Enlarged Amygdala Associated with Autism

The amygdala is also involved in the fight-or-flight syndrome, which parents of children with sensory issues (with or without autism) observe in their kids quite often. I wonder if there’s a connection between sensory overload and fight-or-flight, and an enlarged amygdala?

It doesn’t surprise me. It certainly explains some of the challenges those with autism have perceiving emotions in others but it also explains some of the anxiety responses in some. For many children with autism (and some adults as well) there is a very fine line between upset and intense meltdown and that line can be crossed very quickly (not to mention hard to recover from). This is particularity true when dealing with phobias or obsessions and rituals that are interrupted.
I read an article a few years ago (can’t remember if it was “psychology today” or “scientific american”) where they were studying the stress responses of children with autism and they found that even in something as simple as insisting on eye contact (presumably in someone who struggles with this) that the autistic person’s heart rate increased significantly. They also talked about the enlarged amygdala and increased adrenalin when a person with autism becomes upset. Doesn’t increased adrenalin also change our perception of pain etc.? This could be another factor with self injurious behaviour.

http://www.guardian.co.uk/science/2010/dec/26/social-life-brain-amygdala

I am confused about this.

fascinating article

Hi
There are some additional info to comment if you are interested here
http://www.autismweb.com/forum/viewtopic.php?t=18751
Regards
ML

Does the article hypothesize what mechanism *causes* the increased growth in the Amygdala?

I remember from my neuroanatomy courses in college (Oregon State U.) that when the brain – especially a young brain – has an insult of some sort, it tries to compensate by growing more gray matter (with the help of glial cells and astrocytes). This shows up as enlargements relative to surrounding areas. I recall something about enlargements in the Septum, superior and inferior colliculii, and brocha’s area after infections, toxic exposures, or physical trauma.

It was generally accepted that these enlargements were traumatic or environmental and not genetic. So, assuming this article is valid, it seems to lend support to an environmental etiology of ASD.

Anyone aware of different info?

Maria Lujan – very interesting info.

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“In an apparent paradox, larger amygdala volumes were associated with increased “joint attention,” the ability to follow another person’s gaze or using one’s own eyes to direct the other person’s attention. Such activity is typically diminished in autistic children, who tend to avoid people’s gazes.”
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INTERESTING. THAT SEEMS CONSISTENT WITH THE NOTION OF COMPENSATION. WHEN ONE AREA OF THE BRAIN ISN’T DOING WHAT IT IS SUPPOSED TO DO, IT GROWS MORE GRAY CELLS TO COMPENSATE.
THIS EFFECT IS ALSO SEEN WHEN OTHER AREAS CONNECTED BY WHITE MATTER ARE DYSFUNCTIONAL.

But it was only a minority of autistic children — some 21% — who initiated or responded to a joint attention activity. Those who did so had mean amygdala volume (average of left and right) of 2.45 mm3, compared with about 2.23 for nonparticipants in joint attention (P0.05).

In other words, the autistic children who scored well on joint attention were clustered at the high end of the amygdala volume spectrum.
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IT SEEMS LIKE THE CHILDREN WHO HAD COMPENSATED THE MOST (WHO HAD THE LARGEST VOLUME INCREASE) ALSO HAD THE HIGHEST FUNCTIONAL RESTORATION IN JOINT ATTENTION AND FACIAL RECOGNITION.

THIS SEEMS TO STRONGLY SUGGEST THAT THE INCREASED GROWTH ITSELF ISN’T THE PROBLEM, IT’S THE DEVELOPING BRAIN’S ATTEMPT TO FIND A SOLUTION ..WHATEVER THE REAL PROBLEM IS.

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The study “suggests that amygdala overgrowth in autism may contribute to subsequent cortical face processing system disturbances and core social and cognitive developments,” Dr. Piven and colleagues concluded.
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THAT EXPLANATION IS INCONSISTENT WITH THE “PARADOX” DR. PRIVEN NOTED EARLIER, AND IS TOTALLY UNDERMINED BY DR. RPIVEN’S OWN FINDING THAT THOSE ASD SUBJECTS WITH THE GREATEST SO-CALLED “OVERGROWTH” DEMONSTRATED THE HIGHEST DEGREE OF NORMAL FUNCTION.

