C. Brock Kirwan and Mikle D. South, Psychology
Abstract
Autism is a severe neurodevelopmental disorder characterized by impaired social communication as well as substantial behavioral rigidity. Autism often has a devastating impact on the wellbeing of affected individuals and their families, as well as in community settings such as schools and health care systems. Recent research suggests that some aspects of learning and memory are impaired in autism, but the exact pattern of impaired and spared functions remains unclear. This sponsored MEG project used cross-disciplinary methods to address two main aims: 1) the relationship between anxiety and associative learning and 2) the impact of autism on long-term declarative memory specificity. Mentored students took part in all aspects of the research, including assisting in experimental design, data acquisition and analysis, presenting the research at scientific conferences, and preparing the results for publication. Budget expenses included MRI scan time, support of student wages, and participant compensation. This research will give us a better understanding of autism and guide development of future treatments.
Mentored Students
- Storm Atwood
- Nicholas Top
- Catie Nielsen
- Kevin Stephenson
- Max Maisel
- Cindee Perry
- Chris Finuf
- Chris Doxey
Outcomes
Two separate manuscripts are in preparation presently. The first outlines the results of the experiment examining the relationship between anxiety and associative learning in autism. The main results of this experiment were that autism subjects had delayed neural activation (as measured with fMRI) compared to age-matched controls in a fear conditioning paradigm. An associated finding was that the neural networks underlying the acquisition and extinction of conditioned fear were disrupted in autism. The second manuscript describes the results of the memory study in which the autism group had comparable memory specificity scores to controls. That is not to say, however, that they performed normally on the task. Rather, it appears that the autism group shifted their response criterion in order to avoid misses. This behavior was positively related to independent anxiety scores, possibly reflecting an influence of underlying anxiety on the memory task strategy adopted by the autistic subjects.
These results will also be presented at the upcoming International Meeting for Autism Research (IMFAR) in May 2015. We have submitted 3 abstracts for this meeting, each with student coauthors as listed above. We have attached here the abstracts for this meeting.
Right Place, Wrong Time: Delayed Amygdala and Insula Activation in ASD
During Classical Fear Conditioning and Extinction
D.N. Top, K. Stephenson, C.B. Kirwan, and M. South, Brigham Young University
Background: Improved understanding of the neural mechanisms that underlie unique manifestations of anxiety in ASD may provide targets for etiological research as well as for better treatment specificity. Classical fear conditioning, which is well understood in both animal and human models, offers a useful starting point for research into brain-behavior relationships between anxiety and autism. Several recent studies have shown intact fear acquisition but disrupted extinction or reversal learning in ASD. To date, however, there have been no fMRI studies of brain mechanisms that contribute to fear learning and extinction.
Objectives: We report findings from behavioral and functional neuroimaging studies of potentially atypical function involving medial temporal and frontal systems. We hypothesize that such atypical function during extinction of learned fear may contribute to difficulty adapting to changing contexts in ASD and lead to subsequent symptoms of uncertainty and anxiety.
Methods: Twenty-one adults ages 18-29 diagnosed with ASD were compared to age- and IQ- matched healthy controls on a classical conditioning task used by Phelps and colleagues (Hartley et al., 2011) during fMRI. We conducted whole brain analyses of activation during two functional runs of fear acquisition and two extinction runs. Resulting regions of interest (identified with a minimum 20-voxel cluster size and voxel-wise p < .005) were identified with a 2x2 repeated measures ANOVA comparing diagnostic group (ASD vs. controls) and task condition (threat vs. non-threat stimulus). Post-hoc t-tests were used to determine the direction of reported differences. Results: Analyses of initial early fear acquisition yielded the greatest differences, with right amygdala and left insula activation greater in controls than ASD for threat compared with non-threat stimuli. ROI analysis across all 4 runs revealed that activation patterns for these ROIs show a consistent, statistically significant decrease for the CON group, in contrast to a steady increase across the experiment in the ASD group that persists into the extinction or safety period (see Figure 1). During the final extinction run, both left amygdala and right insula showed significantly greater activity in the ASD group compared to controls (see Figure 2).
Conclusions: Although previous psychophysiological studies of fear conditioning studies in ASD have had mixed findings, several such studies have suggested delayed acquisition of fear conditioning, fear learning, and subsequent updating of fear to safety conditions. These fMRI data support the idea that fear learning networks including amygdala and insula are less activated in ASD during fear acquisition, but show increased activation during contexts (e.g., extinction trials) that should be safe. In other words, the ASD group is delayed in activation of the fear networks and is subsequently delayed in their response to extinction cues, meaning they are afraid when they should be feeling safe. We hypothesize that chronic everyday anxiety in many individuals diagnosed with ASD may arise from uncertainty regarding contextual cues for fear versus safety.
