Developmental brain disorders such as autism and dyslexia are common conditions that are typically diagnosed in childhood, but which can also lead to lifelong impairments.
Many psychiatric disorders are thought to have their origins in early life, even if they are not diagnosed until many years later. We now understand that these conditions involve a complex interplay of genetic and environmental risk factors, but their precise causes are still not known. Current treatment options are often inadequate, and there is an urgent need for new and better therapies.
Developmental disorders are an important target for research at the McGovern Institute. One goal is to identify children at risk as early as possible. For most of these conditions, earlier intervention is associated with better outcomes. Because these conditions are heterogeneous, another goal is to identify different subsets of individuals for which different treatments may be effective.
We are also working to understand the neural basis of these disorders, by studying both human subjects and animal models. Much of this work builds on recent advances in genetics, with the goal of understanding how genetic risk factors affect brain function. We also study environmental factors such as maternal infection, which has been implicated as a risk factor for neurodevelopmental disorders including autism and schizophrenia. A deeper biological understanding of the neural basis of these disorders may allow the design of new therapies, whether behavioral or pharmacological, that will produce better outcomes.
A major focus of our work is on pediatric neuroimaging, including studies of individuals with autism or dyslexia. Along with clinical populations, we also study the development of brain function in normally developing children and adolescents. Understanding the developmental origins of human capacities such as memory, language, and emotion will provide a framework for understanding the basis of developmental disorders, and may also contribute to improved educational methods that will benefit all children. Finally, underpinning our human neuroimaging work is a strong program of basic developmental neuroscience research, aimed at understanding the fundamental mechanisms by which the brain is shaped by experience during development and throughout life.
Developmental disorders are an important target for research at the McGovern Institute. Areas of research include:
Animal models of autism
Guoping Feng has previously developed a mouse model of autism based on a mutation in the shank3 gene, which is linked to autism in humans. In 2016, his team showed that many of the mutation's effects on brain and behavior can be reversed by restoring shank3 gene activity, even in adult mice. These findings offer hope that a similar approach may eventually be possible in human patients, either through the development of new drugs or through other approaches such as gene therapy. Feng is also working to identify brain circuits that are altered in these and other animal models, and to identify potential targets for future therapeutic intervention.
Growing evidence is pointing to maternal viral infection as a risk factor for the development of autism in children. This effect has been modeled in rodents by inducing inflammation in pregnant mice. Gloria Choi and collaborators have shown in mice that the effect is caused by an immune signaling molecule called IL-17, which promotes inflammation and which is released by a specific class of white blood cells known at Th17 cells. Choi is now studying how IL-17 from the mother affects the developing brain and how this leads to the observed behavioral effects. By targeting Th17 cells, it may in the future be possible to reduce the risk of developmental disorders in children born to mothers who develop viral infections during pregnancy.
Altered brain chemistry in autism
Brain activity is controlled by a constant interplay of inhibition and excitation, which is mediated by different neurotransmitters. It has been suggested that the balance between inhibition and excitation is altered in autism, but until recently there was no direct evidence for this in the human brain. In 2015 the lab of Professor Nancy Kanwisher used a technique called magnetic resonance spectroscopy to measure the level of the inhibitory neurotransmitter GABA in the brains of individuals with or without autism. The researchers also tested subjects on a visual task involving perception of ambiguous stimuli, a task that is known to be affected in autism. Their results indicated that GABA is less active in the brains of autistic individuals, consistent with the imbalance hypothesis. Kanwisher’s group is now investigating whether drugs that alter GABA signaling in human patients can change any of the behaviors seen in autistic individuals. They are also exploring whether their test could lead to a new biomarker for better diagnosis and testing of people with autism.
Understanding social cognition in autism
Rebecca Saxe studies the neural mechanisms underlying "theory of mind," the ability of humans to understand the mental states of other people. Individuals with autism often struggle to understand other people’s thoughts, beliefs and emotions, and Saxe is interested in the brain mechansims that may account for this difficulty. Using both behavioral testing and brain imaging methods, she studies how TOM develops in children, and how the relevant patterns of brain activity differ between typically developing individuals and those with autism.
John Gabrieli has a longstanding interest in dyslexia, which he studies through a combination of behavioral testing and brain imaging methods, including magnetic resonance imaging (MRI) and electroencephalography. The goal of this work is twofold: (1) to develop methods for predicting as early as possible which children are at risk for reading difficulties and (2) to understand the brain mechanisms underlying dyslexia and its remediation, in order to develop more effective forms of treatment.