THE LOGICAL CONCLUSION IS THAT SOMETHING CAUSES THE AUTISM. THEN THE BRAIN TRIES TO COMPENSATE FOR THE DEFICIT BY “OVERGROWTH”. THOSE WITH AUTISM WHO HAVE THE GREATEST “OVERGROWTH” SEEM TO DO THE BEST

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In particular, the new study supports an “allostatic overload” model developed to explain the earlier findings.

Under this model, Dr. Piven and colleagues explained, “repeated exposure to a highly stimulating event leads to a compensatory response (allostasis) within the amygdala, including increased dendritic arborization and consequent overgrowth.”
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IT GETS BIG BEFORE IT GETS SMALL? HAVE TO SEE SOME REAL LONGITUDINAL DATA BEFORE THAT COULD BE CONCLUDED.

IF ALLOSTASIS IS THE PROPOSED MECHANISM, THEN THEY STILL HAVE TO EXPLAIN WHY ALLOSTATIC FORCES CAUSE THE INITIAL OVERGROWTH. GLIAL CELLS AND ASTROCYTES REGULATE GROWTH AND DESTRUCTION (INCLUDING ABORTION OF DENDRITES). SO THERE STILL MUST BE A DYSFUNCTION INITIALLY THAT LEADS TO THE INCREASED GROWTH.

IT SEEMS VERY SPECULATIVE TO CONNECT THIS STUDY WITH EARLIER STUDIES OF ADULTS SHOWING DYSTROPHIC AMYGDALAE. NONETHELESS, THEY ARE TWO SIDES OF THE SAME COIN. THE DYSFUNCTION CAUSES COMPENSATORY GROWTH DURING DEVELOPMENT, WHILE ADULT DYSTROPHY WOULD EXPLAIN DIMINISHED FUNCTION.

THE MISSING PIECE IS A LONGITUDINAL STUDY TO SEE IF THESE ARE SIMILAR POPULATIONS. YOU NEED TO KNOW WHETHER THESE CHILDREN WITH OVERGROWTH BECOME ADULTS WITH UNDERGROWTH.

THIS MAY BE A SMALL PIECE OF THE PUZZLE WHICH HELPS EXPLAIN THE NEURAL EXPRESSION OF A COUPLE OF AUTISTIC SYMPTOMS (FACIAL RECOGNITION AND JOINT ATTENTION). UNFORTUNATELY, IT DOESN’T TELL US ANYTHING ABOUT WHAT MECHANISM (INFECTIOUS, TRAUMATIC, OR TOXIC) IS CAUSING THE OVER- OR UNDER- GROWTH OF THE AMYGDALA.

Hi Bob
REcent manuscripts on the topic
J Neurosci Res. 2004 Nov 15;78(4):472-84. Links
Astrocyte-specific overexpression of insulin-like growth factor-I promotes brain overgrowth and glial fibrillary acidic protein expression.Ye P, Popken GJ, Kemper A, McCarthy K, Popko B, D’Ercole AJ.
Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Insulin-like growth factor-I (IGF-I) is widely expressed in the central nervous system (CNS). Whereas during normal development IGF-I is expressed predominantly by neurons and to a much lesser degree by glial cells, its expression in astrocytes, and often in microglia, is increased during and/or after variety of CNS injuries. Recently we have generated a new line of IGF-I Tg mice, called IGF-I(Ast/Tet-Off) Tg mice, in which IGF-I transgene is expressed specifically in astrocytes and is tightly controlled by the tetracycline analog doxycycline. In this study we examined whether IGF-I derived from astrocytes is capable of promoting neural cell growth during development. When the IGF-I transgene is allowed to be expressed, IGF-I(Ast/Tet-Off) Tg mice exhibit markedly increases in 1) brain weight; 2) brain DNA and protein abundance; and 3) number of neurons, oligodendrocytes, and astrocytes, as well as myelination, findings similar to those observed in our other lines of Tg mice that express IGF-I transgene predominantly in neurons. Unlike Tg mice with neuron-specific IGF-I expression, which manifest marked increases in the concentrations of oligodendrocyte/myelin-specific proteins, however, IGF-I(Ast/Tet-Off) Tg mice exhibit an increase in the concentration of glial fibrillary acidic protein, an astrocyte-specific protein. Furthermore, when transgene expression is blunted, brain overgrowth in IGF-I(Ast/Tet-Off) Tg mice ceases. Our data indicate that astrocyte-derived IGF-I is capable of promoting neural cells growth in vivo. Our data also suggest that IGF-I’s actions in CNS depend in part on the location of its expression and cellular microenvironment and that continuous presence of IGF-I expression is necessary for brain overgrowth.

