Two metabolites in the amygdala are associated with clinical impairment in autism.

A review of: Natalia M. Kleinhans, Todd Richards, Kurt E. Weaver, Olivia Liang, Geraldine Dawson, Elizabeth Aylward (2009). Brief Report: Biochemical Correlates of Clinical Impairment in High Functioning Autism and Asperger’s Disorder Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-009-0707-6

This brief yet powerful article is an example of research moving beyond making simple comparisons between typically developing children and children with autism – a move that has implications for how we conduct and evaluate etiological and mechanistic research.

In sum, the authors were interested in examining amygdala functioning in autism. The amygala serves a critical function in emotion recognition and processing, and thus it has been implicated in the neurophysiology of autism. For example, individuals with autism have been found to display atypical amygdala growth processes from childhood into adolescence (see for example Nacewiz et al., 2006. Archives of General Psychiatry, 63,12).

In this study the authors wanted to examine the biochemical integrity of the amygdala among individuals with high functioning autism and typical developing peers. In addition, the authors wanted to examine whether biochemical alterations in the amygdala would be associated with specific clinical symptoms of autism. The participants included 20 adults with high functioning autism (18 males, average age 23.57) and 19 typically developing peers (17 males, average age 23.32). Autism diagnosis was confirmed via ADOS and ADI. The Amygdale’s bilateral biochemical functioning was obtained via magnetic resonance spectroscopy. Four metabolites were measured: N-acetyl aspartate (NAA), creatine/Phosphocreatine (Cre), choline (Cho), and myoinositol (ml).

The authors did not find any differences in the concentrations of any of the metabolites when comparing the HFA and the control groups. Both groups had equal levels of all the metabolites measured. However, among the individuals with HFA, NAA was significantly associated with communication impairments, as measured by the ADI. In addition, Cre and NAA were associated with restrictive interests, and Cre alone was associated with social difficulties. The results therefore, indicate that those with the lowest concentrations of these metabolites tended to have more severe clinical symptoms as reported by the ADI.

The results of this study provide support for the need to conduct examinations that go beyond simple group comparisons. In this case, the authors found no differences in any of the metabolites between the two groups, which could easily lead one to conclude that such metabolites may not play a role in autism. Yet, the results were strong in indicating that key metabolites, while observed at normative levels, play a key role in the clinical presentation of the disorder. Although this is not necessarily new, it is consistent with a paradigm shift in how etiological or mechanistic research is conducted, in that the presence of normative functioning in a particular domain or brain process (when compared to typical peers) does not necessarily indicate that such domain is not implicated in the phenomenology of the condition.

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6 Responses to Amygdala, autism and clinical impairment: When group comparisons are not enough.

  1. Thanks for highlighting this study Nestor. Any idea why High Functioning Autism subjects were chosen rather than Low Functioning Autism subjects or both?

  2. Hi H.,

    I would think it is probably related to the nature of the experimental protocol. Completing a magnetic resonance spectroscopy protocol is very difficult requiring significant amount of compliance and behavior regulation (I once drove the nurse crazy because I could not stay still when getting an MRI of my knee). Thus the degree of completion of the protocol is probably significantly higher with HFA and LFA.

  3. RAJ says:


    This is not a paradigm shift. Studies comparing ASD’d to typically developed children matched by age, sex and IQ are the gold standard for autism research whether it is genetic, environmental, or even abnormalities in brain structure like the amygdala.

    No gene for autism as ever been identified. The genes that are claimed to be autism susceptability genes are commonly reported in a variety of neuro psychiatric conditions as is structural abnormalities in every brain region including the amygdala.

    A paradign shift would be inclusion of controls representing normal, schizophrenic,mentally retarded, language impaired, ADHD and OCD control groups.

    This is the only way to find any condition that is unique to autism, so far none have been found.

  4. RAJ says:


    Here’s a report that implcates the same metabolites the autism study impicated. They found the sam metabolites are pread throughout the brain, not in autism, but in Bipolar Disorder.

