyrus, inferior and superior parietal lobules, precuneus and all global cortical measures. Volume differences between nsALC and sALC were observed only in the putamen. Alcohol consumption measures were not related to volumes in any ROI for ALC; smoking severity measures were related to corpus callosum volume in sCON and sALC. The findings indicate that consideration of smoking status is necessary for a better understanding of the factors contributing to regional brain atrophy in AUD.
PMCID: PMC3528793  PMID: 22943795
Brain volume; magnetic resonance imaging; cigarette smoking; alcohol dependence; brain reward system
7.  Compensatory cortical activation during performance of an attention task by patients with diffuse axonal injury: a functional magnetic resonance imaging study 
To determine how cortical compensation occurs in higher cognitive systems during the recovery phase of diffuse axonal injury (DAI).
12 right‐handed patients with a magnetic resonance imaging (MRI) lesion pattern compatible with pure DAI were identified. Pure DAI was defined as finding of traumatic microbleeds on T2*‐weighted gradient‐echo images in the absence of otherwise traumatic or non‐traumatic MRI abnormalities. 12 matched healthy controls were also enrolled. Functional magnetic resonance imaging (fMRI) was used to assess brain activation during a working memory test (Paced Visual Serial Attention Test (PVSAT)).
No significant group differences were observed in reaction times for the PVSAT. Although patients with pure DAI committed a few errors during the PVSAT, controls respond correctly to each probe. Controls showed activations in the left frontal gyrus, left parietal gyrus and right inferior parietal gyrus. Patients with pure DAI showed activations in the left inferior frontal gyrus, right inferior frontal gyrus and right middle frontal gyrus. Between‐group analysis of the PVSAT task showed significantly greater activation of the right inferior frontal gyrus (BA 45) and right middle frontal gyrus (BA 9) in patient with pure DAI versus controls.
Patients with pure DAI require compensatory activation of the contralateral (right) prefrontal region to carry out activities similar to healthy controls. These findings provide further evidence for the adaptive capacity of neuronal systems and brain plasticity during the recovery stages of DAI.
PMCID: PMC2077668  PMID: 16952916
8.  Regional rates of neocortical atrophy from normal aging to early Alzheimer disease 
Neurology  2009;73(6):457-465.
To evaluate the spatial pattern and regional rates of neocortical atrophy from normal aging to early Alzheimer disease (AD).
Longitudinal MRI data were analyzed using high-throughput image analysis procedures for 472 individuals diagnosed as normal, mild cognitive impairment (MCI), or AD. Participants were divided into 4 groups based on Clinical Dementia Rating Sum of Boxes score (CDR-SB). Annual atrophy rates were derived by calculating percent cortical volume loss between baseline and 12-month scans. Repeated-measures analyses of covariance were used to evaluate group differences in atrophy rates across regions as a function of impairment. Planned comparisons were used to evaluate the change in atrophy rates across levels of disease severity.
In patients with MCI–CDR-SB 0.5–1, annual atrophy rates were greatest in medial temporal, middle and inferior lateral temporal, inferior parietal, and posterior cingulate. With increased impairment (MCI–CDR-SB 1.5–2.5), atrophy spread to parietal, frontal, and lateral occipital cortex, followed by anterior cingulate cortex. Analysis of regional trajectories revealed increasing rates of atrophy across all neocortical regions with clinical impairment. However, increases in atrophy rates were greater in early disease within medial temporal cortex, whereas increases in atrophy rates were greater at later stages in prefrontal, parietal, posterior temporal, parietal, and cingulate cortex.
Atrophy is not uniform across regions, nor does it follow a linear trajectory. Knowledge of the spatial pattern and rate of decline across the spectrum from normal aging to Alzheimer disease can provide valuable information for detecting early disease and monitoring treatment effects at different stages of disease progression.
= Alzheimer disease;
= Alzheimer’s Disease Neuroimaging Initiative;
= analysis of covariance;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes score;
= mild cognitive impairment;
= Mini-Mental State Examination;
= Principal Investigator;
= repeated-measures;
= region of interest;
= total intracranial volume;
= University of California, San Diego.
PMCID: PMC2727145  PMID: 19667321
9.  Thalamic integrity underlies executive dysfunction in traumatic brain injury 
Neurology  2010;74(7):558-564.
To quantify the effects of traumatic brain injury on integrity of thalamocortical projection fibers and to evaluate whether damage to these fibers accounts for impairments in executive function in chronic traumatic brain injury.