Now, there are higher and lower levels of IGF-1 depending on the subgroup and it seems of the age

Neuropediatrics. 2007 Jun;38(3):151-3.
Urinary epidermal and insulin-like growth factor excretion in autistic children.Anlar B, Oktem F, Bakkaloglu B, Haliloglu M, Oguz H, Unal F, Pehlivanturk B, Gokler B, Ozbesler C, Yordam N.
Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Growth factors have been implicated in the pathogenesis of autism. We have investigated daily urinary excretion of insulin-like growth factor-1 (IGF-1), epidermal growth factor, and insulin-like growth factor binding protein-3 in autistic children (n=34, age 2-5 years) and age-matched control children (n=29). The mean urinary IGF-1 level was lower in the autism group than the control group (p=0.03). Height was normal. These findings suggest altered IGF-1 metabolism in young autistic children. The cause-effect relationship should be examined by longitudinal studies and insulin-like growth factor provocation tests.

Clin Endocrinol (Oxf). 2007 Aug;67(2):230-7. Epub 2007 Jun 4. Links
Elevated levels of growth-related hormones in autism and autism spectrum disorder.Mills JL, Hediger ML, Molloy CA, Chrousos GP, Manning-Courtney P, Yu KF, Brasington M, England LJ.
Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health/DHHS, Bethesda, MD 20892, USA.

OBJECTIVE: Children with autism are known to have larger head circumferences; whether they are above average in height and weight is less clear. Moreover, little is known about growth-related hormone levels in children with autism. We investigated whether children with autism were taller and heavier, and whether they had higher levels of growth-related hormones than control children did. DESIGN: A case-control study design was employed. PATIENTS: Boys with autism spectrum disorder (ASD) or autism (n = 71) and age-matched control boys (n = 59) were evaluated at Cincinnati Children’s Hospital. MEASUREMENTS: Height, weight and head circumference were measured. Blood samples were assayed for IGF-1 and 2, IGFBP-3, growth hormone binding protein (GHBP) and for dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS). RESULTS: Subjects with autism/ASD had significantly (P = 0.03) greater head circumferences (mean z-score 1.24, SD 1.35) than controls (mean z-score 0.78, SD 0.93). Subjects with autism also had significantly (P = 0.01) greater weights (mean z-score 0.91, SD 1.13) than controls (mean z-score 0.41, SD 1.11). Height did not differ significantly between groups (P = 0.65); subjects with autism/ASD had significantly (P = 0.003) higher body mass indices (BMI) (mean z-score 0.85, SD 1.19) than controls (mean z-score 0.24, SD 1.17). Levels of IGF-1, IGF-2, IGFBP-3 and GHBP in the group with autism/ASD were all significantly higher (all P

This is fascinating. My autistic son has been diagnosed with a glioma (mass of cells) of the brain stem, which is possibly also gliosis (scar tissue). Maybe it is really an enlarged amygdala. Due to the location it is impossible to get a biopsy on the area. I will bring this up with the neurologist at the next appointment.

Cerebellum. 2005;4(3):206-10.
Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects.Laurence JA, Fatemi SH.
Division of Neuroscience Research, University of Minnesota Medical School, Minneapolis, MN, USA.

Autism is a debilitating neurodevelopmental disorder of early childhood with both genetic and environmental origins. Immune system dysregulation has been hypothesized to be involved in this disorder. We quantified levels of glial fibrillary acidic protein (GFAP) and ss-actin in three areas of the brain, namely, area 9, area 40 and cerebellum, in age matched autistic and control postmortem specimen using SDS-PAGE and western blotting techniques. Significant elevations in levels of GFAP were observed in all three brain areas in autism. This report confirms a recent report showing microglial and astroglial activation in autism. Increased GFAP levels in autistic brains signify gliosis, reactive injury, and perturbed neuronal migration processes.

J Vis Exp. 2009 May 5;(27). pii: 1173. doi: 10.3791/1173.
A neuronal and astrocyte co-culture assay for high content analysis of neurotoxicity.Anderl JL, Redpath S, Ball AJ.
High Content Analysis R&D, Millipore Corporation, Bioscience Division.

