fnsys-10-00104

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 *
1
Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 2 Krembil Research Institute, University Health
Network, Toronto, ON, Canada, 3 Department of Psychiatry, University of Toronto, Toronto, ON, Canada, 4 MRI-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
jonathan.downar@uhn.ca
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 across many psychiatric illnesses
extensive literature of thousands of publications has developed (McTeague et al., 2016) and also as a target for novel
to describe the properties of several other major networks: a therapeutic interventions, such as brain stimulation (Downar
default-mode network most active during non-task cognitive et al., 2016).
states such as rumination or prospection (Raichle, 2015); a As of this writing, over 1500 publications have made reference
central executive network most active during performance to the SN, and a number of excellent reviews are available to
of cognitive tasks involving attention or working memory summarize this literature (Menon and Uddin, 2010; Menon,
(Bressler and Menon, 2010); and more circumscribed networks 2011; Dutta et al., 2014), including a recent book devoted entirely
restricted to somatomotor or visual brain regions (Yeo et al., to the subject (Uddin, 2017). The present review article aims
2011). to build upon this work by considering the SN not just as

FIGURE 1 | Meta-analytic co-activation of salience network (SN) nodes for response selection and inhibition. Neurosynth meta-analytic results following
key word searches for “response inhibition”, “response selection” and “SN”. Considerable overlap exists in the dorsal anterior cingulate cortex (dACC) region (A) and
lateral parietal cortex (B).
a resting-state cortical network, but more specifically as an across a range of psychiatric disorders. Third, we review the
integrated, CSTC network with a particular role in the voluntary available literature on how brain stimulation techniques can
engagement of cognitive control. First, we examine the anatomy modulate the activity of the SN-CSTC, and how this modulation
and function of the SN-CSTC in the healthy state. Second, we may achieve therapeutic effects in psychiatric illness. Finally, we
review the available literature on abnormalities of the SN-CSTC consider a series of promising directions for future investigations
FIGURE 2 | Cortical and subcortical nodes of the SN from meta-analyses of functional magnetic resonance imaging (fMRI) studies of task-based
activation during cognitive control. Subcortical components of SN processing are apparent across a variety of executive functioning tasks, including Stroop task,
set shifting task, Go-No Go task and Flanker interference task, as shown through meta-analytic functional imaging data.

on the role of the SN-CSTC loop circuits in the pathophysiology the supplementary motor area, putamen, ventrolateral globus
and treatment of psychiatric disorders. pallidus interna (GPi) and ventrolateral thalamus; (ii) an
oculomotor CSTC loop from the frontal eye field to the
ANATOMY AND FUNCTION OF THE SN body of the caudate, caudomedial GPi and lateral ventral
CORTICO-STRIATAL LOOP anterior thalamus; (iii) a lateral orbitofrontal CSTC loop
from the lateral orbitofrontal cortex to the ventromedial
Anatomy of the SN caudate, medial dorsomedial GPi and medial ventral anterior
Cortico-Striatal-Thalamic Loop thalamus; (iv) a dorsolateral prefrontal CSTC loop from the
The cortical nodes of the SN are evident in one of the 17 resting- dlPFC to the dorsolateral caudate, lateral dorsomedial GPi
state networks cataloged in the 1000-subject, connectivity-based and parvocellular mediodorsal thalamus; and (v) an anterior
parcellation of resting-state fMRI data by Yeo et al. (2011). cingulate CSTC loop from the dorsal ACC to the ventral
This network is the more anterior of the two subnetworks that striatum, ventral pallidum and posteriomedial mediodorsal
comprise the larger VAN. While the more posterior subnetwork thalamus.
includes posterior insula and mid-cingulate nodes, the more This classical set of five CSTC loops was originally derived
anterior subnetwork includes adjacent AI and dACC regions from nonhuman primate work; in humans, a more complex
(Figure 1). In addition, this network includes nodes in a specific and numerous set of CSTC loops is now considered likely.
region of the dlPFC, on the middle frontal gyrus, distinct from Indeed, a 1000-subject parcellation of resting-state functional
other lateral prefrontal regions assigned to the ‘‘frontoparietal’’ connectivity in the striatum rather than the cortex (Choi et al.,
and ‘‘dorsal attention’’ networks in the Yeo et al. (2011) catalog. 2012) revealed substantially more than five distinct striatal
The SN also includes a specific region of the IPL, in the angular regions, each associated with a specific cortical network cataloged
gyrus. in the parcellation of Yeo et al. (2011). As such, the CSTC
The interested reader can readily perform an independent loop of the SN may be expected to contain features of multiple
replication of this map of regions by using the online, classical loop circuits, rather than corresponding precisely to
automated meta-analytic tool Neurosynth (Yarkoni et al., just one of them. The SN loop contains nodes that appear
2011; Figure 2). Entering the term ‘‘SN’’ yields a set of in the classical dorsolateral prefrontal CSTC loop (i.e., dlPFC,
cortical regions that overlaps very closely with the more dorsolateral caudate and mediodorsal thalamus nodes), but also
anterior cingulo-insular network of Yeo et al. (2011). Entering contains cortical nodes in the anterior cingulate and the AI,
the term ‘‘cognitive control’’—a core domain within the which do not appear in any of the classically described loops.
National Institute of Mental Health’s proposed Research Conversely, each of the classically described CSTC loops of
Domain Criteria for psychopathology research (Insel, 2014)—or Alexander et al. (1986) also includes a specific subregion of the
associated terms for the subdomains of ‘‘response inhibition’’ substantia nigra: rostrolateral for the dlPFC, and rostrodorsal
or ‘‘response selection’’ likewise yields very a similar set of for the anterior cingulate. Substantia nigra activations do not
regions. Note that the purpose of this exercise is not to appear in the meta-analytic renderings of the SN (Figure 2),
infer a particular functional role for these regions, as such as may be expected given the limited spatial resolution of
inferences, based on correlations alone, are vulnerable to validity the fMRI data from which these renderings are derived.
challenges. Instead, this meta-analytic exercise demonstrates However, it should be noted that the substantia nigra and
the consistent co-activation of these regions as a coherent other midbrain dopaminergic centers such as the ventral
network across a variety of studies in the neuroimaging tegmental area (VTA) are important contributors to all
literature, with the functions of this network to be discussed CSTC loops, and that rostral substantia nigra cell populations
subsequently. have been identified as key contributors to the CSTC loops
The meta-analytic maps in Figure 2 are also notable because serving SN cortical regions even in classical descriptions
they reveal distinct subcortical nodes co-activating with the (Alexander et al., 1986).
cortical nodes of the SN during the performance of active tasks, as
opposed to during the resting state, from which the maps of Yeo Functional Roles of Specific SN-CSTC
et al. (2011) were derived. These subcortical nodes are present Nodes
in the head of the caudate nucleus bilaterally, as well as in the Understanding the importance of SN function in cognitive
thalamic MDN. These striatal and thalamic nodes, taken together control requires a thorough review of the broader functional roles
with the cortical nodes of the SN, comprise the complete and of the SN’s individual cortical and subcortical components. As
functionally integrated CSTC loop circuit particular to the SN, noted earlier, key pre-Rolandic cortical nodes of the SN include
for the purposes of the remainder of our review article. the bilateral AI, dACC and dlPFC (Seeley et al., 2007). Separately,
each of these areas have been linked to self-awareness, body
The SN CSTC Loop Circuit in its Classical perception (Craig, 2009) and fundamental cognition (Delevich
Neuroanatomical Context et al., 2015). The AI plays an integral role in the response
The classical description of cortico-striatal-thalamo-cortical loop and experience of emotional states (Craig, 2003), and level
circuits of Alexander et al. (1986) included five parallel, of activity has been shown to correlate with stimulus valence
functionally segregated circuits: (i) a motor CSTC loop through (Anders et al., 2004). In addition to emotional perception, the