High-resolution (voxel size: 0.78 mm × 0.78 mm × 3 mm3) diffusion tensor MRI of the thalamus was conducted on 24 patients with a history of single, closed-head traumatic brain injury (TBI) (12 each of mild TBI and moderate to severe TBI) and 12 age- and education-matched controls. Detailed neuropsychological testing with an emphasis on executive function was also conducted. Fractional anisotropy was extracted from 12 regions of interest in cortical and corpus callosum structures and 7 subcortical regions of interest (anterior, ventral anterior, ventral lateral, dorsomedial, ventral posterior lateral, ventral posterior medial, and pulvinar thalamic nuclei).
Relative to controls, patients with a history of brain injury showed reductions in fractional anisotropy in both the anterior and posterior corona radiata, forceps major, the body of the corpus callosum, and fibers identified from seed voxels in the anterior and ventral anterior thalamic nuclei. Fractional anisotropy from cortico-cortico and corpus callosum regions of interest did not account for significant variance in neuropsychological function. However, fractional anisotropy from the thalamic seed voxels did account for variance in executive function, attention, and memory.
The data provide preliminary evidence that traumatic brain injury and resulting diffuse axonal injury results in damage to the thalamic projection fibers and is of clinical relevance to cognition.
= anterior corona radiata;
= anterior thalamic nucleus;
= body of the corpus callosum;
= cortical-spinal tract;
= diffuse axonal injury;
= dorsomedial nucleus;
= diffusion tensor imaging;
= fractional anisotropy;
= forceps major;
= forceps minor;
= field of view;
= fast spin echo;
= genu of the corpus callosum;
= internal capsule;
= inferior frontal occipital fasciculus;
= loss of consciousness;
= mild TBI;
= moderate to severe TBI;
= number of excitations;
= posterior corona radiata;
= posttraumatic amnesia;
= pulvinar;
= region of interest;
= splenium of the corpus callosum;
= superior longitudinal fasciculus;
= sagittal stratum;
= traumatic brain injury;
= echo time;
= repetition time;
= ventral anterior thalamic nucleus;
= ventral lateral thalamic nucleus;
= ventral posterior lateral nucleus;
= ventral posterior medial nucleus.
PMCID: PMC2830915  PMID: 20089945
10.  Brain Volumetrics, Regional Cortical Thickness and Radiographic Findings in Adults with Cyanotic Congenital Heart Disease☆ 
NeuroImage : Clinical  2014;4:319-325.
Chronic cyanosis in adults with congenital heart disease (CHD) may cause structural brain changes that could contribute to impaired neurological functioning. The extent of these changes has not been adequately characterized.
We hypothesized that adults with cyanotic CHD would have widespread changes including abnormal brain volumetric measures, decreased cortical thickness and an increased burden of small and large vessel ischemic changes.
Ten adults with chronic cyanosis from CHD (40 ± 4 years) and mean oxygen saturations of 82 ± 2% were investigated using quantitative MRI. Hematological and biochemical parameters were also assessed. All subjects were free from major physical or intellectual impairment. Brain volumetric results were compared with randomly selected age- and sex-matched controls from our database of normal subjects.
Five of 10 cyanotic subjects had cortical lacunar infarcts. The white matter (WM) hyperintensity burden was also abnormally high (Scheltens Scale was 8 ± 2). Quantitative MRI revealed evidence of extensive generalized WM and gray matter (GM) volumetric loss; global GM volume was reduced in cyanosed subjects (630 ± 16 vs. 696 ± 14 mL in controls, p = 0.01) as was global WM volume (471 ± 10 vs. 564 ± 18 mL, p = 0.003). Ventricular cerebrospinal fluid volume was increased (35 ± 10 vs. 26 ± 5 mL, p = 0.002). There were widespread regions of local cortical thickness reduction observed across the brain. These changes included bilateral thickness reductions in the frontal lobe including the dorsolateral prefrontal cortex and precentral gyrus, the posterior parietal lobe and the middle temporal gyrus. Sub-cortical volume changes were observed in the caudate, putamen and in the thalamus (p ≤ 0.005 for all regions). Cortical GM volume negatively correlated with brain natriuretic peptide (R = − 0.89, p = 0.009), high sensitivity C-reactive protein (R = − 0.964, p < 0.0001) and asymmetric dimethylarginine (R = − 0.75, p = 0.026) but not with oxygen saturations, packed cell volume or viscosity.