High Content Analysis (HCA) assays combine cells and detection reagents with automated imaging and powerful image analysis algorithms, allowing measurement of multiple cellular phenotypes within a single assay. In this study, we utilized HCA to develop a novel assay for neurotoxicity. Neurotoxicity assessment represents an important part of drug safety evaluation, as well as being a significant focus of environmental protection efforts. Additionally, neurotoxicity is also a well-accepted in vitro marker of the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Recently, the application of HCA to neuronal screening has been reported. By labeling neuronal cells with betaIII-tubulin, HCA assays can provide high-throughput, non-subjective, quantitative measurements of parameters such as neuronal number, neurite count and neurite length, all of which can indicate neurotoxic effects. However, the role of astrocytes remains unexplored in these models. Astrocytes have an integral role in the maintenance of central nervous system (CNS) homeostasis, and are associated with both neuroprotection and neurodegradation when they are activated in response to toxic substances or disease states. GFAP is an intermediate filament protein expressed predominantly in the astrocytes of the CNS. Astrocytic activation (gliosis) leads to the upregulation of GFAP, commonly accompanied by astrocyte proliferation and hypertrophy. This process of reactive gliosis has been proposed as an early marker of damage to the nervous system. The traditional method for GFAP quantitation is by immunoassay. This approach is limited by an inability to provide information on cellular localization, morphology and cell number. We determined that HCA could be used to overcome these limitations and to simultaneously measure multiple features associated with gliosis – changes in GFAP expression, astrocyte hypertrophy, and astrocyte proliferation – within a single assay. In co-culture studies, astrocytes have been shown to protect neurons against several types of toxic insult and to critically influence neuronal survival. Recent studies have suggested that the use of astrocytes in an in vitro neurotoxicity test system may prove more relevant to human CNS structure and function than neuronal cells alone. Accordingly, we have developed an HCA assay for co-culture of neurons and astrocytes, comprised of protocols and validated, target-specific detection reagents for profiling betaIII-tubulin and glial fibrillary acidic protein (GFAP). This assay enables simultaneous analysis of neurotoxicity, neurite outgrowth, gliosis, neuronal and astrocytic morphology and neuronal and astrocytic development in a wide variety of cellular models, representing a novel, non-subjective, high-throughput assay for neurotoxicity assessment. The assay holds great potential for enhanced detection of neurotoxicity and improved productivity in neuroscience research and drug discovery.

Cerebellum. 2005;4(3):206-10. Links
Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects.Laurence JA, Fatemi SH.
Division of Neuroscience Research, University of Minnesota Medical School, Minneapolis, MN, USA.

Autism is a debilitating neurodevelopmental disorder of early childhood with both genetic and environmental origins. Immune system dysregulation has been hypothesized to be involved in this disorder. We quantified levels of glial fibrillary acidic protein (GFAP) and ss-actin in three areas of the brain, namely, area 9, area 40 and cerebellum, in age matched autistic and control postmortem specimen using SDS-PAGE and western blotting techniques. Significant elevations in levels of GFAP were observed in all three brain areas in autism. This report confirms a recent report showing microglial and astroglial activation in autism. Increased GFAP levels in autistic brains signify gliosis, reactive injury, and perturbed neuronal migration processes.

Hi Bob
I do think that there are several clues to consider seriously an environmentally modulated impact on growth factors in ASD , related at least in some subgroups to enlarged amygdala.

Dear Maria

VERY interesting articles. Funny that I’ve never seen these studies before. Thanks so much for your posts — these have really piqued my interest. You are absolutely right – and thankyou again!

Very best,

-Bob

Found Bob’s comments interesting and supportive of theory in relation traumatic birth causing ASD.

I’m dx with Aspergers and I was born with the umbilical cord around my neck. Not breathing, blue and needing to be resuscitated by the attending Dr. Spent two days in intensive care. I’ve always supported the theory of hypoxia as one of the cause effects of ASD.

There are a large number of people on the Wrong Planet ASD website who speak of their bitrh with the umbilical cord around their neck.

No doubt there is a genetic link cause effect in relation to ASDs as well. There appears to be many variations in cause effects in relations to ASDs and these are just to theories.

I am always excited to visit this blog in the evenings.Please churning hold the contents. It is very entertaining.,

What about the relationship between early brain growth and exposure to excessive GH(specifically PRL)? Either pre or postnatal. Such as in a nursing mother with prolactinoma.
Please direct me to relevant articles dealing specifically with prolactinoma/related drug therapies and link to autism…if there are any.