AI is proposed to estimate changing environmental demands to integration and cognition remains incompletely characterized
modulate flexible cognitive control (Jiang et al., 2015). The AI (Mitchell, 2015).
also responds during action selection during decision-making The role of the SN as a coordinator of other networks
(Paulus and Stein, 2006), and is therefore an integral component for cognitive control is supported by coactivation of its
of cognitive control and the SN. Furthermore, the dACC has cortical and subcortical nodes during tasks. For example,
separately been implicated in cognitive regulation (Delevich functional links between the insula, which predicts changing
et al., 2015), divergent thinking, error detection and response cognitive control demand, and ‘‘classic’’ cognitive control
selection (Abraham et al., 2012; Sun et al., 2016). The dlPFC circuits rooted in the dACC and dlPFC, allow for reactive
has extensive projections to striatal nuclei and is involved in attentional control (Jiang et al., 2015). Extensive connections
top-down modulation of goal-directed behavior (Furman et al., from these regions to the dorsal striatum may link reactional
2011). The dlPFC is also a key hub of cognitive control, as it is cognitive control to behavioral guidance, allowing for on-line
implicated in executive function (Kuo and Nitsche, 2012) and behavior regulation in response to salient environmental
has been identified as a dominant cortical area within the brain’s stimuli (Botvinick et al., 2004; Haber, 2016). Specifically,
central cognitive control network (Menon, 2011; McTeague et al., the dACC projects primarily to the dorsal caudate nucleus
2016). and ventral striatum, overlapping partially but not completely
Co-activation among cortical regions of the SN is also with frontostriatal projections from the dlPFC (Haber, 2016).
associated with cognitive and behavioral phenomena related to Strengthened resting state functional connectivity between
decision-making and cognitive control. For one, the AI, dACC the AI and dACC has been associated with enhanced
and dlPFC activate synchronously in response to uncertainty in cue reactivity in other brain areas including the putamen,
the environment; these regions overlap with areas implicated suggesting that functional connections throughout the loop
in negative mood states (Feinstein et al., 2006; Naqvi and allow incoming information to exert downstream effects on
Bechara, 2009; Davis and Hasson, 2016). The dACC and AI modulatory striatal areas (Janes et al., 2015). Although a general
activate together during decision-making; co-activation has been topographic organization exists between the frontal cortex
shown to increase with task difficulty and stimulus ambiguity. and subcortical targets, there exists a complex convergence
This finding suggests that the ‘‘difficulty dependent functional across CSTC loops that originate in prefrontal areas, including
architecture’’ between the dACC and AI plays a role in cognition the ventromedial PFC (vmPFC) and orbitofrontal cortex; this
by filtering and integrating internal and external stimuli during overlap suggests that CSTC circuit integration is structural as
cognitive tasks (Lamichhane et al., 2016). In addition to coactivity well as functional, and provides modulation between and across
with separate functional networks, the dACC also possesses reward, prediction and saliency circuits (Averbeck et al., 2014;
extensive cortico-cortical connections within the PFC, including Haber, 2016).
the cognitive dlPFC hub and premotor regions, placing it At the level of the brainstem, dopaminergic regions also
at the crossroads of learning and behavior systems (Haber, play a significant modulatory role in the SN CSTC loop.
2016). Dopamine is integral to SN function: as noted earlier, the
Like other networks containing regions of association cortex, VTA and rostral substantia nigra project to the basal ganglia
the SN links to subcortical nodes in areas of the striatum regions that subserve the classically described CSTC loops
and limbic system, including (as noted above) the MDN, the serving the anterior cingulate and dlFPC; these dopaminergic
dorsal striatum and dopaminergic nuclei within the midbrain projections consequently play important roles in SN activity
and brainstem. The striatum, along with the entire basal and modulation. Dopamine projections throughout the SN have
ganglia, is important in coordinating and sequencing the diverse been noted to play important roles not only in reward-oriented
functions of the frontal lobes, from goal formation to executive learning and goal-directed behavior, but also in processing
function to cognition and the selection of specific actions and motivational stimuli by directing attention to positive, adaptive
movements (Schultz et al., 2003). Whereas the ventral striatum or rewarding environmental stimuli (i.e., mediating the salience
is involved in reward and motivation, the central and dorsal of environmental stimuli; Berridge, 1996; Koob and Volkow,
striatum—including the caudate nucleus and the putamen—play 2010; Kroemer et al., 2014). Dopaminergic neurons in the
more integral roles in cognition and executive function (Haber, midbrain are critical to CSTC loops that encompass integrated
2016). learning, executive function and motor control. Importantly,
Within the thalamus, the MDN is a relay nucleus the mesolimbic and nigrostriatal dopaminergic pathway have
with reciprocal connections to regions of the medial PFC been implicated in the encoding of ‘‘saliency prediction errors’’,
(mPFC) that assists in flexible action selection by integrating underscoring their broader contributions to the attribution of
information from cortical, limbic and basal ganglia regions salience to environmental stimuli (Kapur, 2003; Haber, 2016).
(Delevich et al., 2015). Loss of functional communication
between the MDN and mPFC due to physical or chemical
lesions has been shown to interrupt behavioral flexibility An SN Architecture for Salience, Cognitive
(Parnaudeau et al., 2013), learning and decision-making in Control and Response Selection
both humans and animals (Mitchell, 2015). The MDN is In summary, the SN CSTC loop appears to function as a
integral to rapid associative learning and other executive tasks distinct, well-integrated regulatory circuit that links cortical and
that involve complex cognition, though its precise role in subcortical regions involved in cognition, attentional control,

motivation, motor control and salience. The SN CSTC loop have revealed both anatomical and functional differences
has been described as a cortical input ‘‘filter’’ that selectively throughout SN nodes relative to healthy controls. Anatomically,
identifies and flags stimuli on which to base cognitive and investigations have revealed reduced gray matter volume
behavioral responses (Furman et al., 2011; Choi et al., 2012). in the anterior cingulate cortex, caudate nucleus, putamen
The dlPFC primarily projects to the dorsolateral caudate to (Bora et al., 2012; Shepherd, 2013). Thalamic volume
serve cognitive control and executive functioning (Furman et al., abnormalities are mixed (Webb et al., 2014; Zhao et al.,
2011), while the thalamic MDN supports cortico-striatal-cortical 2014; Hagan et al., 2015). Neurochemical ligands via PET
information transfer and modulates cortical activity through have shown reduced midbrain and subcortical serotonergic
extensive connections with the PFC and midbrain dopaminergic receptor binding in MDD (Hahn et al., 2014; Yeh et al.,
regions (Mitchell, 2015). Dopaminergic nuclei in the midbrain 2015).
and brainstem, which are often associated with limbic circuitry, While anatomical and neurochemical differences have been
project widely throughout multiple loops of the striatum to identified in SN nodes, symptoms of MDD have often been
serve a variety of functions, both structurally and functionally. attributed to dysfunctional ventral CSTC loops rather than
For example, the substantia nigra makes extensive connections volumetric deviations alone (Bora et al., 2012; Kerestes et al.,
with the striatum, cortex, thalamus and neighboring brainstem 2015). MDD patients generally exhibit reduced sensitivity
regions, allowing dopaminergic outputs to exert far-reaching to reward; this cognitive blunting is reflected by reduced
effects on the flow of CSTC information (Haber, 2016). At ventral CSTC loop activation in the orbitofrontal cortex,
the same time, however, distinct populations of neurons in anterior cingulate and ventral striatum to reward and loss
the rostral substantia nigra may project more specifically to receipt/anticipation (Smoski et al., 2011; Chantiluke et al., 2012;
the CSTC loops serving the cortical regions of the SN, as Schiller et al., 2013; Admon et al., 2015; Manelis et al., 2016).
recognized in classical descriptions of CSTC loop architecture Although MDD has classically been described in terms of
(Alexander et al., 1986). Working together, the subcortical dysfunctional ventral corticostriatal loops that play a role in
components of the SN communicate extensively with their affect and reward, recent reports have identified abnormalities
cortical counterparts to select salient (motivationally relevant) within dorsal, cognitive corticostriatal loops in MDD patients
stimuli, and to enable such stimuli to direct cognition and (Kerestes et al., 2015). Specifically, individuals with depression
behavior. It is this architecture that enables the SN to play are reported to show increased functional connectivity between
its central roles in salience detection, cognitive control and the dorsal caudate nucleus and right dlPFC, with disease
the selection and/or inhibition of behavioral responses during severity correlated to increased connectivity; hyperactivation
healthy brain function. between these regions may indicate a pathological compensation
of cognitive processing over negative emotions and stimuli
ABNORMALITIES OF SN-CSTC LOOP (Furman et al., 2011; Kerestes et al., 2015).
CIRCUITS IN PSYCHIATRIC ILLNESSES In addition to SN structural and functional aberrations in
MDD, symptomatic improvement to conventional treatment is
Aberrations of corticostriatal loop circuits that modulate predicted by differential SN function. Connectivity between the
cognitive control and goal-directed behavior may underlie the putamen, caudate and cingulate during a monetary incentive
pathophysiology of several psychiatric illnesses. Although delay task has been shown to predict response to psychotherapy
specific psychiatric disorders, such as depression and (Admon et al., 2015; Walsh et al., 2016). High baseline ACC
schizophrenia are characterized by distinct constellations of and low striatal activity were also shown to be predictive of
symptoms, structural and functional abnormalities appear improvement on antidepressants in a recent meta-analysis of
throughout similar nodes and networks transdiagnostically, 15 studies (Fu et al., 2013).
across many Axis I disorders (Goodkind et al., 2015). It SN function change is also attributed to symptomatic
is possible that a spectrum of SN aberrations, ranging improvement to conventional interventions. A recent
from hypo- to hyperactivity through the CSTC loop, can meta-analysis based on nine MDD fMRI studies established
trigger a broad range of disabling behavioral and cognitive that antidepressant treatment resulted in increased activation
symptoms that are reflective of disrupted cognitive-attentional in the dlPFC, AI and ACC, and decreased activation in the
processing. The following section briefly explores the potential thalamus and caudate nucleus, during emotional processing,
involvement of such corticostriatal circuits in the etiology, representing normalization of resting state activity (Delaveau
manifestation and treatment of major psychiatric disorders, et al., 2011). Similar analyses consistently identify functional
including MDD, SUD, anxiety disorders including OCD and increases in these areas relative to baseline following SSRI
post-traumatic stress disorder (PTSD), schizophrenia and eating treatment based on functional activity during negative mood
disorders (ED). induction (Fitzgerald et al., 2008) and incentive cue processing
(Stoy et al., 2011).
Major Depressive Disorder (MDD) MDD patients vary widely in terms of symptom presentation;
MDD is characterized by persistent low mood, accompanied by recent work has sought to characterize MDD by distinct
loss of interest and pleasure, increased fatigue and irritability symptomatic and neural subtypes, or ‘‘endophenotypes’’. In
and difficulty concentrating and making decisions (Benazzi, one notable study, MDD was partitioned into three subtypes,
2006). Neuroimaging analyses of individuals with MDD one of which was characterized by regulatory deficits in