We present the first comprehensive analysis of brain structure in adults with chronic neurocyanosis due to congenital heart disease. We demonstrate clear evidence for marked macro- and microvascular injury. Cyanotic patients show global evidence for reduced brain volume as well as specific foci of cortical thickness reduction. The GM volume loss correlated with hsCRP, BNP and ADMA suggesting that inflammation, neurohormonal activation and endothelial dysfunction may have important roles in its pathogenesis.
•A high burden of cerebral small and large vessel ischemic injury.•Extensive white and gray matter (GM) volumetric loss.•Regions of bilateral local cortical thickness reduction within the frontal, parietal and temporal lobes.
PMCID: PMC3913831  PMID: 24501700
ADMA, asymmetric dimethylarginine; CSF, cerebrospinal fluid; CHD, congenital heart disease; GM, gray matter; hsCRP, high-sensitivity C-reactive protein; MRI, magnetic resonance imaging pro-brain natriuretic peptide; BNP, NT pro-brain natriuretic peptide; VBM, voxel-based morphometry; WM, white matter; Cyanosis; MRI; Brain volume; White matter; Gray matter; Cyanosis
11.  Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms☆ 
NeuroImage : Clinical  2013;3:405-415.
22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins.
High-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10–25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed.
Relative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS.
Differential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population.
•22q11DS offers a valuable model for neurobiological mechanisms of psychosis.•First study of multiple structural MRI indices in 22q11DS.•Reduced surface area in multiple neuroanatomic regions in 22q11DS.•Increased cortical thickness in multiple frontal regions and insula in 22q11DS.•Orbitofrontal abnormalities associated with positive symptom severity in 22q11DS.
PMCID: PMC3814944  PMID: 24273724
22q11DS, 22q11.2 deletion syndrome; CNV, copy number variation; CT, cortical thickness; SA, surface area; SIPS, Structured Interview for Prodromal Syndromes; MRI, magnetic resonance imaging; ANCOVA, analysis of covariance; Copy number variation; Structural magnetic resonance imaging; Psychosis; Schizophrenia; Velocardiofacial syndrome
12.  Quantified MRI and cognition in TBI with diffuse and focal damage☆ 
NeuroImage : Clinical  2013;2:534-541.
In patients with chronic-phase traumatic brain injury (TBI), structural MRI is readily attainable and provides rich anatomical information, yet the relationship between whole-brain structural MRI measures and neurocognitive outcome is relatively unexplored and can be complicated by the presence of combined focal and diffuse injury. In this study, sixty-three patients spanning the full range of TBI severity received high-resolution structural MRI concurrent with neuropsychological testing. Multivariate statistical analysis assessed covariance patterns between volumes of grey matter, white matter, and sulcal/subdural and ventricular CSF across 38 brain regions and neuropsychological test performance. Patients with diffuse and diffuse + focal injury were analyzed both separately and together. Tests of speeded attention, working memory, and verbal learning and memory robustly covaried with a distributed pattern of volume loss over temporal, ventromedial prefrontal, right parietal regions, and cingulate regions. This pattern was modulated by the presence of large focal lesions, but held even when analyses were restricted to those with diffuse injury. Effects were most consistently observed within grey matter. Relative to regional brain volumetric data, clinically defined injury severity (depth of coma at time of injury) showed only weak relation to neuropsychological outcome. The results showed that neuropsychological test performance in patients with TBI is related to a distributed pattern of volume loss in regions mediating mnemonic and attentional processing. This relationship holds for patients with and without focal lesions, indicating that diffuse injury alone is sufficient to cause significant neuropsychological disability in relation to regional volume loss. Quantified structural brain imaging data provides a highly sensitive index of brain integrity that is related to cognitive functioning in chronic phase TBI.
•Cognitive deficits in TBI associated with distributed volume loss in grey matter.•Brain-behavior relationship modulated by focal lesions, but holds in diffuse injury.•Volumetrics more sensitive to cognitive deficits than clinical classification.
PMCID: PMC3773881  PMID: 24049744
Structural MRI; Neuropsychological assessment; Executive Function; Attention; Memory; Traumatic Brain Injury
13.  Scale and pattern of atrophy in the chronic stages of moderate-severe TBI 
Background: Moderate-severe traumatic brain injury (TBI) is increasingly being understood as a progressive disorder, with growing evidence of reduced brain volume and white matter (WM) integrity as well as lesion expansion in the chronic phases of injury. The scale of these losses has yet to be investigated, and pattern of change across structures has received limited attention.
Objectives: (1) To measure the percentage of patients in our TBI sample showing atrophy from 5 to 20 months post-injury in the whole brain and in structures with known vulnerability to acute TBI, and (2) To examine relative vulnerability and patterns of volume loss across structures.
