Researchers at the University of Toronto have discovered that autism, attention deficit hyperactivity disorder (ADHD) and Obsessive Compulsive Disorder (OCD) all have “disruptions in the structure of the corpus callosum” in the brain. The corpus callosum is a nerve fiber bundle that links the left and right hemispheres of the brain. Results of the study were reported in the July 1, 2016 issue of the American Journal of Psychiatry.
In the study, the researchers examined the brains of 71 children with autism, 31 children with ADHD, 36 children with OCD and 62 “typical” children using diffusion tensor imaging. Diffusion tensor imaging measures the diffusion of water across the long fibers that connect the nerve cells in the brain’s white matter. There were “widespread disruptions” in the white matter structure in the brains of the children with autism and the brains of the children with ADHD. The OCD brains had “fewer alterations” than the autism or ADHD brains. Researchers also noted that the children who had the “least independence on daily tasks” (as assessed by their parents) were found to have the “most significant disruptions in white matter.”
Researchers noted two caveats. There were changes in only a small section of the corpus callosum in the autism, ADHD and OCD brains; therefore, the clinical meaning of the changes is unclear. Secondly, “movement in the scanner” by the children could not be ruled out as affecting the differences in the three groups of children.
Sources: Scientific American August 9, 2016 and Spectrumnews.org August 8, 2016
Researchers from the Developmental Biology Institute of Marseille and the University of Manchester have identified a link between autism spectrum disorder and abnormal kidneys in children born with a deleted TSHZ3 gene. Their gene research study findings were published September 26 in the journal Nature Genetics.
The TSHZ3 gene region is critical for a syndrome associated with heterozygous deletions at 19q12-q13.11. This syndrome includes autism spectrum disorder. The researchers for this study discovered a patient with this gene deletion who was born with abnormal kidneys and who displayed autism spectrum disorder behaviors. They then reviewed past research in mice and discovered that the mice with this gene deletion not only had kidney problems but also ASD-like learning difficulties. A global search of kidney clinics was then done which found 10 more patients with similar symptoms of abnormal kidneys and autism spectrum disorder behaviors where genetic testing subsequently revealed the deletion of the TSHZ3 gene. The researchers concluded that their gene research findings demonstrate how the TSHZ3 gene is essential for brain cerebral cortical projection neuron (CPN) development and function.
Sources: Genengnews.com (Genetic Engineering & Biotechnology News), Sept. 27, 2016.
Nature.com: “TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons,” Sept. 26, 2016.
According to a study published in the Journal of Biological Psychiatry November 5, 2015, gene deletions and copies at the 16p11.2 BP4-BP5 locus are “highly associated” with autism spectrum disorder and schizophrenia. The study assessed the effects of “62 deletion carriers, 44 duplication carriers and 71 intrafamilial control subjects.”
Results of the study showed that although IQ was decreased for both deletion carriers and duplication carriers, there was variance in language, verbal memory and inhibition between the two types of carriers. Deletion carriers had “severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level.” However, for those with gene duplication, “verbal memory and phonology” was improved compared to the control subjects.
The study authors note that further research is needed to replicate the findings regarding this gene locus associated with autism and to explain the molecular mechanisms that affect these types of cognition.
Update 2019: The ∼600 kb 16p11.2 BP4-BP5 gene deletion is one of the most common causes of autism. Research studies are being done on people who are deletion carriers to assess full scale intelligence quotient (FSIQ) and verbal IQ as compared to non-carriers.
Pitt-Hopkins Syndrome, which is present at birth or develops in early childhood, is caused by mutations in the TCF4 gene located on chromosome 18q21.2. There are reportedly only 500 cases of the syndrome in the world though it is thought the syndrome may be underdiagnosed. One of the major reasons for this likely underdiagnosis is the syndrome has many characteristics that are also associated with autism spectrum disorders; although there are other distinctive features of the syndrome as well.
Like autism spectrum disorders, many of those with Pitt-Hopkins Syndrome have delayed development of mental and motor skills. People with the syndrome typically do not develop speech or learn only a few words. Delays often occur in learning to walk. Additionally, their demeanor is “typically … happy, excitable…with frequent smiling, laughter and hand-flapping movements.” Those with the syndrome commonly experience “anxiety and behavioral problems;” and they may also experience recurrent seizures.
Some unique features of Pitt-Hopkins Syndrome are breathing problems and certain facial and ear characteristics. The breathing problems can fluctuate between hyperventilation and slowed breathing or even apnea and may be triggered by “fatigue, anxiety or excitement.” The distinctive facial features are “thin eyebrows, sunken eyes, a prominent nose with a high nasal bridge, a pronounced double curve of the upper lip called Cupid’s bow, wide mouth with full lips and widely spaced teeth.” Additionally, the ears may be “thick and cup-shaped.”