cognitive control and altered electrical current densities in nodes 2010). Similarly, reduced response to reward is observed across
of the SN, specifically the dlPFC and dACC (Webb et al., the striatum, mPFC and dlPFC (Forbes et al., 2014).
2016). The conflation of several hypothetically heterogenous Additionally, it appears that addictive substances activate
MDD pathophysiological profiles in functional studies to date dopamine-dependent saliency systems in the brain, resulting in
may obscure important characteristics that differentiate one or the replacement of adaptive stimuli by more salient drug-related
more of these subtypes. Future work should further characterize cues (Koob and Volkow, 2010). For example, higher dorsal
the symptomatic and neural heterogeneity of MDD into reliable caudate reactivity during cue induced craving has been found in
endophenotypes. heavy drinkers, while ventral striatal activity was found in lighter
drinkers, and this the functional difference between drinkers
was correlated with compulsive craving severity (Vollstädt-
Substance-Use Disorders (SUDs) Klein et al., 2010). In another study, higher caudate and ACC
SUDs involve abnormal reward and motivational responses
activity during cue-induced craving predicted a transition
to salient drug-related cues in the environment. Impulsivity
to heavier drinking habits (Dager et al., 2014). Increases in
and compulsivity are well-characterized traits of SUD,
compulsive drug-seeking behavior has been hypothesized to
and both traits play important roles in the addiction cycle
represent a shift from ‘‘top-down’’, prefrontal cortical behavior
(Koob and Volkow, 2010). Traditional neurobiological
control to striatal behavioral control due to progressively
research in SUD has attempted to identify how subcortical
altered dopamine transmission (Goldstein et al., 2009;
and dopaminergic systems affect drug seeking behavior
Koob and Volkow, 2010).
(Menon, 2011). For example, combined PET-fMRI data
In summary, drug addiction has been described as a process
suggests that frontostriatal abnormalities may be associated
of maladaptive neuroplasticity that begins in mesolimbic
with a reduction of striatal D2 dopamine receptors and
reward circuits and emanates through interconnected
prefrontal, dlPFC metabolic activity (Tomasi and Volkow,
loops in the dorsal striatum, eventually cascading to the
2013).
cortex where dysregulation results in permanent changes to
Structurally, nodes of the SN display volumetric abnormalities
habitual behavior and impulsivity (Koob and Volkow, 2010).
in SUD. For example, cocaine users display altered cingulate,
SN frontostriatal circuit integrity may be associated with
insula and caudate volume (Ersche et al., 2011; Moreno-López
improved impulse control (Peper et al., 2013); conversely,
et al., 2012). Also, methamphetamine craving was associated
improved top-down cognitive control over the striatum
with volumetric differences in the insula, PFC and thalamus; this
by prefrontal cortical regions may reduce impulsivity
association was further correlated with dopaminergic receptor
(Peters and Büchel, 2011).
availability in the midbrain (Morales et al., 2015). Functional
abnormalities of single SN nodes have been related to SUD
behaviors; the AI is considered critical to conscious drug-seeking Obsessive-Compulsive Disorder (OCD)
motivation (Naqvi and Bechara, 2009). OCD is classically characterized by intrusive thoughts
SN network connectivity is implicated in SUD. For example, (obsessions) that are distressing and disruptive to normal
lower resting-state functional connectivity between the striatum, function, followed by repetitive actions (compulsions) aimed
cingulate and insula have been found in cocaine users; dorsal at reducing the associated distress (American Psychiatric
ACC and dlPFC connectivity was linked to loss of control Association, 1994). In more than half of individuals with
and impulsivity, respectively (Hu et al., 2015). Furthermore, OCD, these symptoms may be severe enough to cause
reduced activation in the dorsal caudate and dlPFC has been absence from work, school or social engagements; further,
found to be correlated with impulsivity and Stroop task treatment of these severe cases is often more difficult (Bourne
errors in SUD (Qiu et al., 2013; Feng et al., 2016; Yuan et al., 2012). Importantly, obsessions and compulsions
et al., 2016). Conversely, gambling addiction has displayed represent dysfunctional cognitive and motor processes
increased PFC connectivity to the striatum; this connectivity that become repetitive and disturbing; it is suggested
was associated with impulsivity, smoking frequency and that hyperactivation within CSTC circuits and changes to
craving severity (Koehler et al., 2013). Stronger functional CSTC topography may underlie such ritualistic thoughts
coherence within SN cortical nodes was recently linked to and behaviors (Graybiel and Rauch, 2000; Nakamae et al.,
enhanced reactivity to smoking cues in individuals with nicotine 2014).
dependance, suggesting that hyperconnectivity within the SN OCD has traditionally been attributed to dysfunction within
may be responsible for increased cue reactivity (Janes et al., orbitofronto-CSTC loops; despite being somewhat distinct
2015). from CSTC loops that traditionally mediate the cognitive
On task-based fMRI, another study used a reward-guided domain, this dysfunction is hypothesized to contribute to
decision-making task to investigate reward prediction the unusual cognitive control of behavioral patterns often
errors—signals that guide learning behaviors—in men with observed in OCD (Graybiel and Rauch, 2000; Dunlop et al.,
alcohol addiction. SUD patients also demonstrated abnormal 2016). CSTC loop circuits are also relevant to OCD due
dlPFC-striatal functional connectivity following ‘‘wins’’, and to their integral role in emotional, cognitive and behavioral
‘‘losses’’, suggesting that learning mechanisms are impaired due self-regulation (Marsh et al., 2009a). Results of a 7-study
to disrupted regulation of frontostriatal interactions (Park et al., meta-analysis examining OCD resting-state fMRI suggested