Methods: Fifty-six TBI patients [complicated mild to severe, with mean Glasgow Coma Scale (GCS) in severe range] underwent MRI at, on average, 5 and 20 months post-injury; 12 healthy controls underwent MRI twice, with a mean gap between scans of 25.4 months. Mean monthly percent volume change was computed for whole brain (ventricle-to-brain ratio; VBR), corpus callosum (CC), and right and left hippocampi (HPC).
Results: (1) Using a threshold of 2 z-scores below controls, 96% of patients showed atrophy across time points in at least one region; 75% showed atrophy in at least 3 of the 4 regions measured. (2) There were no significant differences in the proportion of patients who showed atrophy across structures. For those showing decline in VBR, there was a significant association with both the CC and the right HPC (P < 0.05 for both comparisons). There were also significant associations between those showing decline in (i) right and left HPC (P < 0.05); (ii) all combinations of genu, body and splenium of the CC (P < 0.05), and (iii) head and tail of the right HPC (P < 0.05 all sub-structure comparisons).
Conclusions: Atrophy in chronic TBI is robust, and the CC, right HPC and left HPC appear equally vulnerable. Significant associations between the right and left HPC, and within substructures of the CC and right HPC, raise the possibility of common mechanisms for these regions, including transneuronal degeneration. Given the 96% incidence rate of atrophy, a genetic explanation is unlikely to explain all findings. Multiple and possibly synergistic mechanisms may explain findings. Atrophy has been associated with poorer functional outcomes, but recent findings suggest there is potential to offset this. A better, understanding of the underlying mechanisms could permit targeted therapy enabling better long-term outcomes.
PMCID: PMC3978360  PMID: 24744712
atrophy; chronic; degeneration; traumatic brain injury; progression; MRI
14.  Focal right inferotemporal atrophy in AD with disproportionate visual constructive impairment 
Neurology  2003;61(11):1485-1491.
To explore the structural neuroimaging correlates of visual constructive impairment in patients with mild to moderate Alzheimer disease (AD).
There is considerable heterogeneity in the non-memory cognitive deficits associated with AD. Structural neuroimaging with MRI is an important diagnostic tool that is gaining acceptance as a surrogate measure of brain pathology in AD treatment trials. Most MRI measurements have focused on medial temporal lobe or global cortical atrophy, which may not reflect some important clinical features of AD.
Thirty-two patients with probable AD were stratified into two groups based on their relative performance on a visual constructive task, the copy of a modified Rey-Osterrieth figure (Rey). The two groups did not differ in basic demographic features or in neuropsychological performance, other than on the visual constructive task. MRI measurements of hippocampal volume, cortical gray matter volume, and focal cortical gray matter loss were performed in the patients and a group of 71 age-matched, normal controls.
Both groups showed significant, bilateral hippocampal as well as cortical gray matter volume loss relative to controls. The more spatially impaired AD group (SAD) had more right than left cortical gray matter loss, whereas the opposite was true in the less spatially impaired group (NSAD). The SAD group had significantly less gray matter in the right inferior temporal gyrus relative to the NSAD group. Atrophy of this region was correlated with performance on the Rey task in all patients with AD.
Right inferotemporal atrophy may serve as a neuroimaging marker of visual constructive impairment in mild to moderate AD. Heterogeneous cortical atrophy is a common feature of AD.
PMCID: PMC2744649  PMID: 14663029
15.  Temporal and spatial evolution of grey matter atrophy in primary progressive multiple sclerosis☆ 
Neuroimage  2014;86(100):257-264.
Grey matter (GM) atrophy occurs early in primary progressive MS (PPMS), but it is unknown whether its progression involves different brain regions at different rates, as is seen in other neurodegenerative diseases. We aimed to investigate the temporal and regional evolution of GM volume loss over 5 years and its relationship with disability progression in early PPMS.
We studied 36 patients with PPMS within five years from onset and 19 age and gender-matched healthy controls with clinical and imaging assessments at study entry and yearly for 3 years and then at 5 years. Patients were scored on the expanded disability status scale (EDSS) and MS Functional Composite (MSFC) at each time-point. An unbiased longitudinal voxel-based morphometry approach, based on high-dimensional spatial alignment within-subject, was applied to the serial imaging data. The rate of local (voxel-wise) volume change per year was compared between groups and its relationship with clinical outcomes was assessed.
