Summary of RFI Responses: Biology

Neuroscience:

We need to understand better the basic workings/functions/capabilities of the brain. ASD brains are all affected differently-to different degrees-yet share similar symptoms. How do we re-wire the ASD brain?

Autistic children share a number of unique biologically related symptoms-most importantly, an increase in quantity of neuron networks that may manifest as common signal processing problems, including strange tactile, noise, and other sensitivities, unique thought processes, exceptional memory, and uncanny attention to detail. Also, there is an abnormal brain growth spurt between 1 and 3 years.

Research priority should be given to neuropathological studies. Thus far, there is little to provide construct validity to any studies. Furthermore, what some people call neuropathology is illusory, the term now being used for neuroimaging study, neuroanatomy, etc. The NIMH should distance itself from the model it has followed for other conditions, e.g. schizophrenia.

Do research on brain with the following components: (1) imaging; (2) molecular and cell biology of nerve-nerve and nerve-supporting cells (glial cells) signaling, including neurotransmitters, their receptors, and neurodevelopment (homeoboxes); (3) neuro-behavior, including psycho-behavior, social behavior, and psycho-sociology

Understand the mobility of metals in the brain and their effects as a function of time. If mercury becomes fixed (non-mobile) in brain tissues, can a child have a toxic level of mercury in the brain yet have a clean blood/urine test? Perhaps even identical with a non-ASD typical peer? Once the brain is damaged, does it do any good to remove the metals, or is the damage already and irreparably done? How long does it take for mercury to damage an infant's brain? Hours? Days?

Neuroinflammation and immune system effects on brain development should be added areas of investigation. An understanding of how toxicants alter brain function during various stages of development is needed, especially if linked to examination of autism brains and how they are different from controls.

Research is needed to discover if there is a gene that controls the rate, mechanism, and durability/stability of synaptic development as the brain learns over time.

Research into brain structure and chemistry is in its infancy and has provided us with many specific questions about the possibility of subgroups of people with autism spectrum disorders. Individual studies have shown many different areas of the brain to be affected, including Purkinje fibers, midbrain, hippocampus/amygdale. However, it does not seem that any studies have shown all of these areas to be affected in every child. The recent report on oxytocin in rats has brought increased interest into the chemistry of brain and behavior. More research into the chemical influences on brain in behavior should be done in order to help us understand the biology of autism as well as to begin the use of medication in a more insightful controlled manner.

What early life brain changes are characteristic of children who are later diagnosed with autism versus those children who are not? Although many neural structures have been implicated in autism (amygdala, superior temporal sulcus, anterior cingulate, etc.), do patterns of neural abnormalities map onto phenotypic differences? Can structural neural data be used in combination with an empirical approach to phenotype identification (latent variable modeling, mixture modeling) to better understand sub-types or sub-dimensions of autism? Do immune or other physiological abnormalities map onto particular structural or functional neural changes? What are the micro-level neural changes that contribute to the broad structural and functional changes in each implicated brain region?

Look at the differences in brain development and function using fMRI and other imaging techniques in persons receiving different therapies.

How are the brain patterns in autistic children or adults similar to brain patterns of people with other disorders?

Investigations on how the brain "repairs" itself would aid in treatment approaches.

Do research comparing the brain function of non-verbal autistic children with that of stroke victims. Research has come so far regarding verbal recovery from strokes.

Study not only brain regional changes but pervasive volumetric changes

Are other adults who have noticed that they improve when they drink alcohol? This would indicate, to me, that slowing down the central nervous system (in a similar way) might be helpful.

Are the blood vessels in the brain of autistic children different?

Research is needed to determine if there is a gene that controls the degree of permeability of the blood-brain barrier to various metal compounds.

Consider developmental changes in ASD related to biochemistry, brain structure, and cognition. Also consider the differences, if any, in the skills and abilities, strengths, and weaknesses in ASD.

Study dynamic features of brain function (e.g. with EEG, MEG, fMRI or SPECT) that may show alterations that might be caused by toxicants and track function that may improve with treatment.

Examine post mortem brain tissue for direct and indirect indications of environmental exposures. Brains must be made available for such investigations.

Related Neuropsychological Conditions:

Is bipolar disorder and/or depression a risk factor for ASD? Does it matter whether it has been treated?

A lot of autism issues are the same with those (especially the young) have with traumatic brain injury.

Study neuromodulator alterations that could be associated with plasticity and that could be altered by treatments.

It is important to study what happens when some processing areas lag behind others but may also be impaired and how this impacts on emotional and cognitive development. For example, what happens when a child with relative verbal strengths has visual spatial processing challenges and is visually bound (depends on what he sees rather than what it means or implies) and how can we intervene more effectively?