OCD tends to most reliably demonstrate corticostriatal network heightened activity variability in the insula and ACC, and
abnormalities relative to other anxiety disorders (Peterson lower variability in activity in the dlPFC and striatum (Ke
et al., 2014). While many symptoms of OCD are related et al., 2015). Another study also found increased connectivity
to disruptions within orbitofronto-CSTC loops, regions of between the insula, mPFC, striatum and dorsal ACC during
the SN likely play a large role in specific symptoms; OCD symptom provocation (Cisler et al., 2014). Second, generalization
symptoms. of fear associations in PTSD is associated with heightened
Within nodes of the SN, volumetric changes have been insula and thalamus activity (Morey et al., 2015). Third,
identified in the ACC, striatum and thalamus (Gilbert et al., PTSD severity during an emotional Stroop task was associated
2008; Hoexter et al., 2012; Hou et al., 2013; Atmaca et al., 2016). with higher dlPFC, dmPFC and dorsal ACC activation to
Functionally, the ACC appears to be abnormally altered during emotional stimulation (White et al., 2014). Finally, higher dorsal
disease-relevant tasks. For example, OCD patients experience caudate and frontal activation during inhibitory control predicts
ACC hyperactivity during symptom aggravation and while response to CBT in PTSD, suggesting a role of SN function in
committing errors during a flanker interference task (Bourne symptom improvement following psychotherapy (Falconer et al.,
et al., 2012). Even outside of active task engagement, nodes 2013).
of the SN are abnormally hyperactive: increased resting state Resting state functional connectivity also has revealed
functional activity of the ACC, MDN (Rauch et al., 2006a; Bourne abnormal SN functional connectivity in PTSD. One recent
et al., 2012), dlPFC (Figee et al., 2014) and caudate nucleus meta-analysis showed that PTSD patients display enhanced
(Graybiel and Rauch, 2000) has been noted in individuals with connectivity within the SN, suggesting excessive salience
OCD. Frontostriatal functional connectivity stemming from the processing within the SN serves as a mechanism of abnormal
dlPFC (Vaghi et al., 2016), and altered striatal connectivity hyper-monitoring the external environment (Koch et al.,
to the insula (Bernstein et al., 2016) has been linked to 2016). Similarly, individuals with PTSD demonstrate
OCD severity. hyperactivity relative to controls within the AI and dACC
Interestingly, functional changes within SN nodes are across a variety of executive functioning and emotional
related to OCD symptom improvement. Notably, stereotaxically processing tasks, in conjunction with reduced functional
targeted lesions of the dACC during cingulotomy procedures connectivity between regions involved in fear, stress and
results in symptom improvement in some individuals with negative affect. It is possible that enhanced vigilance combined
treatment-resistant OCD (Dougherty et al., 2002); such with decreased top-down cognitive control over fear responses
lesions also reduce glucose metabolism in the caudate, medial underlies PTSD symptoms (Rauch et al., 2006b; Patel et al.,
dorsal thalamus and caudate (Zuo et al., 2013). Traditional 2012).
pharmacotherapies are shown to attenuate ACC and striatal With regards to abnormalities throughout CSTC loops,
hyperactivity (Rauch et al., 2006a), and normalize thalamic, individuals with PTSD have been shown to have reduced
cingulate and putamen gray matter volume (Hoexter et al., thalamic functional connectivity with a variety of brain regions
2012; Atmaca et al., 2016). On resting-state fMRI, reduced including the rostral ACC and mPFC (Duarte et al., 2011;
dorsal caudate-anterior thalamus functional connectivity was Yin et al., 2011), and it has been suggested that flashback
associated with symptomatic improvement following fluoxetine symptoms occur in part due to dysfunctional corticothalamic
(Anticevic et al., 2014). Such findings highlight the importance activity (Liberzon et al., 1996/1997). Recently, the medial
of SN-CSTC dysfunction in the pathophysiology of OCD. rostral dorsal caudate was identified as a site of convergence
between the IPL, dlPFC and dACC, suggesting that striatal
Post-Traumatic Stress Disorder (PTSD) inputs that mediate and bias attentional salience and cognitive
PTSD occurs in approximately 10% of individuals who have control (Choi et al., 2016). A region allowing for interaction
experienced a traumatic event; symptoms include intrusive of such cortical areas may be strongly implicated in the
re-experiencing of the traumatic event, and avoidance behaviors allocation of stimuli salience and environmental attention,
in order to escape similar or triggering situations (Koch et al., and authors suggest that future investigations probe this
2016). Changes in arousal, behavior and mood, as well as area to learn more about its involvement and potential
impairments in executive functioning, are also commonly seen in therapeutic value in disorders including PTSD (Choi et al.,
individuals with PTSD (American Psychiatric Association, 2013). 2016).
Structurally, PTSD patients exhibit reduced gray matter volume
in SN regions including the ACC, striatum and insula (Meng Schizophrenia
et al., 2016); caudate and insular volumetric reductions correlate Schizophrenia is a disabling psychiatric condition that
with PTSD severity (Herringa et al., 2012). Cortical thinning has manifests in primarily three domains: positive, negative
also been observed in the rostral ACC and insula, and disrupted and cognitive symptoms. Positive symptoms include additions
structurally connectivity is seen between the ACC, thalamus and to an individual’s repertoire of thoughts or behavior, such as
insula in PTSD (Mueller et al., 2015). hallucinations or delusions, whereas negative symptoms refer to
There is evidence that symptoms associated with PTSD flattened affect, anhedonia or catatonic symptoms (American
involve potential changes to both singular SN nodes and Psychiatric Association, 2013). Individuals with this disorder
corticostriatal circuits. First, during symptom provocation, may experience impairments in executive function and have
PTSD symptom severity correlates with ACC activity, and been found to have deficits in cognitive, but not motor, learning

(Foerde et al., 2008; Parnaudeau et al., 2013). In addition to gray matter volumes in a variety of frontal brain areas
cognitive deficits, schizophrenia is defined by psychosis and characterize AN and BN, respectively, and may normalize with
psychotic episodes (American Psychiatric Association, 2013). successful treatment (Van den Eynde et al., 2012). AN and BN
Structural abnormalities within the SN have been observed in patients show reduced gray matter volume specifically in SN
schizophrenia, specifically between the insula, ACC, dlPFC and regions including the caudate nucleus, anterior cingulate cortex
striatum (White et al., 2010; Menon, 2011; Quan et al., 2013; and insula, among other areas (Schäfer et al., 2010; Friederich
Iwabuchi et al., 2015; Chen et al., 2016). Cortical thinning is et al., 2012; Frank et al., 2013; Coutinho et al., 2015). On
also observed in the AI, IFG and ACC; this volumetric change DTI, AN patients show abnormal thalamic connectivity to the
is reflected by altered functional connectivity (Pu et al., 2012; dlPFC and anterior PFC (Frieling et al., 2012; Hayes et al.,
Pujol et al., 2013). Further, schizophrenia has been associated 2015), and reduced fractional anisotrophy in the medial dorsal
with abnormal dopamine signaling within the cortex (Knable and thalamic radiations (Biezonski et al., 2015; Hayes et al., 2015).
Weinberger, 1997). Further, increased structural connectivity between the insula and
Psychosis and salience attribution deficits in schizophrenia striatum is observed in ED (Frank et al., 2016; Shott et al.,
are related to inter-network dysfunction between the SN, 2016).
CEN and DMN (Palaniyappan et al., 2011, 2013; Moran On task-based fMRI, BN patients display low frontostriatal
et al., 2013; Lee et al., 2014; for a comprehensive review, activity on a number of cognitive control tasks, including the
see Nekovarova et al., 2014). Patients experiencing auditory Simon Spatial task (Marsh et al., 2009b, 2011) and Go/No-Go
hallucinations show increases in AI and frontal operculum (Skunde et al., 2016). Similarly, AN patients have also been
activation and altered SN dynamics, indicating that internally shown to have altered frontostriatal activation on executive
generated stimuli are perceived as abnormally salient (Sommer function tasks, including the Wisconsin Card Sorting Task (Lao-
et al., 2008; Lefebvre et al., 2016). Indeed, AI resting-state Kaim et al., 2015), and delay discounting (Wierenga et al., 2014;
functional connectivity is correlated to symptom severity Decker et al., 2015). During reward conditioning, AN patients
(Manoliu et al., 2013). show abnormally high SN activity relative to controls (Frank
Frontostriatal dysconnectivity between the dlPFC, dACC, AI et al., 2012), and an increased preference for delayed rewards
and putamen are observed during an emotion judgment task, over immediate rewards. Dorsal caudate dysfunction is also
indicating that SN inappropriate assigns valence to emotionally associated with AN patients in a number of tasks, including
salient stimuli (Lee et al., 2014). Additionally, certain genes that a monetary choice task (Bischoff-Grethe et al., 2013; Bailer
impart increased risk of developing schizophrenia have been et al., 2016), and food-cue processing (Sanders et al., 2015).
associated with decreased striatal volume and hyperconnectivity This increase in striatal reactivity may be related to a number
within frontostriatal loops (Shepherd, 2013). of trait-based or neurochemical factors, including abnormal
Of note, insular-SN connectivity can discriminate patients trait anxiety (Bailer et al., 2016), harm avoidance (Bailer et al.,
from healthy controls (Mikolas et al., 2016; Wang X. et al., 2013), obsessive thoughts (Rothemund et al., 2011) and striatal
2016). One recent publication associated the severity and dopaminergic receptor availability (Bailer et al., 2013, 2016; Broft
development of psychosis with the extent of hypoconnectivity et al., 2015).
throughout SN CSTC circuitry, specifically between the left Both AN and BN patients have altered SN function during
AI, the bilateral putamen, and caudate nucleus (Wang C. disease-relevant stimuli. In one study, presenting food-related
et al., 2016). Further, Wang C. et al. (2016) demonstrated that visual cues to individuals with either BN or BED resulted
individuals with schizophrenia displayed reduced structural and in increased ACC and insula activation, and BN patients
functional integrity within CSTC tracts of the SN. Reductions in reported higher levels of arousal (Schienle et al., 2009). In
network integrity may also explain interrupted information another study, BN participants displayed low activity in the
processing observed in individuals with schizophrenia, insula to food images, while AN showed higher activity in
which is experienced as abnormal sensory processing the caudate and insula (Brooks et al., 2011). Another study
(White et al., 2010). showed that AN participants show abnormally high activation
to aversive taste in the insula and putamen (Cowdrey et al.,
Eating Disorders (EDs) 2011). Abnormal ACC-insular resting state activity has also
EDs affect about 0.5% of women and can cause significant been observed in ED patients (Amianto et al., 2013; Dunlop
physical and psychological burden; for example, anorexia et al., 2015b). Altered connectivity strength and path length
nervosa (AN) has the highest mortality of any psychiatric between the insula and thalamus has been observed in AN
disorder (Hudson et al., 2007). EDs are characterized by (Geisler et al., 2016), as well as decreased functional connectivity
altered self-image and maladaptive eating behaviors, and include between the thalamus, putamen and insula (Ehrlich et al.,
AN, bulimia nervosa (BN) and binge-eating disorder (BED; 2015). Given all this evidence, the variation in symptoms
McClelland et al., 2013). In recent years, functional imaging across different classes of EDs—for example, the presence
studies of EDs have pinpointed the intersection of cognitive and of binging behavior in BN and BED, but not AN—make it
reward systems as integral to eating behavior regulation (Val- difficult to assess convergent implicated brain regions, and
Laillet et al., 2015). both structural gray matter and functional activity analyses
One systematic review of 10 structural MRI studies suggested in these populations should be expanded (Schäfer et al.,
that compared to healthy controls, both decreased and increased 2010).