Patients deteriorated significantly during the five years follow-up. Patients showed a greater decline of GM volume (p < 0.05, FWE-corrected) bilaterally in the cingulate cortex, thalamus, putamen, precentral gyrus, insula and cerebellum when compared to healthy controls over five years, although the rate of volume loss varied across the brain, and was the fastest in the cingulate cortex. Significant (p < 0.05, FWE-corrected) volume loss was detected in the left insula, left precuneus, and right cingulate cortex in patients at three years, as compared to baseline, whilst the bilateral putamen and the left superior temporal gyrus showed volume loss at five years. In patients, there was a relationship between a higher rate of volume loss in the bilateral cingulate cortex and greater clinical disability, as measured by the MSFC, at five years (Pearson's r = 0.49, p = 0.003).
Longitudinal VBM demonstrated that the progression of GM atrophy in PPMS occurs at different rates in different regions across the brain. The involvement of the cingulate cortex occurs early in the disease course, continues at a steady rate throughout the follow-up period and is associated with patient outcome. These findings provide new insights into the characteristics of GM atrophy across the brain in MS, and have potential consequences for the selection of brain atrophy as an outcome measure in neuroprotective clinical trials.
•Longitudinal VBM and TBM can be used in longitudinal studies in multiple sclerosis.•GM loss is a dynamic process in primary progressive multiple sclerosis.•The highest rate of GM reduction is seen in the cingulate gyri.•GM atrophy may be used as an outcome measure for neuroprotective clinical trials.
PMCID: PMC3898881  PMID: 24099844
Multiple sclerosis; Voxel-based morphometry; Tensor-based morphometry; Brain atrophy; Longitudinal analysis
16.  Thalamic atrophy in antero-medial and dorsal nuclei correlates with six-month outcome after severe brain injury☆ 
NeuroImage : Clinical  2013;3:396-404.
The primary and secondary damage to neural tissue inflicted by traumatic brain injury is a leading cause of death and disability. The secondary processes, in particular, are of great clinical interest because of their potential susceptibility to intervention. We address the dynamics of tissue degeneration in cortico-subcortical circuits after severe brain injury by assessing volume change in individual thalamic nuclei over the first six-months post-injury in a sample of 25 moderate to severe traumatic brain injury patients. Using tensor-based morphometry, we observed significant localized thalamic atrophy over the six-month period in antero-dorsal limbic nuclei as well as in medio-dorsal association nuclei. Importantly, the degree of atrophy in these nuclei was predictive, even after controlling for full-brain volume change, of behavioral outcome at six-months post-injury. Furthermore, employing a data-driven decision tree model, we found that physiological measures, namely the extent of atrophy in the anterior thalamic nucleus, were the most predictive variables of whether patients had regained consciousness by six-months, followed by behavioral measures. Overall, these findings suggest that the secondary non-mechanical degenerative processes triggered by severe brain injury are still ongoing after the first week post-trauma and target specifically antero-medial and dorsal thalamic nuclei. This result therefore offers a potential window of intervention, and a specific target region, in agreement with the view that specific cortico-thalamo-cortical circuits are crucial to the maintenance of large-scale network neural activity and thereby the restoration of cognitive function after severe brain injury.
•Performed acute and chronic structural MRI in 25 severe TBI patients•Tensor brain morphometry (TBM) shows localized thalamic acute-to-chronic atrophy.•Anterior, medio- and lateral-dorsal nuclei are the most significant.•Atrophy in these nuclei predicts 6-month outcome scores (GOSe).
PMCID: PMC3815017  PMID: 24273723
Traumatic brain injury; Thalamus; Tensor brain morphometry; Magnetic resonance imaging
17.  Dorsal Visual Pathway Changes in Patients with Comitant Extropia 
PLoS ONE  2010;5(6):e10931.
Strabismus is a disorder in which the eyes are misaligned. Persistent strabismus can lead to stereopsis impairment. The effect of strabismus on human brain is not unclear. The present study is to investigate whether the brain white structures of comitant exotropia patients are impaired using combined T1-weighted imaging and diffusion tensor imaging (DTI).
