Natalia M. Kleinhans

Abnormal functional connectivity in autism spectrum disorders during face processing

Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning adults with ASD and 21 age-and IQ-matched control adults. Activation during identification of previously viewed faces and houses using a one-back paradigm was compared. The fusiform face area (FFA) was individually localized in each participant and used as the seed point for functional connectivity analyses. The degree of correlation between FFA and the extended neural circuitry involved in face identification was tested. A whole brain analysis was also conducted in order to determine whether connectivity from the FFA to aberrant brain locations was present in the ASD group. Measures of clinical severity (ADOS social score and ADI-R social score) were included as independent variables into the functional connectivity analyses. Significant FFA-amygdala and FFA-superior temporal sulcus functional connectivity was found in both the ASD and control participants. However, the control group had significantly increased connectivity to the left amygdala and the posterior cingulate compared to ASD. Post hoc analyses additionally found increased connectivity to the thalamus in the controls. A significant relationship between abnormal functional connectivity and clinical severity in the ASD group was observed. Specifically, greater social impairment was associated with reduced FFA-amygdala connectivity and increased FFA-right inferior frontal connectivity. These results suggest that abnormal neural connections within the limbic system may contribute to the social impairments observed in ASD.

Executive Functions in Autism and Asperger's Disorder: Flexibility, Fluency, and Inhibition

The Color-Word Interference Test, Trail Making Test, Verbal Fluency Test, and Design Fluency Test from the Delis-Kaplan Executive Function System (Delis, Kaplan, & Kramer, 2001) were administered to 12 high-functioning adults and adolescents with autistic disorder or Aspergers disorder. Each test included a switching condition in addition to baseline and/or other executive-function conditions. Participants performed significantly below average on a composite measure of executive functioning adjusted for baseline cognitive ability. Complex verbal tasks that required cognitive switching and initiation of efficient lexical retrieval strategies produced the most consistent deficits, whereas cognitive inhibition was intact. We discuss implications of these findings for understanding the neurocognitive substrates of autistic spectrum disorders.

Reduced Neural Habituation in the Amygdala and Social Impairments in Autism Spectrum Disorders

OBJECTIVE Amygdala dysfunction has been proposed as a critical component in social impairment in autism spectrum disorders. This study was designed to investigate whether abnormal habituation characterizes amygdala dysfunction in autism spectrum disorders and whether the rate of amygdala habituation is related to social impairment. METHOD Using functional MRI, the authors measured change over time in activation of the amygdala and fusiform gyrus to neutral facial stimuli in adults with autism spectrum disorders and healthy comparison adults. RESULTS The comparison group evidenced significantly greater amygdala habituation bilaterally than the autism spectrum group. There were no group differences in overall fusiform habituation. For the autism spectrum group, lower levels of habituation of the amygdala to the face stimuli were associated with more severe social impairment. CONCLUSIONS These results suggest amygdala hyperarousal in autism spectrum disorders in response to socially relevant stimuli. Further, sustained amygdala arousal may contribute to the social deficits observed in autism spectrum disorders.

Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer's disease

In patients with Alzheimers disease, but not in health controls, longitudinal magnetic resonance spectroscopy shows a striking decline in the neuronal marker, N-acetyl aspartate, despite little decline in underlying grey-matter volume.

Activation in brain energy regulation and reward centers by food cues varies with choice of visual stimulus

Objective:To develop a non-invasive method of studying brain mechanisms involved in energy homeostasis and appetite regulation in humans by using visual food cues that are relevant to individuals attempting weight loss.Design:Functional magnetic resonance imaging (fMRI) was used to compare brain activation in regions of interest between groups of food photographs.Participants:Ten healthy, non-obese women who were not dieting for weight loss.Measurements:Independent raters viewed food photographs and evaluated whether the foods depicted should be eaten by individuals attempting a calorically-restricted diet. Based on their responses, we categorized photographs into ‘non-fattening’ and ‘fattening’ food groups, the latter characterized by high-caloric content and usually also high-fat or high-sugar content. Blood oxygen level-dependent (BOLD) response was measured by fMRI while participants viewed photographs of ‘fattening’ food, ‘non-fattening’ food, and non-food objects.Results:Viewing photographs of fattening food compared with non-food objects resulted in significantly greater activation in the brainstem; hypothalamus; left amygdala; left dorsolateral prefrontal cortex; left orbitofrontal cortex; right insular cortex; bilateral striatum, including the nucleus accumbens, caudate nucleus, and putamen; bilateral thalamus; and occipital lobe. By comparison, only the occipital region had greater activation by non-fattening food than by object photographs. Combining responses to all food types resulted in attenuation of activation in the brainstem, hypothalamus, and striatum.Conclusion:These findings suggest that, in non-obese women, neural circuits engaged in energy homeostasis and reward processing are selectively attuned to representations of high-calorie foods that are perceived as fattening. Studies to investigate hormonal action or manipulation of energy balance may benefit from fMRI protocols that contrast energy-rich food stimuli with non-food or low-calorie food stimuli.

Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders

Difficulty interpreting facial expressions has been reported in autism spectrum disorders (ASD) and is thought to be associated with amygdala abnormalities. To further explore the neural basis of abnormal emotional face processing in ASD, we conducted an fMRI study of emotional face matching in high-functioning adults with ASD and age, IQ, and gender matched controls. In addition, we investigated whether there was a relationship between self-reported social anxiety and fMRI activation. During fMRI scanning, study participants were instructed to match facial expressions depicting fear or anger. The control condition was a comparable shape-matching task. The control group evidenced significantly increased left prefrontal activation and decreased activation in the occipital lobes compared to the ASD group during emotional face matching. Further, within the ASD group, greater social anxiety was associated with increased activation in right amygdala and left middle temporal gyrus, and decreased activation in the fusiform face area. These results indicate that level of social anxiety mediates the neural response to emotional face perception in ASD.