There is evidence that corticostriatal loop circuits are clinical features of psychiatric illnesses are rooted in altered
affected in EDs. Specifically, individuals with EDs often display activity within relevant brain networks. Given that brain
impaired self-regulatory control—this includes inhibition of stimulation treatments are usually targeted to a specific brain
both motor and emotional responses—that can be traced to region, the goal of such a treatment is to normalize regional
dysfunction within dorsal frontostriatal circuits crucial for cortical and downstream network activity.
self-regulation (Berner and Marsh, 2014). Authors who recently The SN has been proposed as a key target for
reviewed the balance between incentive reward and inhibitory neuromodulation treatments across a variety of psychiatric
circuits in EDs (Wierenga et al., 2014) hypothesized that illnesses (Downar et al., 2016; Dunlop et al., 2016). Stimulation-
different patterns of disordered eating represent a spectrum of driven changes in the SN-CSTC loop could restore capacity for
regulatory capability, ranging from extreme cognitive control cognitive control via changes in network activity, resulting in
in AN to deficiencies of cognitive control in BN. The dorsal symptom reduction (Veit et al., 2012; Sale et al., 2015). With
neural system supporting such regulatory capacity—which respect to SN nodes and their downstream regulatory loops, both
includes functions of inhibition, emotion regulation, and invasive and non-invasive brain stimulation techniques appear
goal-directed behavior—includes the dorsal caudate, dACC capable of modulating the activity of these circuits by imposing
and insula, among other SN regions (Wierenga et al., long-term changes in cortical nodes that cascade through the
2014). SN loop. These changes are accompanied by alterations in affect
and behavior in the patient receiving treatment (Di Filippo et al.,
Summary 2009).
Both structural and functional abnormalities within and In this section, we review the effects of DBS, rTMS and
between corticostriatal loop circuits are associated with tDCS on cortico-striatal-thalamo-cortical circuitry through the
psychiatric pathology. Generally, these disorders can be SN specifically, such as they are known at the present time.
characterized by an inability to exert cognitive control over We also review the available evidence to date about how
maladaptive thoughts, impulsive behaviors or attention changes in SN-CSTC function relate to the therapeutic effects of
to appropriate salient internal and external stimuli; for neuromodulation therapies in psychiatric illness.
example, OCD involves disrupted control mechanisms, but
lacks the element of disturbed motivational salience that Deep Brain Stimulation (DBS)
is well defined in MDD and SUD. Regardless of clinical DBS involves neurosurgical implantation of stimulation
phenotype, consistent implication of the dACC, AI and electrodes in target regions of the brain under stereotaxic
dorsal striatal nodes in psychiatric etiology suggests that guidance. The implanted electrodes modulate abnormal neural
the SN-CSTC loop is indeed crucial for psychological activity by applying electric fields that stimulate adjacent axons,
health and adaptive functioning across a variety of resulting in the modification of electrical communication within
disorders. connected functional brain networks (Kühn and Volkmann,
2016; Lin et al., 2016; Rachid, 2016). Although this technique
TARGETING THE SN-CSTC WITH is invasive, expensive and requires subspecialist expertise,
THERAPEUTIC BRAIN STIMULATION DBS does carry the advantage of being able to directly target
the deeper nodes of CSTC circuits, such as the striatum,
For individuals with psychiatric disorders, the mainstays pallidum, subthalamic nucleus or brainstem dopaminergic
of conventional treatment are psychotherapy and structures, as well as the white matter tracts connecting
pharmacotherapy. However, these approaches are ineffective these nodes.
for a substantial proportion of patients. For example, an Some of the earliest uses of DBS were in modulating the
estimated one third of MDD patients do not respond to activity of motor CSTC loops to treat movement disorders,
2–4 sequential trials of pharmacotherapy or psychotherapy including essential tremor and Parkinson’s disease (PD; Chen
(Rush et al., 2006). Therapeutic brain stimulation is an et al., 2013); the latter remains the most common therapeutic
emerging alternative in cases where conventional approaches application of DBS (Fasano and Lozano, 2015). However, more
fail (Figure 3). A number of techniques for therapeutic brain recently, DBS has begun to show promise as a treatment for
stimulation are entering clinical use for treatment-resistant a number of neuropsychiatric disorders (Williams and Okun,
psychiatric illnesses. These include deep brain stimulation 2013), including MDD (Mayberg et al., 2005; Schlaepfer et al.,
(DBS; Lozano and Lipsman, 2013), repetitive transcranial 2014), OCD (Lipsman et al., 2013a) and AN (Lipsman et al.,
magnetic stimulation (rTMS; Lefaucheur et al., 2014) and 2013b).
transcranial direct current stimulation (tDCS; Tortella et al., For DBS in psychiatric disorders, the stimulation targets are
2015). generally found in CSTC circuits outside of motor loop. In
For the neuroscientist, these techniques can serve a dual MDD, for example, targeting the subgenual cingulate cortex
role as both an intervention and a probe for investigating (sgCC) may have modulatory downstream effects on the
human brain function, either in health or in psychiatric illness. dACC by propagating stimulation effects through the rostral
It is possible to assess the neurophysiological effects of brain cingulate cortex (Morishita et al., 2014). Further, sgCC-DBS has
stimulation using neuroimaging techniques, complemented normalized hypoactivity of the dlPFC and ACC, among other
by electrophysiological recordings. As described above, many areas, in depressed patients without any observed cognitive side