Principal Findings
Thirteen patients with comitant strabismus and twelve controls underwent magnetic resonance imaging (MRI) with acquisition of T1-weighted and diffusion tensor images. T1-weighted images were used to analyze the change in volume of white matter using optimized voxel-based morphology (VBM) and diffusion tensor images were used to detect the change in white matter fibers using voxel-based analysis of DTI in comitant extropia patients. VBM analysis showed that in adult strabismus, white matter volumes were smaller in the right middle occipital gyrus, right occipital lobe/cuneus, right supramarginal gyrus, right cingulate gyrus, right frontal lobe/sub-gyral, right inferior temporal gyrus, left parahippocampa gyrus, left cingulate gyrus, left occipital lobe/cuneus, left middle frontal gyrus, left inferior parietal lobule, and left postcentral gyrus, while no brain region with greater white matter volume was found. Voxel-based analysis of DTI showed lower fractional anisotropy (FA) values in the right middle occipital gyrus and right supramarginal gyrus in strabismus patients, while brain region with increased FA value was found in the right inferior frontal gyrus.
By combining VBM and voxel-based analysis of DTI results, the study suggests that the dorsal visual pathway was abnormal or impaired in patients with comitant exotropia.
PMCID: PMC2880591  PMID: 20532166
18.  Quantified MRI and cognition in TBI with diffuse and focal damage☆ 
NeuroImage : clinical  2013;2:534-541.
In patients with chronic-phase traumatic brain injury (TBI), structural MRI is readily attainable and provides rich anatomical information, yet the relationship between whole-brain structural MRI measures and neurocognitive outcome is relatively unexplored and can be complicated by the presence of combined focal and diffuse injury. In this study, sixty-three patients spanning the full range of TBI severity received high-resolution structural MRI concurrent with neuropsychological testing. Multivariate statistical analysis assessed covariance patterns between volumes of grey matter, white matter, and sulcal/subdural and ventricular CSF across 38 brain regions and neuropsychological test performance. Patients with diffuse and diffuse + focal injury were analyzed both separately and together. Tests of speeded attention, working memory, and verbal learning and memory robustly covaried with a distributed pattern of volume loss over temporal, ventromedial prefrontal, right parietal regions, and cingulate regions. This pattern was modulated by the presence of large focal lesions, but held even when analyses were restricted to those with diffuse injury. Effects were most consistently observed within grey matter. Relative to regional brain volumetric data, clinically defined injury severity (depth of coma at time of injury) showed only weak relation to neuropsychological outcome. The results showed that neuropsychological test performance in patients with TBI is related to a distributed pattern of volume loss in regions mediating mnemonic and attentional processing. This relationship holds for patients with and without focal lesions, indicating that diffuse injury alone is sufficient to cause significant neuropsychological disability in relation to regional volume loss. Quantified structural brain imaging data provides a highly sensitive index of brain integrity that is related to cognitive functioning in chronic phase TBI.
PMCID: PMC3773881  PMID: 24049744
Structural MRI; Neuropsychological assessment; Executive Function; Attention; Memory; Traumatic Brain Injury
19.  Traumatic brain injury and grey matter concentration: a preliminary voxel based morphometry study 
Background: Magnetic resonance imaging (MRI) studies have shown diffuse cerebral atrophy following traumatic brain injury. In the past, quantitative volumetric analysis of these changes was carried out by manually tracing specific regions of interest. In contrast, voxel based morphometry (VBM) is a fully automated technique that allows examination of the whole brain on a voxel by voxel basis.
Objective: To use VBM to evaluate changes in grey matter concentration following traumatic brain injury.
Methods: Nine patients with a history of traumatic brain injury (ranging from mild to severe) about one year previously were compared with nine age and sex matched healthy volunteers. T1 weighted three dimensional MRI images were acquired and then analysed with statistical parametric mapping software (SPM2). The patients with traumatic brain injury also completed cognitive testing to determine whether regional grey matter concentration correlated with a measure of attention and initial injury severity.
Results: Compared with controls, the brain injured patients had decreased grey matter concentration in multiple brain regions including frontal and temporal cortices, cingulate gyrus, subcortical grey matter, and the cerebellum. Decreased grey matter concentration correlated with lower scores on tests of attention and lower Glasgow coma scale scores.
Conclusions: Using VBM, regions of decreased grey matter concentration were observed in subjects with traumatic brain injury compared with well matched controls. In the brain injured patients, there was a relation between grey matter concentration and attentional ability.
PMCID: PMC1739692  PMID: 15965207
20.  A voxel-based morphometry study of anosmic patients 
The British Journal of Radiology  2013;86(1032):20130207.
The aim of our study was to compare volume change in grey matter (GM) and white matter (WM) in a group of subjects with anosmia and a healthy control group. We tried to find a regular pattern of atrophy within and between GM and WM and to determine whether any particular areas are more sensitive to olfactory injury.