    Another confirmation of te failure of autism researchers to use proper control groups. Here’s the abstract, for some reason links don’t work well in this blog.

    Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings.

    Yildiz-Yesiloglu A, Ankerst DP.
    Dokuz Eylul Medical School, Department of Psychiatry, Izmir, Turkey.

    OBJECTIVE: To perform systematic analysis of current proton magnetic resonance spectroscopy ((1)H MRS) findings in bipolar disorder (BD). METHOD: We grouped the (1)H MRS studies documenting data on the metabolites of N-acetylaspartate (NAA), Choline (Cho), myo-inositol (mI), Glutamate (Glu)/Glutamine (Gln) and Creatine (Cr) separately, for each of the euthymic, manic, depressed adult and child/adolescent bipolar patients. RESULTS: For NAA resonance, 22 studies involving 328 adult bipolar and 349 control subjects were identified. NAA levels were lower in euthymic bipolar patients in the frontal lobe structures and hippocampus. Lithium seems to have an increasing effect on NAA in those brain regions. Available data in children indicates lower NAA levels in euthymic bipolar patients in dorsolateral prefrontal cortex (DLPFC) and cerebellar vermis. Existing data over 25 studies on 366 adult bipolar and 393 control subjects, although inconsistent, may suggest higher Cho/Cr ratios in the basal ganglia (BG) of euthymic bipolar patients. The metabolite mI seems to be increased both in euthymic and manic bipolar children, while most of the available data does not support such alteration in adults. Glu/Gln levels in adult bipolar patients were higher in all mood states compared to controls. Limited data in children supports such an alteration only in the euthymic state. CONCLUSION: The studies reviewed in this paper suggest regional abnormalities of NAA, Cho and Glu/Gln in BD, with the DLPFC, prefrontal and anterior cingulate cortices, hippocampus, and BG being specifically implicated. Systematic analysis of (1)H MRS findings so far helps to define future strategies in this field for delineation of actual neurochemical framework in BD.

  5. Neuroskeptic says:

    Using appropriate controls is always important, as RAJ says.

    I haven’t read this paper, but as a general rule, I think one should be careful of studies such as this. The problem is that no-one really sets out to find results of this kind. What generally happens is that people search for group differences, don’t find any, and only then decide search for anything interesting going on within the groups (post hoc testing).

    Obviously I can’t prove that this is what happened here, but it’s a classic problem. Reader beware…

  6. Hi RAJ,

    What I meant by paradigm shift is not the presence of a matched control group (I know this is the gold standard in autism and most other clinical research), but the understanding that even when there are no differences between the ASD and the control groups in regards to a specific factor (in this case 2 metabolites), that does not necessarily mean that such factor is not implicated in the phenomenology of the condition.

    I do agree with you in that conducting research focused on the question of specificity would also be a paradigm shift, in that such type of research is unusual.

    However, I do not share your view that ‘lack of specificity’ invalidates or questions current findings in most autism research. You know my views about this issue as I have responded in the past. There is nothing in the logic of developmental psychopathology that says that one factor (brain anomaly, toxin, environmental condition, genetic marker, etc etc etc) should only be implicated in the development of a SINGLE condition. The fact that these metabolites may be implicated in the development of something else, for example bipolar disorder, does not mean that such metabolites could not ALSO be implicated in the development of autism, since the process by which the metabolites affect the development of both disorders can be different. A single condition can be affected by multiple factors and a single factor can affect the development of multiple conditions.

    In my opinion, pressing for that magical factor that is unique to autism will likely be futile, because such a disease-specific risk factor is almost non-existent in psychiatry and medicine. You will always be able to find multiple citations that implicate one potential factor in the development of more than one condition. What would be more useful is research that explains the different mechanisms by which a single factor differentially affects the development of 2 or more conditions. Maybe this is the type of research that you are calling for; and in such a case, I would completely agree.


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