Send Orders for Reprints to reprints@benthamscience.ae 1750 CNS & Neurological Disorders - Drug Targets, 2014, 13, 1750-1758 The Putative Impact of Metabolic Health on Default Mode Network Activity and Functional Connectivity in Neuropsychiatric Disorders Danielle S. Cha 1,2 , Francesco De Michele 1,3 , Joanna K. Soczynska 1,2 , Hanna O. Woldeyohannes 1 , Oksana Kaidanovich-Beilin 4 , Andre F. Carvalho 5 , Gin S. Malhi 6 , Hiren Patel 2,7 , Kang Sim 8 , Elisa Brietzke 1,9 , Rodrigo Mansur 1,9 , Katharine A.M. Dunlop 2 , Mohammad Alsuwaidan 1,10 , Anusha Baskaran 1,11 , Andrea Fagiolini 12 , Roman Reznikov 2,7 , Paul A. Kudlow 1,2,13 and Roger S. McIntyre *,1,2,10,14 1 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; 2 Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 3 Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy; 4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; 5 Department of Clinical Medicine and Psychaitry Research Group, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil; 6 CADE Clinic, Department of Psychiatry, and Advanced Research High-field Imaging Facility, Sydney Medical School - Northern, University of Sydney, Sydney, Australia; 7 Centre for Addiction and Mental Health, Toronto, ON, Canada; 8 Institute of Mental Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 9 Interdisciplinary Laboratory of Clinical Neurosciences (LINC), Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, Brazil; 10 Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 11 Centre for Neuroscience Studies, Queen’s University, Kingston, Canada; 12 Departments of Mental Health and Molecular Medicine, University of Siena, Viale Bracci, Siena, Italy; 13 Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; 14 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada Abstract: The default mode network (DMN) describes a distributed network of brain regions that are predominantly activated and engaged during periods of spontaneous, stimulus independent thought (i.e., at rest) and remain quiescent during attention-demanding, goal-directed tasks. Replicated evidence in functional neuroimaging studies suggests that midline cortical and subcortical brain regions responsible for memory, self-relevant emotional and mental processes, as well as information integration comprise the DMN. The DMN is posited to represent self-referential mental activity via a dynamic interplay of cognitive and emotional processes by integrating information from the external environment with introspective thoughts to generate an autobiographical concept of the self. It has been amply documented that irregularities in the DMN and its functional connectivity are associated with various neuropsychiatric disorders. Moreover, accumulating evidence also suggests that individuals with select medical disorders (i.e., metabolic disorders) demonstrate alterations in DMN activity and functional connectivity. However, there is a paucity of data evaluating whether individuals with metabolically-based medical conditions, exhibiting altered DMN activity and functional connectivity, are at increased risk for developing neuropsychiatric disorders. Likewise, potential mechanisms (e.g., altered brain metabolism, insulin resistance) mediating these changes and their implications for novel treatment approaches have yet to be elucidated. Taken together, the overarching aim of this review is to provide a synthetic overview that suggests that this neural circuit may represent a common (or convergent) substrate affected in individuals with select neuropsychiatric and metabolic disorders. Keywords: Default mode network, functional connectivity, mental disorder, mood disorder, neurological disorder, neuropsychiatric disorder, resting state network, psychiatric disorder, task negative network. INTRODUCTION The Default Mode Network The default mode network (DMN) represents a distributed network of brain regions that are predominantly activated and engaged while at rest during periods of spontaneous, stimulus-independent thought, and is purported to mediate self-referential processing (e.g., daydreaming, planning, thinking about one’s own thoughts and feelings) in *Address correspondence to this author at the Mood Disorders Psychop- harmacology Unit, University Health Network, 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada; Tel: +1 416 603 5279; Fax: +1 416 603 5368; E-mail: Roger.McIntyre@uhn.ca the absence of attention-demanding, goal-directed tasks [1- 3]. The concept of the DMN was derived from traditional functional magnetic resonance imaging (fMRI) studies wherein task-related functional responses are compared to a baseline state of low-frequency fluctuations (approximately 0.01 – 0.1 Hz), as measured by the blood oxygen level dependent (BOLD) signal [4]. The BOLD signal is measured during fMRI to assess changes in the cerebral metabolic rate of oxygen, providing a quantitative proxy for neural activity to generate patterns of brain activation [5, 6]. Periods of rest during task-related fMRI studies display a uniform pattern of activation for these low-frequency fluctuations among disparate regions across the human brain in the “resting-but- awake” state [4, 7, 8]. This uniform activation of disparate 1996-3181/14 $58.00+.00 © 2014 Bentham Science Publishers