Developmental Disorders

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. Finally, a deeper 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 large-scale studies of autism and 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:

Autism

Nancy Kanwisher is leading a project to search for the neural basis of autism. Supported by the Ellison Medical Foundation, the aim of this project is to develop a battery of behavioral tests and standardized neuroimaging protocols designed to look at both the structure and the activity of the brain. These tests will then be applied to a large sample of children with and without autism in order to search for differences that distinguish the two groups.

One area of particular interest in the search for clues to autism is the temporal-parietal junction. This brain area was previously shown by Kanwisher and her former student Rebecca Saxe to be specifically activated by thinking about other people’s mental states – an ability that is impaired in people with autism.


John Gabrieli
, in collaboration with the Boston Autism Consortium, is planning a large scale study of adolescents with autism spectrum disorder (ASD). The study will measure brain activation during a social cognition task in which subjects are asked to respond to emotional faces. Subjects will be scanned using multiple brain imaging methods, in order to identify brain differences that may underlie the difficulties in social interactions that are characteristic of autism.



Poitras Professor of Neuroscience Guoping Feng is investigating how genes regulate neuron-neuron communication and how dysfunction of this communication contributes to autism. One of the genes his lab is investigating is the Shank3 gene, which is implicated in many cases of human autism. This gene is of interest because it is found primarily in a part of the brain called the striatum, which is involved in motor activity, decision-making and the emotional aspects of behavior. Feng has successfully demonstrated that mutations in Shank3 produce autistic-like behavior by interfering with communication between brain cells. He is now conducting studies to determine whether the neuronal mechanism identified in the Shank3 mutations is a common pathology in a group of other genes that are associated with autism. If that turns out to be the case, it should be possible to develop novel treatments that restore the function of neuron-neuron communication and potentially correct autistic-like behaviors.

Rebecca Saxe studies the neural basis of human social cognition and abstract thought. The Saxe Lab uses imaging technologies and behavioral studies to understand how individuals view the mental states of other people (called 'theory of mind'), make moral judgments about others, and construct complex and abstract thoughts about how other individuals think about the world around us. Though they may not have difficulties with logic, individuals with autism spectrum disorders often struggle with understanding other people’s thoughts and attributing beliefs to others. Saxe and her team are studying the development of theory of mind in children and adults with and without autism disorders, in the hopes of learning more about the specific neural differences that people with autism show when reasoning about beliefs of others.


Martha Constantine-Paton’s lab focuses on the activity-dependent development of the major excitatory systems in the brain: namely glutamate mediated circuits. They have recently developed a potentially promising model for an entirely new approach to autism spectrum disorder research—one that effects glutamate circuitry because a transport protein, Myosin Va, that carries many autism associated genes to the synapse has an abnormal genetic duplication that disrupts the function of the normal molecules. This MyosinVa mutant has many of the characteristics of human autism, including early epilepsy that remits with age, repetitive behavior, impaired social interaction, anxiety and impaired learning. The fact that the mutant behaviors are due to the interference of a normal protein by an abnormal variant, rather than the defective function of the single normal gene, promises a new approach to discovering which brain circuits are abnormal in autism. Constantine-Paton believes that by developing procedures to conditionally knockout the mutant protein in specific brain regions in young animals and then ask if specific normal behaviors are recovered it will be possible to identify pathways that underlie the behavior and examine their development to determine what and when synaptic connections and/or functions become abnormal. This would identify the primary developmental events that are defective in many pathways responsible for autistic behaviors. By identifying particular developmental processes that could be disrupted by a wide variety of events during early life, these events rather than particular molecules could be targeted for detailed research and modification to nullify the crippling effects of autism and perhaps other psychiatric diseases.

Several McGovern researchers, including John Gabrieli, Ann Graybiel, Yingxi Lin and Tomaso Poggio, are involved in the Simons Center for the Social Brain.


Dyslexia

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.


Research on brain development and plasticity

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.



Selected References

John Gabrieli
Dyslexia: a new synergy between education and cognitive neuroscience.Gabrieli JD. Science. 2009 Jul 17;325(5938):280-3.

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.

Nancy Kanwisher
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.

Martha Constantine-Paton

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.

Michale Fee
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.

Yingxi Lin
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