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Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: a Central Pathway in Psychiatric Disease and Treatment

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Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: a Central Pathway in Psychiatric Disease and Treatment REVIEW published: 27 December 2016 doi: 10.3389/fnsys.2016.00104 Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: A Central Pathway in Psychiatric Disease and Treatment Sarah K. Peters 1, Katharine Dunlop 1 and Jonathan Downar 1,2,3,4* 1Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 2Krembil Research Institute, University Health Network, Toronto, ON, Canada, 3Department of Psychiatry, University of Toronto, Toronto, ON, Canada, 4MRI-Guided rTMS Clinic, University Health Network, Toronto, ON, Canada The salience network (SN) plays a central role in cognitive control by integrating sensory input to guide attention, attend to motivationally salient stimuli and recruit appropriate functional brain-behavior networks to modulate behavior. Mounting evidence suggests that disturbances in SN function underlie abnormalities in cognitive control and may be a common etiology underlying many psychiatric disorders. Such functional and anatomical abnormalities have been recently apparent in studies and meta-analyses of psychiatric illness using functional magnetic resonance imaging (fMRI) and voxel- based morphometry (VBM). Of particular importance, abnormal structure and function in major cortical nodes of the SN, the dorsal anterior cingulate cortex (dACC) and anterior insula (AI), have been observed as a common neurobiological substrate across a broad spectrum of psychiatric disorders. In addition to cortical nodes of the SN, the network’s associated subcortical structures, including the dorsal striatum, mediodorsal thalamus and dopaminergic brainstem nuclei, comprise a discrete regulatory loop circuit. Edited by: The SN’s cortico-striato-thalamo-cortical loop increasingly appears to be central to Avishek Adhikari, mechanisms of cognitive control, as well as to a broad spectrum of psychiatric illnesses Stanford University, USA and their available treatments. Functional imbalances within the SN loop appear Reviewed by: Vikas Mishra, to impair cognitive control, and specifically may impair self-regulation of cognition, Louisiana State University Health behavior and emotion, thereby leading to symptoms of psychiatric illness. Furthermore, Sciences Center, USA Stefano Delli Pizzi, treating such psychiatric illnesses using invasive or non-invasive brain stimulation University of Chieti-Pescara, Italy techniques appears to modulate SN cortical-subcortical loop integrity, and these effects *Correspondence: may be central to the therapeutic mechanisms of brain stimulation treatments in Jonathan Downar [email protected] many psychiatric illnesses. Here, we review clinical and experimental evidence for abnormalities in SN cortico-striatal-thalamic loop circuits in major depression, substance Received: 14 November 2016 use disorders (SUD), anxiety disorders, schizophrenia and eating disorders (ED). We Accepted: 12 December 2016 Published: 27 December 2016 also review emergent therapeutic evidence that novel invasive and non-invasive brain Citation: stimulation treatments may exert therapeutic effects by normalizing abnormalities in the Peters SK, Dunlop K and Downar J SN loop, thereby restoring the capacity for cognitive control. Finally, we consider a series (2016) Cortico-Striatal-Thalamic Loop Circuits of the Salience of promising directions for future investigations on the role of SN cortico-striatal-thalamic Network: A Central Pathway in loop circuits in the pathophysiology and treatment of psychiatric disorders. Psychiatric Disease and Treatment. Front. Syst. Neurosci. 10:104. Keywords: corticostriatal, salience network, brain stimulation, depression, substance use disorders, anxiety doi: 10.3389/fnsys.2016.00104 disorders, repetitive transcranial magnetic stimulation Frontiers in Systems Neuroscience | www.frontiersin.org 1 December 2016 | Volume 10 | Article 104 Peters et al. Salience Network Circuits in Psychiatric Disease INTRODUCTION Among these brain networks, one in particular is emerging as having particular significance to psychiatric illness: the salience Psychiatric illnesses are among the leading causes of disability network (SN; Seeley et al., 2007; Menon, 2011). Sometimes and disease burden worldwide in the 21st century. For example, known by other terms such as the cingulo-opercular network the 2010 Global Burden of Disease study identified major (Dosenbach et al., 2008), the SN corresponds to the more anterior depressive disorder (MDD) as the second leading cause of years of the two subnetworks of the ‘‘ventral attention network (VAN)’’ of life lost to disability (Ferrari et al., 2013). Overall, mental described by Yeo et al.