Recognition of Amygdala Abnormalities in ASDs Spurs Rehabilitative Modalities

Recent imaging studies have shown that patients with autism spectrum disorders (ASDs) who were presented with images of human faces had lower responses in amygdala activity than controls. These studies strengthen the connection between the amygdala and the abnormal social-emotional behavior seen in patients with ASDs, said Chris Ashwin, PhD, senior research associate at the Autism Research Centre in the Department of Psychiatry at the University of Cambridge, UK. "However, I think research in this area is still only in its infancy. Much more work involving different levels of investigation needs to be done to determine the role of the amygdala in ASDs-and, importantly, whether it is causal in nature or merely a consequence of having autism," he said.

His group previously proposed that the amygdala is one of several neural regions that is abnormal in ASDs, calling this the "amygdala theory of autism."¹ Ashwin's most recent study showed that patients with an ASD had different patterns of activation of social brain areas while processing pictures of fearful faces.² In addition, these patients did not show a response to varying emotional intensity in the pictures. Using functional MRI (fMRI), researchers studied 13 high-functioning men with ASDs or Asperger syndrome and 13 matched controls.

While the control group showed greater activation in the left amygdala and left orbito-frontal cortex, patients with an ASD showed greater activation in the anterior cingulate gyrus and superior temporal cortex. The control group also showed differing responses in social brain areas to varying intensities of fearful expression, including differential activations in the left and right amygdala. However, this response in the social brain was absent in patients with an ASD.

This study showed that patients with ASDs were activating a different group of structures in the social brain while processing the threatening faces, which Ashwin said might reflect the different cognitive processes they may be using during these types of tasks. "While those with autism activated the amygdala less than controls, they also activated areas of the brain involved in conscious perception of emotional information and in processing dynamic features of the face," he said. "This may mean that they find processing facial expressions harder than typical participants from the general population. People with autism may have more difficulty with tasks like this and have to consciously 'work out' which emotion is being expressed using certain cues such as the shape and angle of the mouth and the eyes."

Ashwin believes these findings do more than show that the amygdala is activated less in people with ASDs: "It may show that they are processing different aspects of the face in different ways," he said. "These differences may be what is reflected in the differences in neural activations seen in our studies of the participants with ASDs, which is more of a 'difference' type of model than simply a 'deficit' model. People with autism are able to process social-emotional information; they just are not as adept at it and tend to do this in different ways and by focusing on different aspects."

Based on these results and the results of previous research, he and colleagues at the Autism Research Centre have been developing and testing treatments to help adults and children with ASDs. Using videos of social-emotional stimuli and situations involving faces and emotions, the treatment aims to help persons with ASDs better process this type of information and learn what areas of the face might be important to pay attention to. "These types of treatments have not been a priori developed specifically to address functioning of the amygdala; however, the amygdala would certainly be implicated in what is done in these treatments, since processing social-emotional information is central," said Ashwin.

THE CAUSE OF AMYGDALA DYSFUNCTION
While these results support previous hypotheses that amygdala abnormalities may contribute to symptoms of ASDs, results from previous studies have been inconsistent, Ashwin noted. For example, while some studies have shown that patients with ASDs have lower amygdala volume,³ others have shown that the amygdalae may be larger in patients with ASDs.^4,5 Pressure is growing for researchers to learn how ASDs affect the brain: the CDC has calculated an average ASD rate of 6.6 in 1000 persons, a tremendous difference from last year's estimated rate of 5.5 in 1000 persons.⁶

The genetic origins of autism may cause these amygdala abnormalities, according to Richard J. Davidson, PhD, a clinical psychologist in the Waisman Laboratory for Brain Imaging and Behavior, and colleagues at the University of Wisconsin-Madison. Davidson led a recent study that examined amygdala function using fMRI in patients with ASDs and their healthy siblings.⁷ Previous research has shown that siblings of patients with ASDs may present with the same type of social symptoms, which have been shown to affect language, communication, and human interaction.

