Susan Y. Bookheimer

PATTERNS OF BRAIN ACTIVATION IN PEOPLE AT RISK FOR ALZHEIMER’S DISEASE

BACKGROUND The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimers disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimers disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition. METHODS We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later. RESULTS Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimers disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory. CONCLUSIONS Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimers disease and may predict a subsequent decline in memory.

Modulating emotional responses: effects of a neocortical network on the limbic system.

Humans share with animals a primitive neural system for processing emotions such as fear and anger. Unlike other animals, humans have the unique ability to control and modulate instinctive emotional reactions through intellectual processes such as reasoning, rationalizing, and labeling our experiences. This study used functional MRI to identify the neural networks underlying this ability. Subjects either matched the affect of one of two faces to that of a simultaneously presented target face (a perceptual task) or identified the affect of a target face by choosing one of two simultaneously presented linguistic labels (an intellectual task). Matching angry or frightened expressions was associated with increased regional cerebral blood flow (rCBF) in the left and right amygdala, the brains primary fear centers. Labeling these same expressions was associated with a diminished rCBF response in the amygdalae. This decrease correlated with a simultaneous increase in rCBF in the right prefrontal cortex, a neocortical region implicated in regulating emotional responses. These results provide evidence for a network in which higher regions attenuate emotional responses at the most fundamental levels in the brain and suggest a neural basis for modulating emotional experience through interpretation and labeling.

Remembering episodes: a selective role for the hippocampus during retrieval

Some memories are linked to a specific time and place, allowing one to re-experience the original event, whereas others are accompanied only by a feeling of familiarity. To uncover the distinct neural bases for these two types of memory, we measured brain activity during memory retrieval using event-related functional magnetic resonance imaging. We show that activity in the hippocampus increased only when retrieval was accompanied by conscious recollection of the learning episode. Hippocampal activity did not increase for items recognized based on familiarity or for unrecognized items. These results indicate that the hippocampus selectively supports the retrieval of episodic memories.

Form and Content: Dissociating Syntax and Semantics in Sentence Comprehension

The distinction between syntax (sentence form) and semantics (sentence meaning) is fundamental to our thinking about language. Whether and where this distinction is represented at the neural level is still a matter of considerable debate. In the present fMRI study, we examined the neural correlates of syntactic and semantic functions using an innovative activation paradigm specifically designed to unequivocally disentangle syntactic from lexicosemantic aspects of sentence processing. Our findings strongly indicate that a part of Brocas area (BA 44, pars opercularis) is critically implicated in processing syntactic information, whereas the lower portion of the left inferior frontal gyrus (BA 47, pars orbitalis) is selectively involved in processing the semantic aspects of a sentence.

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)—a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7–64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

The Neural Correlates of Motor Skill Automaticity

Acquisition of a new skill is generally associated with a decrease in the need for effortful control over performance, leading to the development of automaticity. Automaticity by definition has been achieved when performance of a primary task is minimally affected by other ongoing tasks. The neural basis of automaticity was examined by testing subjects in a serial reaction time (SRT) task under both single-task and dual-task conditions. The diminishing cost of dual-task performance was used as an index for automaticity. Subjects performed the SRT task during two functional magnetic imaging sessions separated by 3 h of behavioral training over multiple days. Behavioral data showed that, by the end of testing, subjects had automated performance of the SRT task. Before behavioral training, performance of the SRT task concurrently with the secondary task elicited activation in a wide network of frontal and striatal regions, as well as parietal lobe. After extensive behavioral training, dual-task performance showed comparatively less activity in bilateral ventral premotor regions, right middle frontal gyrus, and right caudate body; activity in other prefrontal and striatal regions decreased equally for single-task and dual-task conditions. These data suggest that lateral and dorsolateral prefrontal regions, and their corresponding striatal targets, subserve the executive processes involved in novice dual-task performance. The results also showed that supplementary motor area and putamen/globus pallidus regions showed training-related decreases for sequence conditions but not for random conditions, confirming the role of these regions in the representation of learned motor sequences.

Noninvasive assessment of language dominance in children and adolescents with functional MRI: a preliminary study.

