Expanding Our Understanding of ASD
Over the past year, new research emerged that deepened the scientific community’s understanding of brain changes in autism spectrum disorder (ASD). In 2018, the National Institute of Health (NIH) estimated that among eight-year-old children in the United States, 1 in 44 are diagnosed with ASD (males 3 to 4 times more likely to be diagnosed than females).[1] Since those with ASD often struggle with ongoing social difficulties throughout life, the latest studies may provide insights and implications for ground-breaking potential treatments.
Study 1: Vocal Prosody
Vocal prosody refers to changes in speech that include volume variations, stress patterns, pauses, intonation, and rhythm.[2] These types of verbal emotional cues are an important aspect of child development, and the inability to pick up on them is considered a prominent component of ASD behavior. There are currently two theories explaining why individuals with ASD have difficulty with verbal cues.[3] The sensory deficit model proposes that the auditory regions of the brain are processing sounds differently when an individual has ASD.[4] A second theory uses social cognition to hypothesize that individuals with autism process auditory sounds normally, but then interpret them differently in the social regions of the brain.[5]
A recent study conducted by Stanford School of Medicine used MRI brain scans to show that both children with autism and a neurotypical control group used the auditory processing region of the brain when listening to voices– but there were differences in how the signal reached the social region of the brain.[6] This supports the social cognitive approach that the auditory processing in both groups is the same, but that sounds are then interpreted differently by individuals with ASD.[7]
Researchers believe that they may now be able to incorporate this knowledge into techniques for treatment. Dr. Simon Leipold, one of the authors of the study, explains these findings indicate that, “the temporoparietal junction might be a promising brain region to target” when looking at future treatments.[8] For example, it is possible that techniques previously examined by Stanford Medicine to help ASD children recognize facial expressions may now be applied to accurately identifying vocal cues.[9]
Study 2: Changes in the Cerebral Cortex
A study led by UCLA found that brain changes in those diagnosed with autism are more pervasive than previously realized.[10] Gandal et al., (2022) conducted RNA sequencing analysis to evaluate differences in 11 distinct brain regions by matching samples from individuals with idiopathic ASD to neurotypical controls.[11] The researchers found changes in all 11 cortical regions, indicating widespread differences at the molecular level.[12] Until this study, it was previously believed that brain changes in ASD only took place in the specific regions believed to affect language and behavior.[13]
These comprehensive findings are the result of more than a decade of research which culminated in developing a full analysis of the autistic brain.[14] Further, Gandal et al., determined the largest differences were found in the visual and parietal cortex, which may help explain the sensory hypersensitivity that is often reported by individuals with ASD. Dr. Daniel Geschwind, a professor of Human Genetics, Neurology and Psychiatry at UCLA who authored the study, stated that these findings can now serve as a starting point to develop new pharmaceutical therapies that specifically address these mechanisms.[15]
Study 3: Neuroinflammation
Neuroinflammation is an immune response that takes place in the central nervous system, and it is believed to be activated by infection, psychological stress, toxins, trauma, aging, and ischemia.[16] Though neuroinflammation does have normal function during the processes of protection and repair, acute or chronic inflammation can result in altered behavior and cognition.[17] A recent study of 1,275 immune genes showed atypical expression patterns that varied by condition in the brains of adults diagnosed with: autism; depression; bipolar disorder; schizophrenia; Parkinson’s disease; and/or Alzheimer’s disease.[18]
Lead researcher, Dr. Chunyu Liu, explains these expressions are “signatures” for each diagnosis that could potentially be used as markers of inflammation, indicating the immune system may be a “major player” in brain disorders.[19] However, from the current study, it is not possible to tell whether these conditions altered immune activation or whether immune activations contributed to the development of these conditions.[20]
The brains of those diagnosed with autism specifically showed 275 genes with varied expression levels compared to controls, with autistic males presenting more variation than autistic females.[21] This study’s analysis also found that ASD was clustered more closely with the neurological disorders of Alzheimer’s Disease and Parkinson’s Disease than psychiatric conditions such as major depressive disorder, bipolar disorder, or schizophrenia.[22] Chen et al., note these findings indicate that different types of immune-related treatment strategies may be needed for different clusters of diseases.[23]