FIGURE 3 | SN cortico-striatal-thalamo-cortical circuit engagement during therapeutic brain stimulation. (A) In healthy controls, 10 Hz repetitive
transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (dlPFC) results in increased dopamine transmission in the ipsilateral caudate nucleus
and thalamus. (B) In depressed individuals, clinical improvement following 10 Hz dmPFC-rTMS was correlated with increased connectivity between the dACC and
the thalamus. (C,D) In obsessive-compulsive disorder (OCD) patients, clinical improvement following 10 Hz dmPFC-rTMS was correlated with decreased functional
connectivity between the dACC and the caudate nucleus, thalamus, putamen and midbrain. Adapted from (A) Strafella et al. (2001); (B) Salomons et al. (2014);
(C,D) Dunlop et al. (2016).
effects (Mayberg et al., 2005). More generally, sgCC-DBS appears This finding illustrates the potential of DBS to modulate
to be an effective intervention for severe, treatment-resistant (i.e., suppress) activity in CSTC circuits for therapeutic
MDD. Follow-up studies and meta-analyses suggest that overall, effect.
sgCC-DBS may continue to ameliorate depressive symptoms One illustrative case study suggests that DBS targeting
over time, with persistence of beneficial effect for over a decade the SN-CSTC may not necessarily exert desirable effects in
in some cases (Giacobbe et al., 2009; Morishita et al., 2014). MDD (Stefurak et al., 2003). In this report, a patient with
It also appears that response rates to ongoing DBS stimulation intractable PD (and a remote history of a major depressive
may improve over time, with benefits accruing and persisting episode) underwent implantation of DBS electrodes bilaterally
over periods of several years among responders (Kennedy et al., in the subthalamic nucleus. Activation of one electrode yielded
2011). the expected improvement in the tremor of the contralateral
Thus far, DBS has not been used to target the SN-CSTC upper limb. However, activation of the other electrode had
loop directly in MDD. However, DBS targeting the nucleus the unexpected effect of inducing an intense dysphoria of
accumbens (NAcc) has been successful in some cases of rapid onset. The patient described feeling ‘‘similar in some
treatment-resistant depression, with responders showing respects to my depression but a thousand times worse. . .
improvements in hedonic capacity (Bewernick et al., 2010). Someone could have come in to shoot me and I could
PET imaging in these cases demonstrated that stimulation not have cared less’’. The effect was reliably reproducible,
of the NAcc yielded reductions in metabolic activity in the and mood returned rapidly to baseline with cessation of
‘‘reward CSTC loop’’ projecting to vmPFC and frontal pole. stimulation. When functional neuroimaging was performed,

stimulation of one electrode yielded reductions in supplementary 20 years, dozens of studies and several meta-analyses have
motor area activity, alongside improvement of the contralateral established high-frequency left, low-frequency right and bilateral
tremor. Stimulation of the other electrode yielded suppression dlPFC-rTMS as superior to sham stimulation in the treatment
of activity in the SN regions including the dACC as well of major depression (Berlim et al., 2013b,c; Berlim and Van
as the caudate nucleus, accompanied by rapid descent into Den Eynde, 2014; Gaynes et al., 2014). rTMS is now approved
dysphoria. This case illustrates the feasibility of using DBS to and used clinically as a treatment for medication-resistant
modulate the SN-CSTC loop circuit, and also illustrates that depression in a variety of jurisdictions around the world
such modulation can be accomplished via deep subcortical (Lefaucheur et al., 2014; Milev et al., 2016; Perera et al.,
targets such as the subthalamic nucleus. However, at the 2016).
same time, it illustrates that suppression of SN activity rTMS is also showing promise as a treatment for a variety of
may impair rather than improve mood regulation, with other psychiatric disorders characterized by hypofunctioning of
deleterious rather than beneficial effects in the setting of the SN. Supportive meta-analyses are now available for rTMS in
MDD. treating SUD (Gorelick et al., 2014; Dunlop et al., 2016), PTSD
The suppressive effects of subcortical DBS on CSTC loop (Berlim and Van Den Eynde, 2014), bipolar disorder (McGirr
functions may be of more benefit in the setting of OCD. DBS et al., 2016) and OCD (Berlim et al., 2013a; Trevizol et al.,
targets in OCD may include the ventral striatum, sgCC, NAcc or 2016).
the medial forebrain bundle (Lipsman et al., 2013a; Williams and The stimulation targets used in these studies typically
Okun, 2013). Although these targets lie outside the main nodes correspond to frontal nodes of the SN. For example, the
of the SN-CSTC loop, there is some evidence that the therapeutic dlPFC region showing greatest efficacy in MDD has been
effects of DBS in OCD ensue from modulation of activity in SN reported to be a region anticorrelated to the sgCC, which
sites. Specifically, a case series of NAcc-DBS in OCD reported also corresponds well to the SN’s dlPFC node (Fox et al.,
considerable inter-individual variability in the degree of clinical 2012). Stimulation of the dACC and adjacent dmPFC has
improvement; resting-state fMRI revealed that the degree of also been employed in MDD (Bakker et al., 2015; Kreuzer
symptom improvement correlated to the degree of reduction in et al., 2015), and stimulation of medial SN nodes in the
functional connectivity between the stimulation target (NAcc) dACC/dmPFC and adjacent pre-supplementary motor area have
and two nodes of the SN: the dACC and the dlPFC (Figee et al., also shown promising effects in OCD (Mantovani et al., 2010;
2014). Indeed, it has been suggested that all of the major DBS Dunlop et al., 2015a) and PTSD (Isserles et al., 2013). In
targets in OCD exert therapeutic effects by modulating activity healthy controls, there is evidence that rTMS of SN nodes
in the ACC and associated regions of the striatum (Bourne et al., such as the dlPFC or dmPFC/dACC can enhance or inhibit
2012). impulse control as measured on a delay-discounting task (Cho
Subcortical DBS for psychiatric disorders is thought to et al., 2010, 2015; Figner et al., 2010), and improve cognitive
influence the regulatory activity of CSTC loops. Investigations processing on executive functioning tasks (Esslinger et al.,
of DBS to central thalamic regions in neurological disorders 2014), suggesting a generalized effect on cognitive control.
have identified several effects of stimulation, including increased Taking together these lines of evidence, recent reviews have
D2 dopamine receptor concentration in the striatum, improved suggested that the therapeutic effects of rTMS may be best
functional connectivity between the thalamus and striatum, understood not as ‘‘antidepressant’’ per se, but more generally
and modulated plasticity in the striatum (Bourne et al., 2012). as enhancement of cognitive control via improved SN integrity
These effects are hypothesized to contribute to improvements in (Downar et al., 2016; Dunlop et al., 2016). This would account
striatal plasticity, resulting in increased regulatory capacity over for its transdiagnostic efficacy across a range of psychiatric
cognition and learning (Lin et al., 2016). disorders involving cognitive control deficiency (McTeague et al.,
2016).
The pertinent issue for the purposes of this review article
Repetitive Transcranial Magnetic is whether the therapeutic mechanisms of rTMS involve
Stimulation (rTMS) modulation of SN-CSTC loop circuits. Two questions thus arise:
rTMS is a non-invasive brain stimulation technique that alters first, does rTMS of cortical targets cause neurophysiological
neural excitability by delivering focused magnetic field pulses changes in the CSTC loop for that target; and second, do these
to cortical areas non-invasively through the skull (Hallett, changes (if present) correlate to the behavioral and clinical effects
2007). Repeated trains of pulses can produce durable increases of rTMS?
or decreases (depending on the stimulation pattern) in the Regarding the first question, the neurophysiological
strength of the synapses of the stimulated neurons, via mechanisms of rTMS are complex and still under investigation;
the mechanisms of long-term potentiation and depression accounts have been proposed at various levels of explanation
(Karabanov et al., 2015). The durable effects of rTMS were from genetic and cell-molecular processes, to neurotransmitters
initially noted via facilitation of motor evoked potentials and their receptors to synapses, to micro- and macro-level
with repeated stimulation of the primary motor cortex. network connectivity changes (for reviews, see Noda et al.,
Subsequently, it was found that rTMS delivered to the 2015). However, several convergent lines of evidence suggest
dlPFC improved mood in patients with depression (George that rTMS does indeed cause neurophysiological effects
et al., 1995; Pascual-Leone et al., 1996). Over the following not merely at the stimulation site, but also throughout its