(2011). The SN features core nodes in and substance use disorders (SUDs) accounted for 22.9% of the dorsal anterior cingulate cortex (dACC) and the bilateral the global burden of years of life lost to disability (Whiteford anterior insula (AI), as well as additional cortical notes in specific et al., 2013), with a prevalence of around one billion cases regions of the dorsolateral prefrontal cortex (dlPFC) and inferior worldwide (Whiteford et al., 2015). These illnesses have high parietal lobule (IPL; Figure 1). In addition to these cortical nodes, chronicity and community burden, and often show low response the SN also includes a specific set of subcortical nodes in the rates to existing treatments. For example, in major depression, head of the caudate nucleus, the mediodorsal nucleus of the conventional interventions are ineffective in at least one-third thalamus (MDN) and dopaminergic brainstem nuclei (Menon, of patients, and relapse rates are high even when remission 2011). Together, these structures complete a discrete cortico- is achieved (Rush et al., 2006; Ferrari et al., 2013). Thus, an striatal-thalamic-cortical (CSTC) loop that can be discerned important task for basic and translational neuroscience is to using structural or functional neuroimaging (Seeley et al., 2007; better understand the underlying pathophysiology of psychiatric Metzger et al., 2010), and that also corresponds to an analogous illness, and to develop treatments that effectively target this loop evident on tract-tracing studies in nonhuman primates pathophysiology. (Choi et al., 2016). Over the last 25 years, one of the major advances in the In healthy brain function, cortical nodes of the SN may field has been the development of increasingly detailed maps be activated passively by ‘‘salient’’ sensory stimuli (i.e., stimuli of the neural pathways that are affected in psychiatric illnesses. that draw attention for being unexpected, novel or behaviorally Steady progress is being made in localizing abnormalities of both relevant; Corbetta et al., 2000; Downar et al., 2000, 2001, 2002). brain structure and brain function. The neurologist’s traditional These cortical activations become accompanied by subcortical question, ‘‘Where is the lesion?’’, formerly had few well-defined activations of the entire cortico-striatal-thalamic loop circuit answers for most psychiatric disorders. However, today there is during active, voluntary engagement of cognitive control, at least a first approximation of an answer to this question for response selection or response inhibition; common examples many of the most prevalent types of mental illness. Progress in include the Stroop task, Go/No-Go task or flanker interference localizing psychiatric neuropathology has come from advances task (Figure 2). As such, the SN has been proposed to play a in non-invasive neuroimaging techniques suitable for in vivo key role in cognitive control (Ham et al., 2013), i.e., switching use in humans. These include structural imaging techniques for brain activity between introspective, ruminative functions of mapping gray and white matter pathology, such as voxel-based the default-mode network and externally focused, task-based morphometry (VBM) and diffusion tensor imaging (DTI), as well functions of the central executive network (Menon and Uddin, as functional imaging techniques including functional magnetic 2010). resonance imaging (fMRI), and positron emission tomography The importance of the SN to psychiatric illness emerges from (PET). an influential meta-analysis of 193 VBM studies enrolling more In healthy control subjects, application of these brain- than 7000 individuals with a wide variety of psychiatric diagnoses imaging techniques has been especially fruitful for delineating including depression, bipolar disorder, schizophrenia, SUD, the overall functional architecture of the human brain. One obsessive-compulsive disorder (OCD) and anxiety disorders major discovery has been that brain activity, during tasks or at (Goodkind et al., 2015). Examining the patterns of decreased rest, is organized into functional networks of regions showing gray matter in each disorder, the authors found a common correlated activity over time. The networks themselves appear to substrate across all diagnoses: loss of gray matter in the dACC be fairly consistent across individuals, with one influential report and bilateral AI. The loci of gray matter loss corresponded identifying a set of seven reliably reproducible major networks, closely with the core cortical nodes of the SN. As such, subdivisible into a finer set of 17 smaller subnetworks (Yeo loss of structural and functional integrity in the SN, and a et al., 2011). The earliest description of resting-state networks resultant impairment of cognitive control, has been proposed was in the motor cortex (Biswal et al., 1995). Since that time, an as a transdiagnostic feature
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