Davidson's group examined 8 male and 4 female patients with ASDs and 7 male and 3 female unaffected siblings. When compared with controls, the siblings' gaze fixations and brain activation patterns were similar to those of the patients with ASDs. The unaffected siblings showed decreased gaze fixation along with diminished fusiform activation. Amygdala volume in the siblings and patients with ASDs was significantly smaller than in those in the control group.

Davidson also led a larger study to examine amygdala size using MRI to test 54 males aged 8 to 25 years, including 23 with autism, 5 with Asperger syndrome or pervasive developmental disorder not otherwise specified, and 26 age- and sex-matched controls.⁸ The patients with autism and small amygdalae distinguished emotional from neutral expressions more slowly than other patients and controls; they also showed the least fixation of eye regions. Overall, the study found there were smaller amygdalae in persons with autism than in control subjects, and the more severe social deficits appeared along with age-predicted patterns of amygdala development.

"Because the anomalies in the volume of the amygdala are reported very early in life, there is reason to believe that this is part of the genetic etiology of autism," said Davidson. "Autism has stronger heritability than any other psychiatric disorder. So, there is reason to think that whatever anomalies are associated with the amygdala are likely to be genetic in origin."

Based on the results of these studies, Davidson is working toward developing behavioral therapies using fMRI to pinpoint responses in the amygdala. "We believe that our work points toward some very important experimental interventions that could immediately be examined. These involve training children behaviorally to more adequately process information from faces," he said. "We call it 'neurally inspired behavioral interventions,' designed specifically around what we understand about brain function." This research is ongoing, and results should be available in a few years, Davidson said.

Davidson also is conducting research to develop brain-based phenotypes, what he calls neurophenotypes, to better identify different ASDs. "There have been a lot of genes that have been linked to autism, and then several months later another group publishes a paper showing that gene's failure to replicate," he said. "One of the problems is that it may well be that there are different genetic etiologies to different subtypes of autism. Without better characterization of the phenotype, we're really in a mess right now."

Patients with mutations of the fragile X mental retardation 1 gene (FMR1) and an ASD may be an important subgroup to examine for amygdala size and function, according to David Hessl, PhD, assistant clinical professor in the Department of Psychiatry and the Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute at the University of California Davis Medical Center, Sacramento. He recently led an fMRI study of men with premutation alleles (55-200 CGG repeats) of FMR1, collaborating with Susan Rivera, PhD, at the M.I.N.D. Institute.⁹ Although these patients had no formal ASDs, relative to a well-matched control group, they demonstrated diminished activation in the amygdala and other areas of the brain that mediate social cognition while viewing fearful faces.

The results of Hessl's study were similar to those of Ashwin and colleagues and Davidson and colleagues. "I'm hypothesizing that the reason we had similar results is because of more subtle social cognition difficulties that are on the same continuum," Hessl said. "Historically, we thought that only persons with the FMR1 full mutation-which typically causes fragile X syndrome, a leading known cause of ASD-were affected psychiatrically, but our study and others suggest possible involvement in some 'carriers' of the premutation as well, and we want to address this question carefully, especially given how common the premutation is: about 1 per 800 men and about 1 per 250 women."

THE RELEVANCE OF THE AMYGDALA
These imaging studies complement one another; they suggest that variables such as age and diagnosis may be important factors affecting amygdala differences in patients with ASDs, said Ashwin. These variables also may affect what patients with ASDs are thinking about or paying attention to during the tasks presented in these studies.

Previous research has shown that patients with amygdala damage tended to pay attention to the mouth rather than the eyes, and Davidson's studies showed that eye contact might be associated with heightened amygdala response in autism, Ashwin pointed out. He believes this could demonstrate that patients with ASDs avoid looking at the eyes to reduce heightened amygdala arousal and stress responses. "These findings not only suggest that the amygdala is involved in autism but also outline a model where the amygdala may be a key brain structure in the behaviors seen in ASDs," he said.

While these findings are all associative, they do not address whether there might be a causal role for the amygdala, said Ashwin. "Given the many studies now showing differences of the amygdala in autism, I think the interesting questions for further research are whether the involvement of the amygdala may be causal, consequential, or compensatory in nature," he said.