Study 4: Differences Among Males & Females
There are new indications that autism may shift the brain towards typically male characteristics.[24] To evaluate this question, Floris et al., conducted research predicting the sex of a brain based on brain images and found that the accuracy of sex prediction was higher for autistic males compared to both autistic females and neurotypical males. More accurate predictions were also found in adults than children, indicating these differences may vary throughout developmental stages. Specifically, researchers found that visual and auditory processing areas normally associated with facial and speech recognition indicated a shift towards male brain structure. A comparison of neurotypical and autistic female brains further reinforced this idea, with autistic females showing sensory pathways that are normally seen in neurotypical males. This finding supports sensory-based theories which suggest that early disruptions to motor and sensory processing may lead to some of the social symptoms seen in ASD.[25]
It is also important to note that a similar test conducted on the brains of those diagnosed with attention deficit hyperactivity disorder (ADHD) did not produce the same results.[26] This research by Floris et al., furthers the biological understanding of ASD and creates the groundwork for a deeper understanding of differences in ASD between sexes.[27]
Study 5: Genetic Mutation
A seven-year study conducted by Rutgers University analyzed a gene mutation in ASD known as R451C in the gene Neurologin-3.[28] Prior to this research, studies on the mutation in the synapses of mice indicated there was a causative relationship between the mutation and the pathophysiology of ASD, but it was not clear if these findings could be extended to humans.[29] Wang et al., (2022) conducted this study with the goal of understanding whether the mutation would have a similar effect on the function of synapses in human neurons.[30]
The research team used CRISPR (a unique gene editing technology) to alter the genetic material of human stem cells and derive human neuron cells, which carried the mutation they wanted to analyze.[31] They then implanted human cells both with and without the mutation into the brains of mice to compare the results.[32] Evidence from their research showed a burst of electrical activity (indicating an overstimulation) in the mutated genes which was more than double what was observed in the non-mutated cells.[33] The results were consistent with earlier hypotheses and indicate there may be a physiological path between increased excitatory synaptic activity and the development of ASD.[34] Senior author of this study, Dr. Zhiping Pang, hopes that the unique techniques developed to perform this experiment will be used by future researchers to not only conduct further studies on mental disorders, but also potentially develop new therapeutics.[35]
Study 6: Phelan-McDermid Syndrome
A team of researchers at Northwestern University Feinberg School of Medicine, led by Dr. Peter Penzes, developed a new therapy to treat a subtype of ASD, known as Phelan-McDermid syndrome (PMS). PMS, a rare genetic condition, is known to be caused by a specific mutation within the SHANK3 gene that is characterized by epilepsy, global developmental delay, and absent or delayed speech.[36,37]
Rohman (2022) notes the team developed a derivative of an insulin-like growth factor-binding protein (IGFBP2) that was previously shown to improve cognitive functions and neuroplasticity.[38] Researchers administered the derived peptide (JB2) to mice with similar mutations and evaluated the results with brain imaging.[39] The treatment showed improvement in ultrasonic vocalization, learning, memory, synaptic function and plasticity, and motor functions in addition to normalizing seizure susceptibility and neuronal excitability.[40] Dr. Penzes believes this study may lead to a pediatric treatment that could be used to address symptoms while the brain is developing, though acknowledges it is difficult to get revolutionary types of treatment approved.[41]
The afore-mentioned studies conducted over the past year illustrate significant gains in the scientific understanding of ASD. As technologies such as CRISPR become more commonplace, the potential exists to develop new biomarkers to diagnose ASD and develop novel treatments that can intervene early in the process of development by addressing the root cause of symptoms. These studies serve to clarify our understanding of the unique needs of individuals with autism and provide hope for families in the future.
Contributed by: Theresa Nair
Editor: Jennifer (Ghahari) Smith, Ph.D.