Nancy Kanwisher is studying the localization of different language functions within the brain. In one recent study, for example, she identified a brain area that is specifically activated by written words in the subject’s native language but not an unfamiliar language -- a clear demonstration of how education can shape the brain. Understanding how the brain processes spoken and written language will provide the essential framework for understanding the basis of language learning impairment and dyslexia.
Martha Constantine-Paton studies how the mammalian brain becomes wired in response to experience. This is a fundamental question for normal development and is also relevant to a range of brain disorders, many of which are thought to have their origins during early development long before they are diagnosed. Constantine-Paton’s work focuses specifically on the visual system, particularly the changes that occur during the critical period following eye-opening when the brain first responds to visual experience. The principles that emerge are also relevant to other senses and to higher cognitive functions such as language acquisition.
Michale Fee is studying the neural basis of song learning in birds. Like human infants learning to speak, young birds learn their song by imitating adults. This is a process of trial and error, in which young birds go through a period of babbling, before the song crystallizes into its mature song. Fee and colleagues have recently identified a circuit in the brain that drives the variable, exploratory vocalizations that form the basis for this trial-and-error learning.
Yingxi Lin studies the development of inhibitory connections, which act as a counterbalance to excitatory connections and thus help to set the proper level of electrical activity within the brain. A deficiency in inhibitory signaling can lead to epilepsy, and Lin’s research also suggests that they may play a role in the development of autism.
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Cognitive and neural development of individuated self-representation in children. Ray RD, Shelton AL, Hollon NG, Michel BD, Frankel CB, Gross JJ, Gabrieli JD. Child Dev. 2009 Jul-Aug;80(4):1232-42.
Modifying the brain activation of poor readers during sentence comprehension with extended remedial instruction: a longitudinal study of neuroplasticity. Meyler A, Keller TA, Cherkassky VL, Gabrieli JD, Just MA. Neuropsychologia. 2008. Aug;46(10):2580-92.
Development of the declarative memory system in the human brain. Ofen N, Kao YC, Sokol-Hessner P, Kim H, Whitfield-Gabrieli S, Gabrieli JD. Nat Neurosci. 2007 Sep;10(9):1198-205.
Prediction of children’s reading skills using behavioral, functional, and structural neuroimaging measures. Hoeft F, Ueno T, Reiss AL, Meyler A, Whitfield-Gabrieli S, Glover GH, Keller TA, Kobayashi N, Mazaika P, Jo B, Just MA, Gabrieli JD. Behav Neurosci. 2007 Jun;121(3):602-13.
Functional and morphometric brain dissociation between dyslexia and reading ability. Hoeft F, Meyler A, Hernandez A, Juel C, Taylor-Hill H, Martindale JL, McMillon G, Kolchugina G, Black JM, Faizi A, Deutsch GK, Siok WT, Reiss AL, Whitfield-Gabrieli S, Gabrieli JD. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4234-9.
Visual word processing and experiential origins of functional selectivity in human extrastriate cortex. Baker CI, Liu J, Wald LL, Kwong KK, Benner T, Kanwisher N. Proc Natl Acad Sci U S A. 2007 May 22;104(21):9087-92.
Understanding other minds: linking developmental psychology and functional neuroimaging. Saxe R, Carey S, Kanwisher N. Annu Rev Psychol. 2004;55:87-124.
Non-symbolic arithmetic in adults and young children. Barth H, La Mont K, Lipton J, Dehaene S, Kanwisher N, Spelke E. Cognition. 2006 Jan;98(3):199-222.
Development of hemodynamic responses and functional connectivity in rat somatosensory cortex. Colonnese MT, Phillips MA, Constantine-Paton M, Kaila K, Jasanoff A. Nat Neurosci. 2008 Jan;11(1):72-9.
Eye opening rapidly induces synaptic potentiation and refinement. Lu W, Constantine-Paton M. Neuron. 2004 Jul 22;43(2):237-49.
A specialized forebrain circuit for vocal babbling in the juvenile songbird. Aronov D, Andalman AS, Fee MS. Science. 2008 May 2;320(5876):630-4.
Activity-dependent regulation of inhibitory synapse development by Npas4. Lin Y, Bloodgood BL, Hauser JL, Lapan AD, Koon AC, Kim TK, Hu LS, Malik AN, Greenberg ME. Nature. 2008 Oct 30;455(7217):1198-204.
Identifying autism loci and genes by tracing recent shared ancestry. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA. Science. 2008 Jul 11;321(5886):218-23.
|Image: Justin Knight Photography