Sally Durgerian

Motor Sequence Complexity and Performing Hand Produce Differential Patterns of Hemispheric Lateralization

Studies in brain damaged patients conclude that the left hemisphere is dominant for controlling heterogeneous sequences performed by either hand, presumably due to the cognitive resources involved in planning complex sequential movements. To determine if this lateralized effect is due to asymmetries in primary sensorimotor or association cortex, whole-brain functional magnetic resonance imaging was used to measure differences in volume of activation while healthy right-handed subjects performed repetitive (simple) or heterogeneous (complex) finger sequences using the right or left hand. Advanced planning, as evidenced by reaction time to the first key press, was greater for the complex than simple sequences and for the left than right hand. In addition to the expected greater contralateral activation in the sensorimotor cortex (SMC), greater left hemisphere activation was observed for left, relative to right, hand movements in the ipsilateral left superior parietal area and for complex, relative to simple, sequences in the left premotor and parietal cortex, left thalamus, and bilateral cerebellum. No such volumetric asymmetries were observed in the SMC. Whereas the overall MR signal intensity was greater in the left than right SMC, the extent of this asymmetry did not vary with hand or complexity level. In contrast, signal intensity in the parietal and premotor cortex was greater in the left than right hemisphere and for the complex than simple sequences. Signal intensity in the caudal anterior cerebellum was greater bilaterally for the complex than simple sequences. These findings suggest that activity in the SMC is associated with execution requirements shared by the simple and complex sequences independent of their differential cognitive requirements. In contrast, consistent with data in brain damaged patients, the left dorsal premotor and parietal areas are engaged when advanced planning is required to perform complex motor sequences that require selection of different effectors and abstract organization of the sequence, regardless of the performing hand.

Semantic memory activation in amnestic mild cognitive impairment

Cognitively intact older individuals at risk for developing Alzheimers disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65-85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimers disease based on having at least one ApoE epsilon4 allele and a positive family history of Alzheimers disease (At Risk); and cognitively intact participants without Alzheimers disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame--Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimers disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.

Functional magnetic resonance imaging response to increased verbal working memory demands among patients with multiple sclerosis

Multiple sclerosis (MS) patients frequently experience impaired verbal working memory (VWM). Functional magnetic resonance imaging (fMRI) may help identify neural mechanisms underlying these deficits. Neuroimaging studies of healthy adults have characterized responses associated with increased VWM demands during the n‐Back task, suggesting that this experimental paradigm could help identify neural correlates of VWM deficits among MS patients. Fifteen MS patients and 15 matched control participants completed the n‐Back during whole‐brain fMRI. Mean signal during adjacent 0‐Back blocks was subtracted, on a voxel‐wise basis, from mean signal observed during n‐Back blocks. Resulting difference scores for 1‐, 2‐, and 3‐Back were compared across groups and difficulty levels. Signal intensity was positively related to difficulty level in anterior regions, including premotor, supplementary motor, and dorsolateral prefrontal cortices. MS patients exhibited significantly greater intensity in these areas compared to controls during the 1‐Back, while portions of the left superior frontal gyrus, cingulate, and parahippocampal gyri were relatively less intense at more difficult levels. MS group responses were slower during the 1‐Back and tended to be slower during the 3‐Back; however, accuracy did not differ at any level. Lesion load was positively related to only 1‐Back activity and unrelated to any performance measure. Results suggest that compensatory activity occurs among MS patients matched on performance accuracy. Furthermore, compensatory activity occurs predominantly in regions associated with VWM, and this may decline relative to controls as task demands increase. These findings may help to explain why MS patient performance decreases as a function of effort on neuropsychological tests. Hum Brain Mapp, 2005.

Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease

We examined the impact of physical activity (PA) on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimers disease (AD). Hippocampal volume was measured from structural magnetic resonance imaging (MRI) scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-ε4) allele. Four subgroups were studied: Low Risk/High PA (n = 24), Low Risk/Low PA (n = 34), High Risk/High PA (n = 22), and High Risk/Low PA (n = 17). Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, pre-central gyrus, caudal middle frontal gyrus, cortical white matter (WM), and total gray matter (GM). These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories.

Interactive Effects of Physical Activity and APOE-ε4 on BOLD Semantic Memory Activation in Healthy Elders

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimers disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65-85) cognitively intact adults. A cross-sectional design was used with four groups (n=17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous>unfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline.

Semantic memory activation in individuals at risk for developing Alzheimer disease

Objective: To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE ε4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names. Methods: Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no ε4 allele (control [CON]); 2) family history, no ε4 allele (FH); and 3) family history and ε4 allele (FH+ε4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). Results: Cognitively intact older adults with AD risk factors (FH and FH+ε4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+ε4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. Conclusions: Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.

fMRI study of episodic memory in relapsing-remitting MS: Correlation with T2 lesion volume

Objective: To determine whether memory loss in patients with multiple sclerosis (MS) results from faulty encoding or retrieval, we correlated extent of T2-weighted lesion involvement with brain activation patterns on fMRI scans obtained while patients performed a verbal episodic memory task. Methods: We performed a neurologic examination, neuropsychological testing, and an event-related fMRI scan on 36 patients with relapsing-remitting MS. In addition, we obtained T2-weighted structural MRI scans to measure lesion volume. We performed a regression analysis to examine the association between lesion volume and regional brain activation. Results: Increasing lesion volume correlated with increasing magnitude of brain activation, primarily in the left frontal and parietal association cortices. Significant correlations of function with lesion volume were primarily observed during the memory retrieval phase of the task. Conclusions: These results extend previous fMRI studies in multiple sclerosis (MS) by demonstrating an association between greater disease burden and increased neural recruitment during episodic memory. In addition, the stronger correlations observed between lesion volume and brain activation during retrieval than encoding would suggest that retrieval processes are more affected by MS-related cerebral pathology.