REFERENCES
1 Autism spectrum disorder (ASD). National Institute of Mental Health (NIMH) Web site. https://www.nimh.nih.gov/health/statistics/autism-spectrum-disorder-asd. Updated 2022. Accessed Feb 4, 2023.
2 Meredith A. Prosody and articulation. Apraxia Kids Web site. https://www.apraxia-kids.org/apraxia_kids_library/prosody-and-articulation/. Accessed Feb 4, 2023.
3 Leipold S, Abrams DA, Karraker S, Phillips JM, Menon V. Aberrant emotional prosody circuitry predicts social communication impairments in children with autism. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2022. https://www.sciencedirect.com/science/article/pii/S2451902222002452. doi: 10.1016/j.bpsc.2022.09.016.
4 Digitale E. Brain wiring explains why autism hinders grasp of vocal emotion, says stanford medicine study. News Center Web site. http://med.stanford.edu/news/all-news/2023/01/brain-autism-speech-emotion.html. Updated 2023. Accessed Jan 20, 2023.
5 Digitale (2023)
6 Ibid.
7 Leipold et al. (2022)
8 Digitale (2023)
9 Ibid.
10 Brain changes in autism are far more sweeping than previously known, study finds: The study is the most comprehensive effort yet to study how autism affects the brain at the molecular level -- ScienceDaily. Science Daily. 2022. https://www.sciencedaily.com/releases/2022/11/221102123603.htm. Accessed Jan 17, 2023.
11 Gandal MJ, Haney JR, Wamsley B, et al. Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD. Nature. 2022;611(7936):532-539. https://www.nature.com/articles/s41586-022-05377-7. Accessed Jan 18, 2023. doi: 10.1038/s41586-022-05377-7.
12 SD (2022)
13 Ibid.
14 Ibid.
15 Ibid.
16 Chen Y, Dai J, Tang L, et al. Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders. Mol Psychiatry. 2022. doi: 10.1038/s41380-022-01854-7.
17 Ibid.
18 Dattaro L. Immunity-linked genes expressed differently in brains of autistic people. Spectrum | Autism Research News Web site. https://www.spectrumnews.org/news/immunity-linked-genes-expressed-differently-in-brains-of-autistic-people/. Updated 2023. Accessed Jan 21, 2023.
19 Ibid.
20 Ibid.
21 Ibid.
22 Chen et al. (2022)
23 Ibid.
24 Hernandez L. Sex-differential neuroanatomy in autism: A shift toward male-characteristic brain structure | american journal of psychiatry. . 2023. https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.20220939. Accessed Jan 20, 2023.
25 Ibid.
26 Ibid.
27 Ibid.
28 MacPherson K. Gene mutation leading to autism found to overstimulate brain cells. Rutgers | The State University of New Jersey Web site. https://www.rutgers.edu/news/gene-mutation-leading-autism-found-overstimulate-brain-cells. Updated 2022. Accessed Jan 29, 2023.
29 Wang L, Mirabella VR, Dai R, et al. Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism. Mol Psychiatry. 2022:1-16. https://www.nature.com/articles/s41380-022-01834-x. Accessed Jan 29, 2023. doi: 10.1038/s41380-022-01834-x.
30 Ibid.
31 MacPherson (2022)
32 Ibid.
33 Ibid.
34 Wang et al. (2022)
35 MacPherson (2022)
36 Rohman M. Northwestern investigators develop new therapy for autism subtype. Northwestern Medicine News Center Web site. https://news.feinberg.northwestern.edu/2022/12/26/northwestern-investigators-develop-new-therapy-for-autism-subtype/. Updated 2022. Accessed Jan 21, 2023.
37 Burgdorf JS, Yoon S, Dos Santos M, Lammert CR, Moskal JR, Penzes P. An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of phelan-McDermid syndrome. Mol Psychiatry. 2022:1-11. https://www.nature.com/articles/s41380-022-01904-0. Accessed Jan 25, 2023. doi: 10.1038/s41380-022-01904-0.
38 Rohman (2022)
39 Ibid.
40 Burgdorf et al. (2022)
41 Rohman (2022)