Conduct research on behaviors associated with ASD, including obsessions and compulsions; hypo-sensitivity and sensory deprivation; anosognosia; pathological demand avoidance and bizarre deviance; pica-cravings for and ingestion of non-nutrient substances; stereotypies, particularly self-stimulatory behaviors ranging from tics to paraphilias; spying and indirect behaviors that replace adequate or direct social experiences; skills and learning; ego-syntonic psychology of ASD; and, volitional issues as separate from libido.

It will be of extreme importance to elucidate the structure and source of the opioid peptides found in autistic children. By finding the mediators of the disorder, a more rational and etiological intervention can be carried out.

Identify phenotypes of ASD population with abnormal neurotransmitter/ catecholamine metabolism issues and determine if adverse reactions to common interventions can be predicted and avoided (i.e., dopamine transport polymorphisms and responses to methylphenidate, risperidone, etc.).

One recent article suggested that autism is overall a growth disorder, specifically citing children who are larger in stature and have large head circumferences. Similarly, the MTA study has noticed that children with ADHD (who are not treated with stimulants) also seemed to be larger in general than their siblings or same-age peers with ADHD who are treated with stimulants. It would be very interesting to see if these developmental disorders are also related to a much more a basic biochemical disorder in growth and development that is likely modulated through the dopamine system or perhaps through the serotonin system.

Consider the impact of the overall health status, physical and psychological, in neurocognition and testing of learning in ASD.

Is autism a part of the PANDAS spectrum? Is PANDAS an ASD? Does PANDAS occur in patients with autism but without Tourette's and tics? What is the genetic link between the two, if they are distinct disorders?

Link brain and nervous system function with physiological alterations-e.g. cytokines with seizures, sleep, sensory threshold alterations, or e.g. excitotoxicity with electrophysiology, or e.g. dietary factors with autonomic nervous system arousal.

Research relationship between low muscle tone and fine motor problems in children with ASD.

Establish funding priorities for research into the underlying sensory/motor and regulatory difficulties often associated with, but under-addressed, in persons diagnosed with ASD.

We would like to know whether the inability to imitate is causing the communication barrier. Do children with greater difficulties in imitation also have greater communication difficulties?

What significance does hypotonia have in ASD? What is the current percentage of hypotonia among the ASDs and does it occur most commonly among the lower functioning children? Is imitation and communication more significantly impaired when hypotonia is present? Do these children improve more slowly through the common interventions of ABA and speech therapy etc.? Are they a completely different subtype?

Medical Issues:

Eventually, approximately 30% of all children with autism will be diagnosed with a seizure disorder. So many children with autism experience significant regression. Short term EEGs do not always give us accurate information. I would like to recommend that more MEG studies be done for children with autism. MEG testing has proven to be a very accurate and helpful tool in identifying the frequency, duration, and location of epileptiform activity.

Studies must be initiated immediately to increase the focus on the identification of co-morbid disease states, since many biomedical imbalances are amenable to medical and nutritional interventions as reported by clinicians treating autism. Additional investigations into these associated disease states also offers the promise of the identification of biomarkers and more effective clinical interventions targeted on identified abnormalities.

Study the role of metabolic/mitochondrial problems in ASD, including testing, detection, and treatment of abnormalities

Study classes of tissue changes such as inflammation, microglial activation, oxidative stress, and hypoperfusion, and the effect these might have at varying stages of development.

A research focus must regard autism as a chronic impairment, resulting from oxidative stress. For example, there exists evidence showing that autism is characterized by the presence of "sick" neurons rather than "dead" ones or even impaired development processes (e.g., GABAergic neuron migration). This type of research highlights the inherent reversibility of the disorder and must be pursued with urgency in order to develop and validate treatment of the disorder.

Why do so many autistics have such a susceptibility to life threatening strep?

Build on promising immune system findings to more clearly understand the role of immune alterations in ASD and how these alterations might arise from environmental exposures, both chemical and viral.
Why do ASD children seem to improve in their behaviors and ability to communicate when they are sick?

The occasional brief improvements seen in children with autism who have a fever or who have received anesthesia should also be a research priority. The underlying biological changes responsible for these inexplicable events likely hold important clues to the pathophysiology of autism.

Databases of phenotype characteristics should cover not just behaviors and core deficits but also a comprehensive list of co-occurring medical and psychiatric conditions and systems alterations including CNS, sensory/perceptual, metabolic, immune, renal, and gastrointestinal. Metabolic alterations should include detoxification pathways, cell signaling, methylation, apoptosis, growth factors, and porphyrin profiles. How these characteristics change over time should be captured.