Network topology and functional connectivity disturbances precede the onset of Huntington’s disease

Cognitive, motor and psychiatric changes in prodromal Huntingtons disease have nurtured the emergent need for early interventions. Preventive clinical trials for Huntingtons disease, however, are limited by a shortage of suitable measures that could serve as surrogate outcomes. Measures of intrinsic functional connectivity from resting-state functional magnetic resonance imaging are of keen interest. Yet recent studies suggest circumscribed abnormalities in resting-state functional magnetic resonance imaging connectivity in prodromal Huntingtons disease, despite the spectrum of behavioural changes preceding a manifest diagnosis. The present study used two complementary analytical approaches to examine whole-brain resting-state functional magnetic resonance imaging connectivity in prodromal Huntingtons disease. Network topology was studied using graph theory and simple functional connectivity amongst brain regions was explored using the network-based statistic. Participants consisted of gene-negative controls (n = 16) and prodromal Huntingtons disease individuals (n = 48) with various stages of disease progression to examine the influence of disease burden on intrinsic connectivity. Graph theory analyses showed that global network interconnectivity approximated a random network topology as proximity to diagnosis neared and this was associated with decreased connectivity amongst highly-connected rich-club network hubs, which integrate processing from diverse brain regions. However, functional segregation within the global network (average clustering) was preserved. Functional segregation was also largely maintained at the local level, except for the notable decrease in the diversity of anterior insula intermodular-interconnections (participation coefficient), irrespective of disease burden. In contrast, network-based statistic analyses revealed patterns of weakened frontostriatal connections and strengthened frontal-posterior connections that evolved as disease burden increased. These disturbances were often related to long-range connections involving peripheral nodes and interhemispheric connections. A strong association was found between weaker connectivity and decreased rich-club organization, indicating that whole-brain simple connectivity partially expressed disturbances in the communication of highly-connected hubs. However, network topology and network-based statistic connectivity metrics did not correlate with key markers of executive dysfunction (Stroop Test, Trail Making Test) in prodromal Huntingtons disease, which instead were related to whole-brain connectivity disturbances in nodes (right inferior parietal, right thalamus, left anterior cingulate) that exhibited multiple aberrant connections and that mediate executive control. Altogether, our results show for the first time a largely disease burden-dependent functional reorganization of whole-brain networks in prodromal Huntingtons disease. Both analytic approaches provided a unique window into brain reorganization that was not related to brain atrophy or motor symptoms. Longitudinal studies currently in progress will chart the course of functional changes to determine the most sensitive markers of disease progression.

Neural activation during response inhibition differentiates blast from mechanical causes of mild to moderate traumatic brain injury.

Military personnel involved in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) commonly experience blast-induced mild to moderate traumatic brain injury (TBI). In this study, we used task-activated functional MRI (fMRI) to determine if blast-related TBI has a differential impact on brain activation in comparison with TBI caused primarily by mechanical forces in civilian settings. Four groups participated: (1) blast-related military TBI (milTBI; n=21); (2) military controls (milCON; n=22); (3) non-blast civilian TBI (civTBI; n=21); and (4) civilian controls (civCON; n=23) with orthopedic injuries. Mild to moderate TBI (MTBI) occurred 1 to 6 years before enrollment. Participants completed the Stop Signal Task (SST), a measure of inhibitory control, while undergoing fMRI. Brain activation was evaluated with 2 (mil, civ)×2 (TBI, CON) analyses of variance, corrected for multiple comparisons. During correct inhibitions, fMRI activation was lower in the TBI than CON subjects in regions commonly associated with inhibitory control and the default mode network. In contrast, inhibitory failures showed significant interaction effects in the bilateral inferior temporal, left superior temporal, caudate, and cerebellar regions. Specifically, the milTBI group demonstrated more activation than the milCON group when failing to inhibit; in contrast, the civTBI group exhibited less activation than the civCON group. Covariance analyses controlling for the effects of education and self-reported psychological symptoms did not alter the brain activation findings. These results indicate that the chronic effects of TBI are associated with abnormal brain activation during successful response inhibition. During failed inhibition, the pattern of activation distinguished military from civilian TBI, suggesting that blast-related TBI has a unique effect on brain function that can be distinguished from TBI resulting from mechanical forces associated with sports or motor vehicle accidents. The implications of these findings for diagnosis and treatment of TBI are discussed.

Lifestyle and Genetic Contributions to Cognitive Decline and Hippocampal Structure and Function in Healthy Aging

BACKGROUND Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ε4 allele could moderate the effect of PA or CA on hippocampal structure or function. METHODS Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI. RESULTS After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE 4 status such that engagement in PA reduced the risk of cognitive decline in APOE 4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus. CONCLUSIONS Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.