Mental disorders, including depression, bipolar disorder, schizophrenia, and anxiety disorders, represent some of the most serious and intractable of all diseases. They cause untold suffering and a massive economic burden on society. It is estimated that one in every four American adults suffer from a mental disorder in any given year, and depression is among the leading causes of disability worldwide. Unfortunately psychiatric disorders are also among the most mysterious of all diseases. Their underlying causes are still poorly understood, and their diagnosis is still based purely on behavioral criteria. No physical diagnostic test has yet been developed for any psychiatric disorder.
Existing treatments, whether through drugs or behavioral therapy, are at best only partly effective. The absence of good animal models and the ignorance of the biological mechanisms that cause these diseases are the fundamental obstacles to the development of new treatments.
Nevertheless, there is good reason to be optimistic that psychiatry is on the verge of a new era. The past few years have seen enormous advances in human genetics, and researchers are rapidly uncovering the genetic risk factors for the major psychiatric diseases. New imaging technologies allow us to study how genetic and environmental factors affect the brain. At the same time, advances in molecular biology have led to new animal models that will provide fundamental insights into disease mechanisms and ultimately into the development of the new therapies that are so urgently needed.
McGovern Institute researchers are tackling this problem at multiple levels, from imaging of clinical patients at the Martinos Imaging Center to the development of new animal models to study the fundamental brain mechanisms that are disrupted by psychiatric disorders. Much of this research is supported by the Poitras Center for Affective Disorders Research, which funds research on major mental illnesses both within and beyond the McGovern Institute.
The following faculty members are conducting research relevant to psychiatric disorders:
The laboratory of Feng Zhang designs molecular tools that manipulate the living brain, enabling precise regulation of the genes and neural circuits involved in brain processes, including those that play important roles in depression, schizophrenia, and other neurologic illnesses. Zhang’s team is developing new approaches to understanding and eventually treating complex brain diseases by introducing changes directly into the genome of cells or repairing genetic mutations in the living brain. They are also investigating how environmental influences change the way genes are expressed in people genetically predisposed to psychiatric illnesses, and testing how light can be used to control specific neural pathways implicated in affective disorders.
Robert Desimone studies the brain mechanisms underlying the control of attention and executive function, capacities that are disrupted in disorders such as ADHD and schizophrenia. His recent work suggests that the prefrontal cortex exerts ’top-down’ control over multiple brain regions, and helps us to selectively attend to sensory information. He found that neurons in the prefrontal cortex fire in unison and send signals to the visual cortex to do the same, generating high-frequency waves that oscillate between these distant brain regions like a vibrating spring. These waves, known as gamma oscillations, have long been associated with cognitive states such as attention, learning, and consciousness. They are also known to be disrupted in people with schizophrenia, ADHD, and other brain disorders.
John Gabrieli uses neuroimaging and behavioral methods to study the basis of psychiatric disease. By scanning individuals with and without disease, he hopes to understand the brain mechanisms that underlie these diseases, and to find changes in the brain that are associated with effective treatment of these conditions. Much of this work is carried out in collaboration with clinicians at local hospitals. His recent work in this field includes studies on depression, schizophrenia and anxiety disorders, as well as basic work on the brain mechanisms underlying human memory, thought, and emotion.
Guoping Feng is using genetic methods to develop animal models of psychiatric disorders, including obsessive-compulsive disorder and bipolar disorder. These model systems provide insights into fundamental mechanisms underlying the disease process, and they are also essential for the development of new drug treatments. Feng is also collaborating with clinical geneticists to link his animal findings to human psychiatric patients.
Bob Horvitz has recently identified a new class of receptors for dopamine, a neurotransmitter implicated in many psychiatric diseases. These previously unknown receptors are blocked by antipsychotic drugs. The discovery of these receptors could lead to new therapeutic targets for psychiatric disorders if similar receptors are found in humans.
Nancy Kanwisher, an expert on human visual perception, has recently collaborated with psychiatrists to examine how perception of faces is affected in patients with schizophrenia.
Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW, Shenton ME, Green AI, Nieto-Castanon A, LaViolette P, Wojcik J, Gabrieli JD, Seidman LJ. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1279-84. Epub 2009 Jan 21. Erratum in: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4572.
Subgenual anterior cingulate activation to valenced emotional stimuli in major depression. Gotlib IH, Sivers H, Gabrieli JD, Whitfield-Gabrieli S, Goldin P, Minor KL, Canli T. Neuroreport. 2005 Nov 7;16(16):1731-4.
Amygdala reactivity to emotional faces predicts improvement in major depression. Canli T, Cooney RE, Goldin P, Shah M, Sivers H, Thomason ME, Whitfield-Gabrieli S, Gabrieli JD, Gotlib IH. Neuroreport. 2005 Aug 22;16(12):1267-70.
Brain activation to emotional words in depressed vs healthy subjects. Canli T, Sivers H, Thomason ME, Whitfield-Gabrieli S, Gabrieli JD, Gotlib IH. Neuroreport. 2004 Dec 3;15(17):2585-8.
Striosomes and mood dysfunction in Huntington’s disease. Tippett LJ, Waldvogel HJ, Thomas SJ, Hogg VM, van Roon-Mom W, Synek BJ, Graybiel AM, Faull RL. Brain. 2007 Jan;130(Pt 1):206-21. Epub 2006 Oct 12.
Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, Feliciano C, Chen M, Adams JP, Luo J, Dudek SM, Weinberg RJ, Calakos N, Wetsel WC, Feng G. Nature. 2007 Aug 23;448(7156):894-900.
Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study. Bienvenu OJ, Wang Y, Shugart YY, Welch JM, Grados MA, Fyer AJ, Rauch SL, McCracken JT, Rasmussen SA, Murphy DL, Cullen B, Valle D, Hoehn-Saric R, Greenberg BD, Pinto A, Knowles JA, Piacentini J, Pauls DL, Liang KY, Willour VL, Riddle M, Samuels JF, Feng G, Nestadt G. Am J Med Genet B Neuropsychiatr Genet. 2009 Jul 5;150B(5):710-20.
Ligand-gated chloride channels are receptors for biogenic amines in C. elegans.
Ringstad N, Abe N, Horvitz HR. Science. 2009 Jul 3;325(5936):96-100.
What’s in a face? Effects of stimulus duration and inversion on face processing in schizophrenia. Butler PD, Tambini A, Yovel G, Jalbrzikowski M, Ziwich R, Silipo G, Kanwisher N, Javitt DC. Schizophr Res. 2008 Aug;103(1-3):283-92. Epub 2008 May 2.
Image: Justin Knight Photography