There were 19 anosmic patients and 20 age- and sex-matched control subjects. We acquired MR images on a 3-T scanner and performed voxel-based morphometry using the VBM8 toolbox and SPM8 in a MATLAB® (MathWorks®, Natick, MA) environment.
Patients with anosmia showed a significant decrease in GM volume, mainly in the anterior cingulate cortex, middle temporal gyrus, superior temporal gyrus, fusiform gyrus, supramarginal gyrus, superior frontal gyrus, middle frontal gyrus, middle occipital gyrus, anterior insular cortex and cerebellum. In addition, we observed volume decreases in smaller areas such as the piriform cortex, the inferior temporal gyrus, the precuneus and the subcallosal gyrus. All WM areas with atrophy were near those GM areas that experienced volume loss. There was more volume atrophy in GM areas corresponding to WM areas with more volume loss. Atrophy increased with disease duration.
There is simultaneous atrophy in GM and WM, and the degree of atrophy is greater with longer disease duration. Different GM and WM areas have different sensitivities to olfactory injury.
Advances in knowledge:
This study examines the atrophy pattern in and between GM and WM—a subject that has not been widely researched previously.
PMCID: PMC3856544  PMID: 24133057
21.  Multi-parametric neuroimaging evaluation of cerebrotendinous xanthomatosis and its correlation with neuropsychological presentations 
BMC Neurology  2010;10:59.
Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder. Recent studies show that brain damage in CTX patients extends beyond the abnormalities observed on conventional magnetic resonance imaging (MRI). We studied the MRI and 99 mTc-ethyl cysteinate dimer single photon emission computed tomography (SPECT) findings of CTX patients and made a correlation with the neuropsychological presentations.
Diffusion tensor imaging (DTI) and 3D T1-weighted images of five CTX patients were compared with 15 age-matched controls. Voxel-based morphometry (VBM) was use to delineate gray matter (GM) and white matter (WM) volume loss. Fractional anisotropy (FA), mean diffusivity (MD), and eigenvalues derived from DTI were used to detect WM changes and correlate with neuropsychological results. SPECT functional studies were used to correlate with GM changes.
Cognitive results showed that aside from moderate mental retardation, the patient group performed worse in all cognitive domains. Despite the extensive GM atrophy pattern, the cerebellum, peri-Sylvian regions and parietal-occipital regions were correlated with SPECT results. WM atrophy located in the peri-dentate and left cerebral peduncle areas corresponded with changes in diffusion measures, while axial and radial diffusivity suggested both demyelinating and axonal changes. Changes in FA and MD were preceded by VBM in the corpus callosum and corona radiata. Cognitive results correlated with FA changes.
In CTX, GM atrophy affected the perfusion patterns. Changes in WM included atrophy, and axonal changes with demyelination. Disconnection of major fiber tracts among different cortical regions may contribute to cognitive impairment.
PMCID: PMC2909944  PMID: 20602799
22.  Modulation of the cAMP signaling pathway after traumatic brain injury 
Experimental neurology  2007;208(1):145-158.
Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipram-treated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI.
PMCID: PMC2141537  PMID: 17916353
camp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI
23.  Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury 
Brain  2011;134(3):759-768.
Cognitive dysfunction is a devastating consequence of traumatic brain injury that affects the majority of those who survive with moderate-to-severe injury, and many patients with mild head injury. Disruption of key monoaminergic neurotransmitter systems, such as the dopaminergic system, may play a key role in the widespread cognitive dysfunction seen after traumatic axonal injury. Manifestations of injury to this system may include impaired decision-making and impulsivity. We used the Cambridge Gambling Task to characterize decision-making and risk-taking behaviour, outside of a learning context, in a cohort of 44 patients at least six months post-traumatic brain injury. These patients were found to have broadly intact processing of risk adjustment and probability judgement, and to bet similar amounts to controls. However, a patient preference for consistently early bets indicated a higher level of impulsiveness. These behavioural measures were compared with imaging findings on diffusion tensor magnetic resonance imaging. Performance in specific domains of the Cambridge Gambling Task correlated inversely and specifically with the severity of diffusion tensor imaging abnormalities in regions that have been implicated in these cognitive processes. Thus, impulsivity was associated with increased apparent diffusion coefficient bilaterally in the orbitofrontal gyrus, insula and caudate; abnormal risk adjustment with increased apparent diffusion coefficient in the right thalamus and dorsal striatum and left caudate; and impaired performance on rational choice with increased apparent diffusion coefficient in the bilateral dorsolateral prefrontal cortices, and the superior frontal gyri, right ventrolateral prefrontal cortex, the dorsal and ventral striatum, and left hippocampus. Importantly, performance in specific cognitive domains of the task did not correlate with diffusion tensor imaging abnormalities in areas not implicated in their performance. The ability to dissociate the location and extent of damage with performance on the various task components using diffusion tensor imaging allows important insights into the neuroanatomical basis of impulsivity following traumatic brain injury. The ability to detect such damage in vivo may have important implications for patient management, patient selection for trials, and to help understand complex neurocognitive pathways.