Functional MRI of motor sequence acquisition: Effects of learning stage and performance.

Neural networks of motor control are well understood and the motor domain therefore lends itself to the study of learning. Neuroimaging of motor learning has demonstrated fronto-parietal, subcortical, and cerebellar involvement. However, there is conflicting evidence on the specific functional contributions of individual regions and their relative importance for early and advanced stages of learning. Using functional MRI (fMRI), we examined hemodynamic effects in seven right-handed men during brief episodes of explicit learning of novel six-digit sequences (experiments 1 and 2) and during prolonged learning of an eight-digit sequence (experiment 3), all performed with the dominant hand. Brief episodes of new learning were predominantly associated with bilateral activations in premotor and supplementary motor areas, superior and inferior parietal cortices, and anterior cerebellum. In experiment 2, which included a control condition matched for complexity of motor execution, we also found unexpectedly strong activation in the bilateral inferior frontal lobes. In experiment 3, analysis of task by learning stage interactions showed greater involvement of the bilateral superior parietal lobes, the right middle frontal gyrus, and the left caudate nucleus during early stages, whereas left occipito-temporal and superior frontal cortex as well as the bilateral parahippocampal region were more activated during late learning stages. Analysis of task by performance interactions (based on each subjects response times and accuracy during each scan) showed effects in bilateral fronto-polar, right hippocampal, and anterior cerebellar regions associated with high levels of performance, as well as inverse effects in bilateral occipito-parietal regions. We conclude that superior parietal and occipital regions are most intensely involved in visually driven explicit digit sequence learning during early stages and low performance, whereas later stages of acquisition and higher levels of performance are characterized by stronger recruitment of prefrontal and mediotemporal regions.

fMRI evidence of neural abnormalities in the subcortical face processing system in ASD

Recent evidence suggests that a rapid, automatic face detection system is supported by subcortical structures including the amygdala, pulvinar, and superior colliculus. Early-emerging abnormalities in these structures may be related to reduced social orienting in children with autism, and subsequently, to aberrant development of cortical circuits involved in face processing. Our objective was to determine whether functional abnormalities in the subcortical face processing system are present in adults with autism spectrum disorders (ASD) during supraliminal fearful face processing. Participants included twenty-eight individuals with ASD and 25 controls group-matched on age, IQ, and behavioral performance. The ASD group met diagnostic criteria on the ADI-R, ADOS-G, and DSM-IV. Both the ASD and control groups showed significant activation in bilateral fusiform gyri. The control group exhibited additional significant responses in the right amygdala, right pulvinar, and bilateral superior colliculi. In the direct group comparison, the controls showed significantly greater activation in the left amygdala, bilateral fusiform gyrus, right pulvinar, and bilateral superior colliculi. No brain region showed significantly greater activation in the ASD group compared to the controls. Thus, basic rapid face identification mechanisms appear to be functional in ASD. However, individuals with ASD failed to engage the subcortical brain regions involved in face detection and automatic emotional face processing, suggesting a core mechanism for impaired socioemotional processing in ASD. Neural abnormalities in this system may contribute to early-emerging deficits in social orienting and attention, the putative precursors to abnormalities in social cognition and cortical face processing specialization.

Linguistic theory and neuroimaging evidence: an fMRI study of Broca's area in lexical semantics

There has been a long debate on the functional characterization of left inferior frontal cortex, including proposals regarding syntactic and lexico-semantic involvement. We studied nine right-handed adults, using functional magnetic resonance imaging (fMRI) during performance on a semantic decision task in which subjects had to determine whether noun-verb pairs were semantically associated. In comparison with a visuoperceptual control task, activation clusters were seen in left inferior frontal and middle temporal regions, as well as the bilateral superior frontal gyrus. In agreement with previous studies, our findings suggest that Brocas area is involved in semantic processing. Findings of lexico-semantic as well as syntactic processing in the inferior frontal lobe may be accounted for in terms of working memory demands.

N-acetyl aspartate in autism spectrum disorders: Regional effects and relationship to fMRI activation

Rapid progress in our understanding of macrostructural abnormalities in autism spectrum disorders (ASD) has occurred in recent years. However, the relationship between the integrity of neural tissue and neural function has not been previously investigated. Single-voxel proton magnetic resonance spectroscopy and functional magnetic resonance imaging of an executive functioning task was obtained in 13 high functioning adolescents and adults with ASD and 13 age-matched controls. The ASD group showed significant reductions in N-acetyl aspartate (NAA) in all brain regions combined and a specific reduction in left frontal cortex compared to controls. Regression analyses revealed a significant group interaction effect between frontal and cerebellar NAA. In addition, a significant positive semi-partial correlation between left frontal lobe NAA and frontal lobe functional activation was found in the ASD group. These findings suggest that widespread neuronal dysfunction is present in high functioning individuals with ASD. Hypothesized developmental links between frontal and cerebellar vermis neural abnormalities were supported, in that impaired neuronal functioning in the vermis was associated with impaired neuronal functioning in the frontal lobes in the ASD group. Furthermore, this study provided the first direct evidence of the relationship between abnormal functional activation in prefrontal cortex and neuronal dysfunction in ASD.