Alexander C. Mamourian

Brain activation during working memory 1 month after mild traumatic brain injury : A functional MRI study

Objective: To assess patterns of regional brain activation in response to varying working memory loads shortly after mild traumatic brain injury (MTBI). Background: Many individuals complain of memory difficulty shortly after MTBI. Memory performance in these individuals can be normal despite these complaints. Methods: Brain activation patterns in response to a working memory task (auditory n-back) were assessed with functional MRI in 12 MTBI patients within 1 month of their injury and in 11 healthy control subjects. Results: Brain activation patterns differed between MTBI patients and control subjects in response to increasing working memory processing loads. Maximum intensity projections of statistical parametric maps in control subjects showed bifrontal and biparietal activation in response to a low processing load, with little additional increase in activation associated with the high load task. MTBI patients showed some activation during the low processing load task but significantly increased activation during the high load condition, particularly in the right parietal and right dorsolateral frontal regions. Task performance did not differ significantly between groups. Conclusion: MTBI patients differed from control subjects in activation pattern of working memory circuitry in response to different processing loads, despite similar task performance. This suggests that injury-related changes in ability to activate or to modulate working memory processing resources may underlie some of the memory complaints after MTBI.

Differential Working Memory Load Effects after Mild Traumatic Brain Injury

The objective of this study was to explore the effects of increasing working memory (WM) processing load on previously observed abnormalities in activation of WM circuitry shortly after mild traumatic brain injury (MTBI). Brain activation patterns in response to increasing WM processing load (auditory n-back: 0-, 1-, 2-, and 3-back conditions) were assessed with fMRI in 18 MTBI patients within 1 month of their injury and in 12 healthy controls. Performance accuracy on these tasks was also measured. Brain activation patterns differed between MTBI patients and controls in response to increasing WM processing loads. Controls maintained their ability to increase activation in regions of WM circuitry with each increase in WM processing load. MTBI patients showed disproportionately increased activation during the moderate processing load condition, but very little increase in activation associated with the highest processing load condition. Task performance did not differ significantly between groups on any task condition. MTBI patients showed a different pattern of allocation of processing resources associated with a high processing load condition compared to healthy controls, despite similar task performance. This suggests that injury-related changes in ability to activate or modulate WM processing resources might underlie some of the memory complaints after MTBI.

Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI

Objective: To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI). Methods: Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis. Results: The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level. Conclusions: Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.

Neuroanatomic substrates of semantic memory impairment in Alzheimer's disease: patterns of functional MRI activation.

Impairment in semantic processing occurs early in Alzheimers disease (AD) and differential impact on subtypes of semantic relations have been reported, yet there is little data on the neuroanatomic basis of these deficits. Patients with mild AD and healthy controls underwent 3 functional MRI auditory stimulation tasks requiring semantic or phonological decisions (match-mismatch) about word pairs (category-exemplar, category-function, pseudoword). Patients showed a significant performance deficit only on the exemplar task. On voxel-based fMRI activation analyses, controls showed a clear activation focus in the left superior temporal gyrus for the phonological task; patients showed additional foci in the left dorsolateral prefrontal and bilateral cingulate areas. On the semantic tasks, predominant activation foci were seen in the inferior and middle frontal gyrus (left greater than right) in both groups but patients showed additional activation suggesting compensatory recruitment of locally expanded foci and remote regions, for example, right frontal activation during the exemplar task. Covariance analyses indicated that exemplar task performance was strongly related to signal increase in bilateral medial prefrontal cortex. The authors conclude that fMRI can reveal similarities and differences in functional neuroanatomical processing of semantic and phonological information in mild AD compared to healthy elderly, and can help to bridge cognitive and neural investigations of the integrity of semantic networks in AD.

Regional brain atrophy in cognitively intact adults with a single APOE ε4 allele

Objective: To determine whether cognitively intact adults with the APOE ε3/ε4 genotype show reduced gray matter density on voxel-based morphometry (VBM) vs those homozygous for the ε3 allele. Methods: Participants were healthy, cognitively intact, right-handed adults, age 19 to 80, who completed genotyping, neuropsychological testing, and MRI. Forty-nine participants had the ε3/ε3 genotype and 27 had the ε3/ε4 genotype. Gray matter data were analyzed using the general linear model as implemented in the Statistical Parametric Mapping package, adjusting for age and sex. Results: The ε3/ε4 participants showed lower gray matter density than the ε3/ε3 participants in right medial temporal and bilateral frontotemporal regions as well as other areas. There were no regions in which ε3/ε4 participants showed higher gray matter density than ε3/ε3 participants. Conclusions: Regionally reduced gray matter density is detectable in cognitively intact adults with a single copy of the APOE ε4 allele.