Research Sudden Infant Death Syndrome's "Back to Sleep" campaign implemented worldwide for a correlation between infants sleeping on their backs instead of stomachs and eventual ASD diagnosis. Evaluate this in those "predisposed" to ASD (those with an immediate family member with ASD or those with the much-talked-about genetic predisposition yet to be discovered) as a possible environmental trigger providing a neurological explanation to support positive findings, if any.

Do research into the link between male hypogonadism and ASDs and causes for same. By extension, if there is profoundly delayed puberty in a male with an ASD, would the ASD continue at its childhood severity until puberty kicked in regardless of when puberty occurred?

Investigate precocious puberty in ASD, including testing and adequate treatment.

My daughter is extremely overweight. I've read that there are a lot of ASD kids who have the heavy weight gain.

A topic that needs more research is the changes an autistic person goes though at puberty. There seems to be little information on teenagers with autism, especially if they are non verbal.

Conduct DNA methylation and epigenetics studies among autistic children.

Develop a screening protocol (involving the GI, immune, liver/kidney/glutathione system status, xenobiotics management, nutritional/metabolic status in terms of cofactors and activities of Krebs/urea cycle, dietary aspects) in parallel to the ASD diagnosis with the DSMIV. Include testing that can detect concomitant medical problems to ASD, which today can remain undetected/undiagnosed/untreated.

How did blood tests, brain patterns, or other measurable metabolic functions of an ASD subject change when the subject improved significantly or recovered?

Are there people whose tests results are substantially the same as the test results of ASD sufferers who do not show the symptoms of ASD?

Develop biological outcome measures, such as intermediary metabolism measures in blood, urine or cerebrospinal fluid; electrophysiology; brain perfusion; and metabolic markers. These can be employed in clinical trials and in development of a treatment algorithm.

Cross Cultural Studies:

Investigate racial diversity in the presentation and etiology of autism. This may be an underresearched area but is of significance as studies are often conducted in countries where there is poor representation of South Asian populations. But the prevalence of autism in these groups is equal if not higher than countries with Western European populations. In addition, low-functioning non-verbal autism seems to be over represented in this racial group (South Asian).

Is there biological variation between groups based on different exposures to risk factors?

Research Considerations:

Please encourage new approaches and fresh concepts. It will be difficult for researchers of different philosophies and paradigms to work together, but as in any battle, the coordination of these different mind and skill sets could be used to our advantage if given creative leadership.

Basic science that is somewhat afield from autism per se, such as the mechanism for MECP2 gene action, the regulation of songbird learning, or basic aspects of cell signaling, may ultimately be very important to understanding basic constructs related to autism and should not be automatically disregarded because the impact on treatment or prevention is not immediate. While the press for effective treatment and diagnosis is upon us, we would be short sighted not to look to a future of biologic understanding and true prevention.

Funding mechanisms should be set up for cross-disciplinary collaboration and should encourage cutting edge measurements (e.g., immune, metabolic) rather than have conservative reviewers reject these as "too exploratory" which holds back the field at a time when there is urgency to get fresh perspectives and answers.

Coordinate between caring centers and research centers to facilitate investigation of autism. Develop a national registry.

Further involve adults themselves; opening up to, hearing, and acting for real on their growing list of concerns.

Focus more on areas of data-based research that focuses on the living, rather than biomedical research geared towards the future. The biomedical research has its role to play, we know, even if we, like smaller peer-run organizations, worry about the ethical motives behind this research (i.e. is it geared towards treatment, or towards pre-natal testing and the ever-arguable "cure"). No matter what, biomedical research currently holds too high a disproportionate amount of funding over data and evidence-based research.

Miscellaneous Comments:

We offer our specific suggestions to "advance research" with a high degree of skepticism born from extreme frustration with the public health response to the autism epidemic. Over many years we have repeatedly made our suggestions known, both as an organization and as individuals, only to be visited with one bureaucratic effort after another, such as "autism summits," "roadmaps," conferences, councils, roundtables and the like, that yield little help. We welcome your effort to reach out to stakeholders-while skeptical, we issue a challenge that we expect results. You must demonstrate that your only responsibility is to the only "stakeholders" who truly matter in this effort: the very sick children who are suffering every day, and their families. They need results NOW!

Research into the biology of autism should be tempered by knowledge of how this information will be used. I'm naturally curious about the cause of autism, but 90 percent of prenatally diagnosed children with Down Syndrome are aborted, and I do not want a similar statistic to become true for autism. Science does not occur outside of the societal context and should not pretend that it does.