Neural Networks for Anxiety? Decreased Integration in ASD of Sensorimotor and Emotional Pathways that Support Classical Fear Conditioning
M. South, C.R. Doxey, D.N. Top, K. Stephenson, and C.B. Kirwan, Brigham Young University
Background: Multimodal neuroimaging methods have the potential to elucidate specific networks underlying behavioral symptoms related to autism spectrum disorders. We recently performed a classical fear conditioning fMRI experiment that revealed abnormal right amygdala and left anterior insula activation in ASD during early fear acquisition. We collected diffusion tensor imaging (DTI) data from the same individuals and hypothesized that DTI based on our fMRI results could expand understanding of the neural basis for co-morbid anxiety that is commonly seen in ASD.
Objectives: We hypothesized that atypical function during acquisition and extinction of learned fear may be due to differences in white matter connectivity in neural networks related to integrating fear recognition and response. Low connectivity measures may be associated with a decreased ability to adapt to changing contexts and lead to subsequent symptoms of uncertainty and anxiety.
Methods: Participants included seventeen adults ages 18-29 diagnosed with ASD and age- and IQmatched healthy controls. ROIs in right amygdala and left insula, defined from our fear conditioning fMRI data, were used as seeds for a tractography analysis using FSL’s probtrackx software; this software estimates a “connectivity distribution” for each participant based on the initial seed. These participantspecific connectivity distributions were used to create a mask for each ROI such that voxels in the mask had connections with the ROI in at least half of the participants (collapsed across groups). We logtransformed the connectivity distribution maps to minimize skew, then performed group t-tests on the connectivity distribution measures for voxels within the masks using a voxel-wise threshold of p <.02 (two-tailed) and spatial extent threshold of >20 contiguous voxels.
Results: Analyses of the right amygdala revealed significantly lower connectivity within the uncinate fasciculus (see Figure 1), inferior fronto-occipital fasciculus, and inferior temporal gyrus white matter tracts for ASD. Our left anterior insula mask showed greater connectivity of the inferior frontal gyrus in ASD, but overall decreased connectivity in the thalamocortical tract, superior longitudinal fasciculus, corticospinal tract, and superior frontal gyrus white matter compared to controls (see Figure 2).
Conclusions: These DTI data expand on our fMRI BOLD data showing decreased amygdala and insula activation during fear acquisition but increased activation during contexts (e.g., extinction trials) that should be safe. DTI highlights underconnected networks from amygdala to frontal lobe monitoring and decision making areas, and insula cortex to integration of sensorimotor information. These data support our hypothesis that chronic everyday anxiety in individuals with ASD may arise from uncertainty regarding environmental cues related to fear and safety. Improved understanding of the neural mechanisms that underlie unique manifestations of anxiety in ASD may provide targets for etiological research as well as for better treatment specificity.
Negative Emotionality Disrupts Pattern Separation in Adults Diagnosed with Autism Spectrum Disorders
South, M., Nielson, C., Stephenson, K., Top, D.N., & Kirwan, C.B.
Background: Cognitive function is frequently and broadly disrupted in autism spectrum disorder (ASD) in areas of cognitive control, attention, and memory. However, many questions of specificity remain: which cognitive functions are disrupted for which individuals in which dimensions of function. Growing evidence indicates that significant levels of anxiety in ASD may be associated with difficulties in cognitive decision making in a circuit involving amygdala, hippocampus, and medial frontal lobes.
Objectives: This study aims to discover how pattern separation memory—the ability to keep sets of similar memories distinct from each other–is affected by emotion regulation in ASD.
Methods: Participants for the memory task included 70 adults ages 17 to 36, including 25 adults diagnosed with an ASD and 45, age- and IQ-matched college student controls. There were no significant between-group differences in age or Full Scale IQ. Participants viewed digital images of everyday objects appearing one at a time. Three categories of images appeared in random order: One group of images (foils) only appeared once during the experiment. A second group of images (repeats) appeared twice throughout the study. The final group (lures) consisted of paired images that were visually and conceptually similar but not identical to previously-shown images. For each image, participants were asked to determine if the image was new, old, or similar. 42 participants (24 ASD and 18 Control) completed an additional battery of emotion symptom questionnaires.
Results: On the memory task, the ASD and control groups performed similarly when responding to novel “foil” stimuli. However, when responding to “repeat” stimuli, the ASD group chose “new” and “similar” (incorrect answers) significantly more often than controls. The ASD group also chose “new” more often than controls for the “lure” stimuli. Analysis of these errors in relation to the survey data showed significant associations between the repeat-as-new and lure-as-new choices with cognitive worry, state and trait anxiety, depression, and BAS activation arousal score. The control group had no such correlations between memory scores and emotion regulation measures.
Conclusion: The ASD group’s increased tendency to identify as “new” many stimuli that were either identical or very similar to ones seen before seems to indicate particular problems with memory. Some of this trouble may reflect distraction due to emotion regulation difficulties in the ASD group. We have previously suggested that decision making in autism reflects a risk-avoidance strategy that may be in play here, in that the ASD group tries to avoid being tricked by new stimuli and thus oversamples from that choice. This unique association between negative emotionality and everyday cognitive memory skills suggests the need for further exploration of memory substrates in ASD but also for intervention tailored to a risk-avoidance style.