A recent gene research breakthrough that may lead to a treatment for Pitt-Hopkins Syndrome was discovered by scientists at the Johns Hopkins University-affiliated independent laboratory, the Lieber Institute for Brain Development. The researchers studied the brains of rats affected by Pitt-Hopkins Syndrome and found “alternative channels in the brain interrupting normal cell activity.” The gene research showed these interruptions caused inappropriate responses to stimuli in the environment. Further, the researchers discovered a drug being “investigated for use on chronic pain” that blocked these alternative channels resulting in cells behaving normally. However, at this point, researchers are not sure what restoring normal cell activity would do to those with the syndrome but are hopeful that some of the deficits could be eliminated.
Sources: CapitalGazette.com of March 11, 2016.
Ghr.nlm.nih.gov; “Pitt-Hopkins Syndrome;” Last reviewed February 2015.
A new study published this month by the American Association of the Advancement of Science indicates that immune cells “may have a direct role in causing behaviors linked to autism.” The study abstract noted that previous research has already shown “viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder in offspring.”
For this study, researchers at New York University Langone studied a subset of T-helper lymphocyte cells called TH17 and the production of cytokine interleukin-17a (IL-17a). The study in mice mimicked a viral invasion and showed using genetic mutants and blocking antibodies that TH17 and IL-17a caused maternal immune activation (MIA) behavior abnormalities in mice offspring. Additionally, the study demonstrated that “blocking the action of TH17 and IL-17a completely restored normal structure and functioning” in the mice offspring brains. The study’s authors suggest that the “therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced” autism spectrum disorder behaviors.
Scientists in France have identified a genetic marker for autism that they found in a “less deep fold of Broca’s area” — an area of the brain that specializes in language and communication. The scientists at the Institut de Neurosciences de la Timone, located in Marseille, focused on this “new geometric marker called the sulcal pit.” The sulcal pit is the “deepest point of the sulcus in the cerebral cortex from which points all the folds on the brain’s surface develop.”
Using MRI scans, the scientists analyzed the sulcal pits of 102 young boys aged 2-10 according to three groups: Autism spectrum disorder, pervasive developmental disorder not otherwise specified and “normal developing” children. Comparing the three groups, the depth of the sulcal pit in the brain was less in the autism spectrum disorder group than in the other two groups. The scientists also noted in the autistic children that the deeper the sulcal pits were, the more “impaired the language production” was in the children.
Additionally, the study disproved a previously held belief that brain “cortical folding was complete at birth.” The French scientists noted that some of the brains’ “superficial folding continued to deepen with age in both the autistic and other children.”
Source: http://www.sciencedaily.com/releases/2016/01/160113101121.htm including journal reference Brun Lucile, Auzias Guillaume, Viellard Marine, Villeneuve Nathalie, Girard Nadine, Poinso François, Da Fonseca David, Christine Deruelle. Localized misfolding within Broca’s area as a distinctive feature of autistic disorder. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2015; DOI: 10.1016/j.bpsc.2015.11.003 published 12 January 2016.
Researchers recently published a study in the Journal of Autism and Developmental Disorders called “Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum.” The study found that the brains of those with autism have “unstable blood vessels disrupting proper delivery of blood to the brain.” “Typical” brain blood vessels are stable.
The researchers conducted the study by looking microscopically at post-mortem age-matched normal brains and autistic brains. The researchers did not know which brains had had an autism diagnosis and which brains did not thus eliminating bias in their observations. The study found formation of new blood vessels (angiogenesis) in the brains from individuals who had had an autism diagnosis; no such angiogenesis was noted in the normal brains. The areas of the brain affected were the “superior temporal cortex (primary auditory cortex), fusiform cortex (face recognition center), pons/midbrain and cerebellum.” Specifically, the researchers found increased levels of the proteins nestin and CD34 which are markers of angiogenesis. Importantly, the study findings found that the angiogenesis was not the kind that caused the sprouting of new vessels but instead of splitting, thus causing continuous fluctuations in blood circulation.