Background Assessment of language organization is crucial in patients considered for epilepsy surgery. In children, the current techniques, intra-carotid amobarbital test (IAT) for language dominance, and cortical electrostimulation mapping (ESM), are invasive and risky. Functional magnetic resonance imaging (fMRI) is an alternative method for noninvasive functional mapping, through the detection of the hemodynamic changes associated with neuronal activation. We used fMRI to assess language dominance in children with partial epilepsy. Methods Eleven right handed children and adolescents performed a word generation task during fMRI acquisition focused on the frontal lobes. Areas where the signal time course correlated with the test paradigm (r = 0.7) were considered activated. Extent and magnitude of signal changes were used to calculate asymmetry indices. Seven patients had IAT, ESM, or surgery outcome available for comparison. Results fMRI language dominance always agreed with IAT (6 cases) and ESM (1 case), showing left dominance in six and bilateral language in one. fMRI demonstrated left dominance in three additional children, and right dominance in one with early onset of left temporal epilepsy. Four children whose initial studies were equivocal due to noncompliance or motion artifacts were restudied successfully. Conclusions fMRI can be used to assess language lateralization noninvasively in children. It has the potential to replace current functional mapping techniques in patients, and to provide important data on brain development.

Language switching and language representation in Spanish-English bilinguals: An fMRI study

The current experiment was designed to investigate the nature of cognitive control in within- and between-language switching in bilingual participants. To examine the neural substrate of language switching we used functional magnetic resonance imaging (fMRI) as subjects named pictures in one language only or switched between languages. Participants were also asked to name (only in English) a separate set of pictures as either the actions or the objects depicted or to switch between these two types of responses on each subsequent picture. Picture naming compared to rest revealed activation in the dorsolateral prefrontal cortex, which extended down into Broca’s area in the left hemisphere. There were no differences in the activation pattern for each language. English and Spanish both activated overlapping areas of the brain. Similarly, there was no difference in activation for naming actions or objects in English. However, there was increased intensity of activation in the dorsolateral prefrontal cortex for switching between languages relative to no-switching, an effect which was not observed for naming of actions or objects in English. We suggest that the dorsolateral prefrontal cortex serves to attenuate interference that results from having to actively enhance and suppress two languages in alternation. These results are consistent with the view that switching between languages involves increased general executive processing. Finally, our results are consistent with the view that different languages are represented in overlapping areas of the brain in early bilinguals.

An fMRI investigation of race-related amygdala activity in African-American and Caucasian-American individuals

Functional magnetic resonance imaging (fMRI) was used to examine the nature of amygdala sensitivity to race. Both African-American and Caucasian-American individuals showed greater amygdala activity to African-American targets than to Caucasian-American targets, suggesting that race-related amygdala activity may result from cultural learning rather than from the novelty of other races. Additionally, verbal encoding of African-American targets produced significantly less amygdala activity than perceptual encoding of African-American targets.

Neural Correlates of Facial Affect Processing in Children and Adolescents With Autism Spectrum Disorder

OBJECTIVE To examine the neural basis of impairments in interpreting facial emotions in children and adolescents with autism spectrum disorders (ASD). METHOD Twelve children and adolescents with ASD and 12 typically developing (TD) controls matched faces by emotion and assigned a label to facial expressions while undergoing functional magnetic resonance imaging. RESULTS Both groups engaged similar neural networks during facial emotion processing, including activity in the fusiform gyrus (FG) and prefrontal cortex. However, between-group analyses in regions of interest revealed that when matching facial expressions, the ASD group showed significantly less activity than the TD group in the FG, but reliably greater activity in the precuneus. During the labeling of facial emotions, no between-group differences were observed at the behavioral or neural level. Furthermore, activity in the amygdala was moderated by task demands in the TD group but not in the ASD group. CONCLUSIONS These findings suggest that children and adolescents with ASD in part recruit different neural networks and rely on different strategies when processing facial emotions. High-functioning individuals with ASD may be relatively unimpaired in the cognitive assessment of basic emotions, yet still show differences in the automatic processing of facial expressions.