PMCID: PMC3044832  PMID: 21310727
traumatic brain injury; diffusion tensor imaging; decision-making
24.  Magnetic Resonance Imaging And Brain Histopathology In Neuropsychiatric Systemic Lupus Erythematosus 
Magnetic resonance imaging (MRI) often demonstrates brain lesions in neuropsychiatric systemic lupus erythematosus (NPSL). The present study compared post-mortem histopathology with pre-mortem MRI in NPSL.
200 subjects with NPSLE were studied prospectively with MRI over a 10-year period during which 22 subjects died. In 14 subjects, a brain autopsy with histopathology that permitted direct comparison with pre mortem MRI was successfully obtained. Surface anatomy was used to determine the approximate location of individual lesions.
Pre mortem MRI findings in fatal NPSLE were small focal white matter lesions (100%), cortical atrophy (64%), ventricular dilation (57%), cerebral edema (50%), diffuse white matter abnormalities (43%), focal atrophy (36%), cerebral infarction (29%), acute leukoencephalopathy (25%), intracranial hemorrhage (21%), and calcifications (7%). Microscopic findings in fatal NPSLE included global ischemic changes (57%), parenchymal edema (50%), microhemorrhages (43%), glial hyperplasia (43%), diffuse neuronal/axonal loss (36%), resolved cerebral infarction (33%), microthomboemboli (29%), blood vessel remodeling (29%), acute cerebral infarction (14%), acute macrohemorrhages (14%), and resolved intracranial hemorrhages (7%). Cortical atrophy and ventricular dilation seen by MRI predicted brain mass at autopsy (r = -0.72, p = 0.01, and r = -0.77, p =0.01, respectively). Cerebral autopsy findings, including infarction, cerebral edema, intracranial hemorrhage, calcifications, cysts, and focal atrophy were also predicted accurately by pre mortem MRI.
Brain lesions in NPSLE detected by MRI accurately represent serious underlying cerebrovascular and parenchymal brain injury on pathology.
PMCID: PMC3586567  PMID: 19880162
SLE; Neuropsychiatric; Magnetic Resonance; NPSLE; MRI; Autopsy
25.  Traumatic injury to the immature frontal lobe: A new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits 
Developmental neuroscience  2013;35(6):474-490.
Traumatic brain injury in children commonly involves the frontal lobes, and is associated with distinct structural and behavioral changes. Despite the clinical significance of injuries localized to this region during brain development, the mechanisms underlying secondary damage and long-term recovery are poorly understood. Here we have characterized the first model of unilateral focal traumatic injury to the developing frontal lobe. Male C57Bl/6J mice at postnatal day (p) 21, an age approximating a toddler-aged child, received a controlled cortical impact or sham surgery to the left frontal lobe and were euthanized 1 and 7 d later. A necrotic cavity and local inflammatory response were largely confined to the unilateral frontal lobe, dorsal corpus callosum and striatum anterior to Bregma. While cell death and accumulated beta-amyloid precursor protein were characteristic features of the peri-contusional motor cortex, corpus callosum, cingulum and dorsal striatum, underlying structures including the hippocampus showed no overt pathology. To determine the long-term functional consequences of injury at p21, two additional cohorts were subjected to a battery of behavioral tests in adolescence (p35-45) or adulthood (p70-80). In both cohorts, brain-injured mice showed normal levels of anxiety, sociability, spatial learning and memory. The signature phenotypic features were deficits in motor function and motor learning, coincident with a reduction in ipsilateral cortical brain volumes. Together, these findings demonstrate classic morphological features of a focal traumatic injury, including early cell death and axonal injury, and long-term volumetric loss of cortical volumes. The presence of deficits in sensorimotor function and coordination in the absence of abnormal findings related to anxiety, sociability and memory, likely reflect several variables including the unique location of the injury and the emergence of favorable compensatory mechanisms during subsequent brain development.
PMCID: PMC3923401  PMID: 24247103
Traumatic brain injury; frontal lobe; behavior; pathology; development; motor deficit

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