The Relationship between fMRI Activation and Cerebral Atrophy: Comparison of Normal Aging and Alzheimer Disease

Functional MRI has recently been used to examine activation associated with aging and dementia, yet little is known regarding the effect of cerebral atrophy on fMRI signal. The purpose of this study was to examine the relationship between measures of global and regionally specific atrophy and fMRI activation in normal aging and in Alzheimer disease (AD). Two groups of subjects were studied with echoplanar imaging and quantitative structural volumetry: healthy controls spanning a broad age and atrophy range (n = 16) and patients with mild AD (n = 8). Results from a semantic task previously found to activate left inferior frontal (LIFG) and left superior temporal (LSTG) gyri were analyzed. The correlations between clusters of activation in the LIFG and LSTG and measures of local atrophy in the LIFG and LSTG regions were evaluated. For control subjects, there was no significant correlation between activation and regional or total brain atrophy (for LIFG r = -0.03, NS; for LSTG r = 0.20, NS). In contrast, for AD patients, there was a significant positive correlation between atrophy and activation in LIFG (r = 0.70, P = 0.05) but not LSTG (r = 0.00, NS). These results suggest that activation of language regions and atrophy within those regions may be independent among healthy adults spanning a broad age and atrophy range. However, in AD, a relationship exists in the LIFG that may reflect compensatory recruitment of cortical units or disease-specific changes in the hemodynamic response.

Event-related functional magnetic resonance imaging of response inhibition in obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) has been hypothesized to involve inhibitory control dysfunction related to abnormal frontal-striatal-thalamic-cortical (FSTC) circuitry. METHODS We examined the neural substrates of response inhibition in adults with OCD using functional magnetic resonance imaging (fMRI) and a go/no-go task. Participants consisted of 12 adults with OCD and 14 healthy comparison subjects. RESULTS During response inhibition, healthy adults showed predominantly right-hemisphere activation including the right inferior frontal gyrus, whereas the patient group showed a more diffuse, bilateral pattern of activation. Furthermore, the OCD group demonstrated less activation than the comparison group in several right-hemisphere regions during response inhibition, including inferior and medial frontal gyri. Symptom severity was inversely correlated with activation in right orbitofrontal and anterior cingulate gyri and positively correlated with thalamic and posterior cortical activations. Neither depressed mood nor medication status could account for the results. CONCLUSIONS These findings indicate that adults with OCD demonstrate underactivation of FSTC circuitry during response inhibition. Results suggest that the thalamus and related circuitry may play a role in the expression or intensity of OCD symptoms, whereas right frontal subregions may be involved in the suppression of symptoms.

Brain activation patterns associated with working memory in relapsing-remitting MS.

Background: Patients with multiple sclerosis (MS) show changes in brain activation patterns during visual and motor tasks that include decreases in the typical local network for a function and increases in other brain regions. Objective: To determine whether brain activation patterns associated with working memory are affected by MS. Methods: Activation of working memory circuitry was examined using an fMRI n-back task in adults with mild relapsing-remitting MS (RRMS; n = 10) and demographically matched healthy controls (n = 10). Results: Group differences in brain activation emerged during both low- and high-demand conditions (p < 0.001). Overall, patients showed less activation than controls in core prefrontal and parietal regions of working memory circuitry, and greater activation in other regions within and beyond typical working memory circuitry, including bilateral medial frontal, cingulate, parietal, bilateral middle temporal, and occipital regions. Conclusions: Relative to controls, patients with mild RRMS showed shifts in brain activation patterns within and beyond typical components of working memory circuitry.

Regionally specific atrophy of the corpus callosum in AD, MCI and cognitive complaints

The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimers disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests.

Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay.

Interstitial duplications of proximal 15q containing the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region have been found in patients with autism or atypical autism. In these cases with an abnormal phenotype, the duplications were maternally derived. Paternal origin of the duplication has been associated with a normal phenotype. We report on a patient who presented with nonspecific developmental delay and partial agenesis of the rostral corpus callosum. Fluorescence in situ hybridization (FISH) studies using probes specific for the PWS/AS region demonstrated a double signal on one chromosome 15, indicating the presence of an interstitial duplication of proximal 15q involving the PWS/ AS region in the patient. Parental chromosomes were normal with FISH studies. Methylation analysis at exon alpha of the SNRPN locus showed a maternal band at 4.2 kb and a paternal band of apparent double intensity at 0.9 kb, suggestive of one copy of the maternal allele and two copies of the paternal allele in the patient. Microsatellite analysis was informative at the GABRB3 locus in the family, which showed the inheritance of two different paternal alleles and a maternal allele in the patient consistent with the origin of this duplication from an unequal crossing over between the two chromosome 15 homologs in the father. This is the first report of an abnormal phenotype associated with a paternally derived duplication of proximal 15q shown to contain the PWS/AS region by molecular techniques.