CSTC loop circuit, targeting the entire loop in a precise, There is also growing evidence that the therapeutic effects
well-demarcated fashion. For example, PET studies using of rTMS in psychiatric illness may be mediated by changes
the D2 receptor tracer 11C-raclopride have shown that in SN-CSTC loop circuit integrity. One supportive study used
rTMS of the left primary motor cortex induces dopamine resting-state fMRI to examine CSTC functional connectivity in
release specifically in the ipsilateral putamen, in a region MDD patients who underwent a course of rTMS directed at
corresponding to the known projection zone for corticostriatal the dmPFC/dACC. In this study, patients with low baseline
projections from the primary motor cortex; no changes were functional connectivity from the dACC to the putamen (a
seen in other striatal regions such as the caudate nucleus, region corresponding to that identified in the PET study of
NAcc or the contralateral putamen (Strafella et al., 2003). dmPFC-rTMS by Cho et al., 2015) and MD thalamus showed
Another study by the same group, using the same tracer, a greater degree of clinical improvement, and the degree
demonstrated that rTMS of the left dlPFC induced dopamine of clinical improvement correlated to increases in functional
release specifically in the head of the ipsilateral caudate nucleus, connectivity from the stimulation target (dACC) and the MD
but not the NAcc, putamen or contralateral caudate nucleus thalamus (Salomons et al., 2014). The finding of dACC CSTC
(Strafella et al., 2001). A subsequent PET-rTMS study with a functional connectivity as both a predictor and correlate of
D2/D3 tracer demonstrated that rTMS of the dmPFC/dACC clinical improvement was replicated in a follow-up study in
induced dopamine release in a circumscribed region of the ED patients undergoing dmPFC-rTMS for binge and purge
dorsal putamen and underlying globus pallidus (Cho et al., behaviors (Dunlop et al., 2015a). In another follow-up study
2015). in patients with OCD (Dunlop et al., 2016), connectivity
fMRI-rTMS studies support the premise that rTMS pulses from the dACC to the head of the caudate nucleus and the
activate not only the target region of cortex but also its MD thalamus was also a predictor and a correlate of clinical
associated striatal partner. fMRI-rTMS studies in healthy improvement; however, reductions rather than increases in
controls have directly demonstrated that rTMS pulses to connectivity within this CSTC loop were required for clinical
the frontopolar cortex caused BOLD activations in both the improvement, paralleling the findings of Figee et al. (2014) in
frontal pole and in the ventral striatum; rTMS pulses to OCD patients undergoing DBS (as discussed in the previous
the dlPFC, in contrast, caused BOLD activations in both section). These findings suggest that the therapeutic effects of
the dlPFC and the dorsal caudate nucleus (Hanlon et al., rTMS in MDD, ED and OCD may be mediated by changes
2013, 2016). A session of inhibitory, continuous theta-burst in the integrity of the SN-CSTC circuit. Future studies will
stimulation to the frontopolar cortex reduced the BOLD be required to determine whether these findings also apply to
response to individual pulses at the same target, with the the more commonly employed protocol of dlPFC- rather than
effect seen prominently in ventral striatum (Hanlon et al., dmPFC-rTMS.
2015). Thus, the available neuroimaging evidence from fMRI
and PET studies suggests that rTMS directly activates not
only the stimulation site but also the associated subcortical Transcranial Direct Current Stimulation
loop circuit, in a circumscribed fashion; these activations are (tDCS)
accompanied by changes in dopamine neurotransmission in the tDCS is another non-invasive brain stimulation technique that
subcortical projection zones of the stimulation target. rTMS of uses scalp electrodes to deliver mild (1–2 mA) electrical currents
SN cortical targets (i.e., the dlPFC) appears to modulate activity to target brain regions, thereby modulating ongoing brain
in the subcortical components of the SN-CSTC loop circuit activity (Blumberger et al., 2015). The mechanisms of tDCS
as well. and related techniques such as transcranial alternating current
Regarding the second question of whether these changes in stimulation (tACS) are still under investigation and debate (for
SN-CSTC loop circuit function are related to the behavioral reviews, see Nitsche et al., 2008; Tortella et al., 2015). However,
and clinical effects of rTMS, several lines of evidence from a clinical perspective, the technique is attractive for offering
are now supportive. In a PET-rTMS study in healthy a favorable profile of safety, tolerability and low cost. For this
controls, an inhibitory form of rTMS (continuous theta- reason, tDCS is under active investigation not only as a research
burst stimulation) delivered to the left dlPFC impaired tool but also as a potential therapeutic intervention in psychiatric
performance on the Montreal Card Sorting Task, a illness (Tortella et al., 2015). The best-studied indication to
set-shifting task requiring the cognitive control functions date has been MDD, with several randomized controlled trials
of the SN. This impairment was associated with reduced published; recent meta-analyses of these trials have found tDCS
dopamine release in a circumscribed region of the head to be more effective than sham stimulation, with an effect size
of the caudate nucleus (Ko et al., 2008). Likewise, in the comparable to antidepressant medications (Meron et al., 2015;
previously mentioned PET study of dmPFC-rTMS (Cho Brunoni et al., 2016).
et al., 2015), rTMS-induced changes in dopamine release Lateral cortical nodes of the SN are widely used as tDCS
in the globus pallidus showed a U-shaped relationship targets, both in basic science and clinical studies. One of
to change in impulsivity, as indexed on the delayed the most common targets for tDCS in the literature to
discounting task. Thus, the effects of rTMS on SN-CSTC date has been the dlPFC, often operationalized as EEG sites
loop circuits appear to translate into effects on cognitive control F3 and F4 in the standard 10–20 montage. The F3 site
capacity. has been shown to correspond fairly closely to the dlPFC

node appearing in the SN (Mir-Moghtadaei et al., 2015), literature on the effects of tDCS on CSTC activity in general
suggesting that tDCS of F3 and F4 is anatomically positioned remains very limited (as reviewed in the preceding paragraph).
to stimulate the SN. Research studies and clinical trials of Alternative possibilities are that the therapeutic effects of
tDCS have targeted the dlPFC due to its hypothesized central tDCS ensue purely through modulation of cortico-cortical
role in executive function and cognitive control (Kuo and network connectivity, or conceivably through local modulation
Nitsche, 2012). tDCS targeting this region has been shown to of synaptic connections under the cortical stimulation site alone.
improve performance across the domains of working memory Future studies of therapeutic tDCS in psychiatric illness will
(Fregni et al., 2005), impulsivity (Fecteau et al., 2007) and social need to incorporate not only larger sample sizes, but also
cognition (Knoch et al., 2008). tACS has also been performed more detailed measures of cognitive control capacity, as well
with electrodes placed bilaterally over the dlPFC (EEG sites as neuroimaging observations before and after treatment, in
F3 and F4) and its parietal counterpart sites (EEG sites order to identify the behavioral and neural correlates of clinical
P3 and P4), with one study reporting frequency-dependent improvement. Such studies may help to determine whether tDCS
enhancements of lucid dreaming during REM sleep (Voss et al., of SN nodes enhances cognitive control, and if so, whether
2014). this enhancement ensues via modulation of the SN-CSTC loop
The dlPFC has also been a tDCS target in the clinical circuits.
treatment of substance use and ED. It is hypothesized
that stimulating the dlPFC enhances top-down control over UNRESOLVED QUESTIONS AND FUTURE
maladaptive eating behaviors and substance consumption, and
suppresses cravings generated by dysfunctional reward circuitry
DIRECTIONS FOR STUDY
(Fregni et al., 2005; Lapenta et al., 2014). Indeed, tDCS of the The emerging picture from the evidence reviewed in the previous
dlPFC has been shown to reduce cravings, consumption and three sections is that: (i) the SN-CSTC loop may play a critical
behavioral impulsivity in long-term smokers (Rachid, 2016), role in the voluntary engagement of cognitive control; (ii)
which may represent effects in attentional salience or inhibition abnormalities of cognitive control are a common, pervasive
networks (Fregni et al., 2005; Lapenta et al., 2014). and transdiagnostic feature of many psychiatric illnesses; (iii)
An important question for the purposes of this review these transdiagnostic deficits of cognitive control may arise
article is whether tDCS actually stimulates any of the deeper from abnormalities of functioning within a specific member
nodes of CSTC circuits, or whether its effects are confined of the brain’s many CSTC loops—namely, the CSTC loop
to superficial cortical regions. A purely cortical mechanism of serving the SN; and (iv) emerging brain stimulation therapies
localized changes in synaptic plasticity is often postulated in such as DBS, rTMS and tDCS exert neurophysiological effects
the literature, given that the relatively weak electrical fields on targeted CSTC loop circuits, and these effects may be
employed in tDCS may not penetrate beyond the cortex central to the mechanisms by which they alleviate psychiatric
(Nitsche et al., 2008). However, several recent findings suggest illness.
that tDCS may indeed modulate neural activity in subcortical At the moment, this account of the CSTC loop through
structures of the CSTC loop circuits. First, a study using the SN must be considered preliminary, with many findings
resting-state fMRI found that tDCS of the primary motor requiring further replication and study, and many questions still
cortex increased its functional connectivity to the thalamus, outstanding. In this final section, we review some potentially
and additionally increased connectivity between the parietal fruitful directions for further study.
cortex and the caudate nucleus (Polanía et al., 2012). Second,
a study using the MRI-based perfusion technique of arterial
spin labeling (ASL) demonstrated that anodal right and cathodal Particular Contributions of the SN-CSTC
left dlPFC-tDCS caused decreases in resting perfusion of Loop to Voluntary Cognitive Control
the head of the caudate nucleus as well as the medial and At present, it would be helpful to have a clearer understanding
lateral orbitofrontal cortex (Weber et al., 2014). Finally, a of the SN’s role in cognitive control. Specifically, more
recent study using magnetic resonance spectroscopy (MRS) information should be generated about the contributions of
has for the first time directly demonstrated that active but the SN to self-regulation of cognition, emotion and behavior
not sham dlPFC-tDCS (anodal left, cathodal right) increases in healthy brain function. The particular contributions of
levels of glutamate and glutamine in the striatum as well as the SN should be distinguished from contributions of
N-acetylaspartate in the dlPFC itself (Hone-Blanchet et al., other functional networks involved in executive function,
2015). Taken together, these findings suggest that tDCS such as the neighboring frontoparietal networks known as
can indeed modulate both neurotransmission and network dorsal attention or central executive networks. It would
connectivity patterns in the subcortical as well as the cortical also be helpful to have a clearer understanding of the
components of CSTC loops when targeting the SN (i.e., via the distinct roles of the SN vs. its immediately posterior
dlPFC). counterpart comprising the posterior insula and mid-cingulate
So far, little information is available that speaks to whether cortex. Finally, it is necessary to better understand how
the therapeutic mechanisms of tDCS in psychiatric illness ensue engagement of the subcortical projection sites of the
via modulation of CSTC loop circuits, as appears to be the SN (in the head of the caudate, globus pallidus, MD
case for DBS and potentially for rTMS. As of this writing, the thalamus, and rostral substantia nigra) relates to the