While the amygdala is known to be a major contributor in regulating emotional behavior, the research has not yet shown if the amygdala plays a major role in ASDs, said Margaret Bauman, MD, pediatric neurologist at Massachusetts General Hospital and associate professor at Harvard Medical School, Boston. She has led a number of studies examining postmortem brains of persons with ASDs and was one of the first researchers to recognize amygdala abnormalities in these specimens.

In 1994, her group reported on areas of the forebrain that were found to have been abnormal, which included structures that comprise a major portion of the limbic system including the hippocampus, subiculum, entorhinal cortex, amygdala, mammillary body, anterior cingulate gyrus, and septum. These areas also showed reduced neuronal cell size and increased cell packing density bilaterally in specimens of all ages when compared with controls.¹⁰ Of note, cell packing density was most significantly increased in the most medially placed nuclei in the amygdala. "It's been known for a long time that the amygdala has a lot to do with emotion and behavior," Bauman said. "That's one of the reasons that we began looking in that area, since a core feature of autism is impaired social skills and poor pragmatic language."

Her team also has shown that the cerebellums of these brains have significantly reduced numbers of Purkinje cells, specifically in the posterior inferior regions of the hemispheres. Different patterns of change were also noted in the vertical limb of the diagonal band of the broca, cerebellar nuclei, and inferior olive. In this area, brains of younger patients with autism had plentiful and abnormally enlarged neurons, while brains of adults with autism had small, pale neurons that were reduced in number. This, along with other reports of overall age-related changes in brain weight and volume, led Bauman's group to conclude that the neuropathology of autism may represent an ongoing process. "In a lot of these studies, you have autistic people with big amygdalae and small amygdalae and big cerebellums and small cerebellums," she said. "We haven't come up with the common thread here that ties all these people together, and I think there are vast differences in these brains."

Previous research has found that the g-aminobutyric acid (GABA)ergic system in cerebellar and limbic structures is affected in autism, and the cerebellums of persons with ASDs can contain 50% to 90% fewer GABAergic Purkinje cells.^10-12 That's why Bauman's team recently conducted a study on the GABAergic system in patients with ASDs in which the hippocampus from 4 patients with autism and 3 controls were studied. The group found fewer hippocampal benzodiazepine binding sites (average of 20%), which suggested alterations in the modulation of GABA_A receptors in the presence of GABA in the autistic brain. Bauman and colleagues concluded that this may result from altered inhibitory functioning of hippocampal circuitry.^13,14

Pointing to results such as those from Bauman's research, Ashwin comments that the amygdala may be viewed as one of a number of interacting brain regions involved in processing social-emotional information, such as in the "social brain" theory proposed by Leslie Brothers, which states that a number of brain regions work together to process social-emotional information.¹⁵

"The amygdala may be a key brain structure in this network, but each brain region has a certain set of functions or abilities that is key for processing social-emotional information," he said. "Together, the activity in these separate but coordinated brain regions may help us process the various types of information and perform the cognitive processes that enable us to work out what others are thinking and feeling," said Ashwin.

Other researchers have questioned the amygdala theory of autism. A recent study by Dziobek and colleagues¹⁶ examined 17 adults with Asperger syndrome and 17 controls. The team examined amygdala volume using MRI scans; they also studied emotion recognition, social cognition, and other symptoms of Asperger syndrome. The study showed that patients with Asperger syndrome had impairments in emotion recognition and social cognition compared with controls, and that smaller amygdala volumes involved higher levels of restricted-repetitive behavior. However, the group concluded that the amygdala is not crucially involved in social and emotional understanding and may just be a player in the patient's routines and rituals.

While the results of these imaging studies of the amygdala are interesting, Bauman points out that they are in high-functioning adults or older children with ASDs. "These patients are able to lie in the scanner and respond to the images," Bauman said. "The ones we'd really like to know about are the low-functioning kids, but you can't sedate them and put them in the scanner because then they can't perform the task you're asking them to do. So, while these data are interesting, it's still not getting down to what we need. And I don't know if we have the technology or the ability to do that just yet."

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