As published on Cell.com on July 20 of this year, researchers tested the sniff response in 36 children, 18 with autism spectrum disorder and 18 without, to see if the sniff response in children with autism is different than the neurotypical. To measure the sniff response, the researchers built a “computer-controlled air-dilution olfactometer equipped with a custom-designed double-barreled pediatric nasal cannula that allowed [the researchers] to simultaneously deliver odors and measure nasal airflow.” This instrument was used to measure the sniff response to “pleasant (rose or shampoo) and unpleasant (sour milk or rotten fish) odors.” The procedure took 10 minutes and consisted of 20 different smells (10 of each type) while the children watched a cartoon. The four parameters measured to quantify the sniff response were “sniff volume, peak airflow rate, mean airflow rate, and duration.” Note, the sniff response was not done in relation to any verbal cues or task.
Results of the study showed that children without autism spectrum disorder took “larger sniffs” for pleasant odors versus unpleasant odors. There was no difference in the sniffs between pleasant and unpleasant smells in the autism group. The researchers also found that the greater aberrant sniffing (non-adjustment of the sniff based on the properties of the odor), the more severe the autism. The difference in the two groups persisted even with “equal reported odor perception” (children identified equally between the two groups whether smell was supposed to be pleasant or unpleasant).
I would caution on extrapolating too much from the study regarding aberrant sniffing as the sample size is small. Also, from personal experience, the intensity of the smell, irrespective of whether the particular smell is deemed “pleasant” or “unpleasant” makes a big difference as to how I (who am on the autism spectrum) react to the smell. For example, I cannot stand intense perfume smells that emanate from a person or a cleaning product regardless of whether the actual smell is something pleasant like a flower.
Dozens of genes have been found to be correlated with autism. However, according to James P. Noonan, an associate professor of genetics, ecology and evolutionary biology at the Kavli Institute for Neuroscience at Yale University, one of these genes, CHD8, has been found to be a “master regulator in the developing human brain” and to “control the expression of many other genes.” The function of CHD8 is thought to be to regulate gene expression by “modifying the way DNA interacts with histones, proteins present in the nucleus of every cell that wind long strands of DNA.” People who have “a loss-of-function mutation in this gene, which inactivates the corresponding protein, are very likely to have an autism diagnosis.” Noonan’s study was published in March in the journal Nature Communications.
In the study, Noonan and his fellow researchers looked at developing brains of people and mice as well as neuronal stem cells. They found that CHD8 bound to thousands of sites in the brains of the humans and mice as well as the stem cells. Next, they reviewed previous genetic studies and found that “autism-associated genes were more likely to be targeted by CHD8 than expected by chance.” Finally, they looked at whether CHD8 had a regulatory effect on these genes associated with autism. The researchers looked to accomplish this goal by “reducing the expression of the CHD8 gene in cultured human neuronal stem cells and explored what, if any, gene expression levels changed.” The result of this reduced gene expression was the impaired regulation of many of the targeted genes but “autism risk genes were most strongly affected.” Mr. Noonan believes that as a result of this type of research, answers to what “biological pathways and developmental processes that are affected in autism” will be developed.
Source: News.Yale.edu March 10, 2015
The Medical Research Council UK Autism Imaging Multicentre Study which was comprised of the Institute of Psychiatry at Kings College in London, the Autism Research Centre at the University of Cambridge and the Autism Research Group at the University of Oxford analyzed the brains of males with autism versus male controls using quantitative magnetic resonance imaging. The study was comprised of 89 men with autism spectrum disorder (mean age 26 and “full-scale IQ 110”) and 89 “male control participants” (mean age 28 and “full-scale IQ 113”). The differences in the two groups were identified statistically through “partial least squares analysis.”
The results of the study showed significant brain anatomy differences between the two groups although the adults with autism spectrum disorder did not “differ significantly from the controls in overall brain volume.” Study individuals with autism did have “significantly increased gray matter volume in the anterior temporal and dorsolateral prefrontal regions and significant reductions in the occipital and medial parietal regions as compared with controls.” The importance of these regional differences in neuroanatomy is that there was a “significant correlation between these differences and the severity of specific autistic symptoms.” Additional differences between those with autism spectrum disorder and the male controls were that those with autism had “spatially distributed reductions in white matter volume.”
In summary, quantitative MRI showed that although the overall brain volume of those with autism spectrum disorder and the controls (commonly referred to as the neurotypical) is not significantly different, there are significant brain anatomy differences in gray matter volume as well as white matter volume in those with autism spectrum disorder compared to the neurotypical; and further, the regional differences correlated with autistic symptom severity.
Source: Journal of the Archives of General Psychiatry; Jan. 2, 2012; copyrighted by the American Medical Association as detailed on the Nuffield Department of Clinical Neurosciences Medical Sciences Division of University of Oxford website: http://www.ndcn.ox.ac.uk/publications/343223.