voluntary vs. passive engagement of cognitive control Effects of Brain Stimulation Techniques on
functions. SN-CSTC Function
The available literature to date provides mounting evidence
that brain stimulation treatments are capable of modulating
Abnormalities of SN-CSTC Loop Integrity
the activity of CSTC circuits, and that these effects may
and Function in Psychiatric Illness be central to the therapeutic properties of such treatments.
In parallel with the previous theme, it would be helpful to have Nonetheless, further evidence is needed to demonstrate and
more detailed descriptions of the abnormalities present in the characterize the effects of brain stimulation treatments on CSTC
functional integrity, structural integrity and neurochemistry of function—to some extent for DBS, more so for rTMS, and
the SN-CSTC loop circuit in the major categories of psychiatric especially so for tDCS and tACS. As stated above, a variety of
illness. fMRI, ASL, DTI, VBM and PET studies will all be useful in techniques will be useful in this regard: in addition to fMRI
this regard. The ‘‘intervention-probe’’ properties of DBS, rTMS, studies of network integrity, PET and MRS—and potentially
and tDCS may also yield useful information of a causal rather voltammetry—will be useful for characterizing neurochemical
than correlational nature. It will be helpful to understand which effects, while electrophysiological recordings (noninvasive MEG
psychiatric disorders share SN-CSTC dysregulation as a common and EEG, and invasive intracortical recordings when available)
feature, and whether there are disorders (for example, AN) will be essential in assessing the direct effects of stimulation
where such pathology is relatively absent. Finally, as relatively on neural activity. Much of the available literature to date has
few studies to date have explored the neural heterogeneity of focused on motor CSTC loops rather than other prefrontal
illness among individuals with MDD, PTSD, OCD, SUD or loops. However, in light of the increasing popularity of brain
other Axis I disorders (as defined by the DSM-IV), it will be stimulation in treating psychiatric illness, more attention is due
helpful to understand whether SN-CSTC pathology is a pervasive to the SN-CSTC loop in future study.
feature across most individuals within each disease category, or
whether instead only a certain sub-population of patients within
MDD, PTSD, OCD or SUD show abnormalities of SN-CSTC Optimizing Brain Stimulation Protocols for
functioning. The latter case, if true, may help to explain the Modulating SN-CSTC Function
problematic heterogeneity of outcomes currently seen with brain The optimal parameters for therapeutic DBS, rTMS and
stimulation therapies, and may lead to methods for predicting tDCS/tACS in psychiatric illness are still being refined, and in
which individuals are the best candidates for treatments many cases are entirely unknown. To date, very few studies
targeting the SN-CSTC loop circuits. Better characterization have sought to optimize the frequency, intensity, protocol,
of individual patients’ pathology using the Research Domain inter-session interval or even dose (i.e., session number) for
Criteria (e.g., cognitive control, response selection and response therapeutic brain stimulation as a primary aim. The assessment
inhibition) may be useful in this regard (Morris and Cuthbert, of relative efficacy in most cases has been empirical, based
2012). on clinical measures (e.g., standardized symptom scales) that
may not be well suited to capturing the nuanced effects of
therapeutic brain stimulation. For example, after 20 years of
Contributions of Other CSTC Circuits to clinical trials of rTMS in MDD, there is a wealth of evidence
Psychiatric Illness about crude response and remission rates for this heterogeneous
Although mounting evidence suggests that SN-CSTC pathology population, but very little evidence about which types of
may be a common feature of many psychiatric disorders, it is patients respond best to treatment, or whether responders are
also clear that such pathology is far from the only, or even characterized specifically by deficiencies of cognitive control
the most important, pathological feature in many individuals. rather than conventional mood symptoms per se, as proposed
For example, pathology of the ‘‘reward’’ or ‘‘incentive’’ CSTC in this review. A more nuanced outcome measure (behavioral,
loop from the NAcc to the vmPFC and frontal pole increasingly cognitive or neurophysiological) may be helpful in providing a
appears to be important across a variety of disorders. Aside benchmark for optimizing the parameters of stimulation. For
from the well-established example of SUD, pathology of this example, if the mechanism of effect for dlPFC- or dmPFC-rTMS
loop may be important in OCD, MDD (particularly for the does indeed depend upon enhancements in deficient cognitive
symptom of anhedonia), schizophrenia, and other psychiatric control and SN-CSTC loop circuit integrity, then obtaining
disorders (as noted throughout the previous three sections markers of cognitive control and SN integrity will be essential
of this review). In addition, interactions (such as mutual to any parameter-optimization study. Candidate markers might
inhibition) between the activity of the dorsal striatal-SN loop include behavioral measures such as performance on flanker
and the ventral striatal reward loop may be important for or delayed discounting tasks, electrophysiological measures
understanding psychiatric pathology and its heterogeneity; such as coupling between theta and gamma oscillations, or
such interactions between dorsal and ventral CSTC loops neuroimaging markers such as D2 receptor occupancy on PET
are an increasingly prevalent theme of study in recent work or SN-striatal-thalamic functional connectivity on fMRI. Future
combining neuroimaging and neurostimulation in psychiatric studies of therapeutic brain stimulation may need to make
illness (for example, Liston et al., 2014; Hanlon et al., use of such markers in order to make progress in exploring
2016). the many dimensions of stimulation parameters that are still

awaiting optimization. Future studies involving fMRI should also brain stimulation treatments. With a better understanding of
consider the false-positive rate of fMRI in the application of CSTC function in health and psychiatric disease, it may become
past research, and study design and processing (Eklund et al., possible to tailor the target and parameters of stimulation
2016); this point highlights the importance of replication studies to the individual, depending on the underlying pathology.
and meta-analyses in developing new rTMS targets and in This individualized, brain-based approach to psychiatric
interpreting the effects of rTMS on brain function. treatment would constitute an important step forward in
addressing the daunting prevalence and burden of mental illness
around the world.
CONCLUSION
Converging evidence suggests that, of the brain’s many CSTC AUTHOR CONTRIBUTIONS
loop circuits, the specific circuit serving the SN may be of
particular relevance to cognitive control, and of transdiagnostic SKP, KD and JD wrote and edited the manuscript and figures.
relevance to psychiatric pathology. This proposal, if supported
by future work, is of more than purely academic interest. FUNDING
With the emergence of anatomically selective brain stimulation
technologies as therapeutic tools, it is becoming possible to SKP has received funding from the University of Toronto
target specific CSTC loop circuits of the brain in an increasingly Ontario Graduate Fund. KD has received funding from
precise manner, and to modulate their activity in a variety of the Canadian Institute for Health Research (CIHR)
ways. Therapeutic brain stimulation of the SN-CSTC loop circuit Vanier Scholarship. JD has received research support
may constitute a method for directly targeting the underlying from CIHR, NIH, the Klarman Family Foundation, the
pathophysiology of several types of psychiatric illness, or at Buchan Family Foundation and the Toronto General and
least a subpopulation of individuals within these categories Western Hospital Foundation. He has also received a travel
of illness. Stimulation targeting other CSTC loops, such as stipend from Lundbeck and from ANT Neuro, and in-kind
those through the ventral striatum, may further expand the equipment support for an investigator-initiated study from
range of disorders and individuals whose illness is amenable to Tonika/Magventure.
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published: 27 December 2016

Frontiers in Systems Neuroscience | www.frontiersin.org 1 December 2016 | Volume 10 | Article 104

INTRODUCTION Among these brain networks, one in particular is emerging as

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