Opinion

The Neural Crossroads

of Psychiatric Illness:
An Emerging Target for Brain
Stimulation
Jonathan Downar,1,2,3,4,* Daniel M. Blumberger,1,2,5 and
Zafiris J. Daskalakis1,2,5
Recent meta-analyses of structural and functional neuroimaging studies are
Trends
converging on a collective core of brain regions affected across most psychi-
The structural and functional correlates
atric disorders, centered on the dorsal anterior cingulate cortex (dACC) and of most major psychiatric disorders are
anterior insula. These nodes correspond well to an anterior cingulo-insular becoming increasingly well character-
ized, owing to expanding databases of
(aCIN) or ‘salience’ network, and stand at a crossroads within the functional neuroimaging studies and new quanti-
architecture of the brain, acting as a switch to deploy other major functional tative meta-analytic techniques.
networks according to motivational demands and environmental constraints.
A ‘common core’ of areas is affected
Therefore, disruption of these ‘linchpin’ areas may be disproportionately dis- across most categories of psychiatric
abling, even when other networks remain intact. These regions may represent illness; key nodes include the dACC
and anterior insula.
promising targets for a new generation of anatomically directed brain stimula-
tion treatments. Here, we review the potential of the psychiatric core areas as This common core corresponds well to
targets for therapeutic brain stimulation in psychiatric disease. a one of the resting-state networks of
the brain, known as the aCIN or ‘sal-
ience’ network; standing in a ‘cross-
Neurology and Psychiatry: An Intuitive Cartesian Divide roads’ position in the network
While most organs have one dedicated medical specialty, the brain has been divided into two: architecture of the brain, it is active
neurology and psychiatry. For a variety of historical reasons (see [1] for an interesting review), during behavioral self-control, emotion
regulation, and social cognition.
these two specialties have diverged over the course of the 20th century, and today view each
other as separate and distinct. Classically, neurology has laid claim to disorders with identifiable The common core network may be
‘organic’ lesions in the central nervous system, leaving psychiatry to focus on disorders variously amenable to therapeutic brain stimula-
described as ‘functional’, ‘psychogenic’, or ‘supratentorial’ in origin, which have historically tion via repetitive transcranial magnetic
stimulation (rTMS), transcranial direct
lacked readily identifiable lesions [2]. current stimulation (tDCS), and deep
brain stimulation (DBS). Its nodes
Yet, the schism cannot be neatly explained simply in terms of the presence or absence of brain may represent a promising target for
pathology. Many brain disorders with well-established neuropathological abnormalities [e.g., future studies of therapeutic brain
stimulation.
bipolar disorder (BP), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD)] are
studied almost exclusively in psychiatric journals. Conversely, other brain disorders with well-
established effects on mood, behavior, and social interaction (e.g., Huntington's disease,
Alzheimer's and Parkinson's dementia, and multiple sclerosis) are overwhelmingly allocated
toward neurological journals (Figure 1).
1
Department of Psychiatry, University
of Toronto, Toronto, ON, Canada
The polarization of brain medicine into two specialties may in part reflect an intuitive Cartesian 2
Institute of Medical Science,
dualism in human psychology. Children intuitively accept that certain mental functions, such as University of Toronto, Toronto, ON,
perception, planning, or mental calculation, require the brain; however, other functions, such as Canada
3
Krembil Research Institute, University
emotion, desire, belief, or pretense, are independent of the physical organ [3]. Related studies Health Network, Toronto, ON,
have demonstrated that even adults struggle to acquire scientific knowledge that clashes with Canada

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 http://dx.doi.org/10.1016/j.tics.2015.10.007 107
© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 4
(A) Figure 1. Allocations of Citations MRI-Guided rTMS Clinic, University
Bias Health Network, Toronto, ON, Canada
(Neuro> 0 Neuro Psych Total among Neurological and Psychiatric 5
Search term > Psych) % Neuro Citations Citations Citations Journals for 32 Prevalent Brain Temerty Centre for Therapeutic Brain
Meningitis 0.988 99.4% 482 3 485 Intervention and Campbell Family
Disorders. (A) Citation counts were deter-
Multiple sclerosis 0.986 99.3% 3752 27 3779 Research Institute, Centre for
mined using the PubMed database, over
Parkinson 0.985 99.3% 1457 11 1468 Addiction and Mental Health, Toronto,
Migraine 0.952 97.6% 1060 26 1086
the period from July 1, 1990 to June 30,
ON, Canada
Stroke 0.950 97.5% 3991 103 4094 2015, searching for appearances of each
Huntington 0.931 96.5% 195 7 202 search term in the title or abstract of four
Epilepsy 0.919 96.0% 3276 138 3414 top-cited neurological journals (Lancet:
Headache 0.913 95.6% 1093 50 1143 *Correspondence:
Neurology, Annals of Neurology, Archives
Alzheimer 0.848 92.4% 2003 165 2168 jonathan.downar@uhn.ca (J. Downar).
of Neurology, and Neurology), and four
Dementia 0.754 87.7% 3772 530 4302
top-cited psychiatric journals (JAMA Psy-
Pain 0.695 84.8% 1258 226 1484
Traumatic brain injury 0.581 79.1% 204 54 258 chiatry/Archives of General Psychiatry,
Mental retardation 0.575 78.8% 282 76 358 American Journal of Psychiatry, Biological
Developmental delay 0.540 77.0% 87 26 113 Psychiatry, and Neuropsychopharmacol-
Tourette 0.126 56.3% 103 80 183 ogy). The ‘bias’ score in the first data col-
Conversion disorder 0.091 54.5% 12 10 22 umn is based on the percentage of
Delirium –0.306 34.7% 50 94 144
citations in neurological versus psychiatric
Autism –0.601 19.9% 131 526 657
Asperger –0.765 11.8% 2 15 17
journals, with +1 indicating all-neurological
Attention deficit –0.825 8.8% 72 750 822 citations, –1 indicating all-psychiatric cita-
Somatoform –0.833 8.3% 3 33 36 tions, and 0 indicating an even balance of
Anxiety –0.850 7.5% 208 2568 2776 neurological and psychiatric citations. (B)
Obsessive compulsive –0.860 7.0% 56 745 801
Distribution of publication ratios in neuro-
Post-traumatic stress –0.891 5.4% 5 87 92
logical and psychiatric journals, for com-
Addiction –0.927 3.6% 26 690 716
Major depression –0.938 3.1% 59 1856 1915
mon brain disorders. Each data point
Bipolar –0.948 2.6% 49 1830 1879 along the horizontal axis represents the
Substance dependence –0.961 2.0% 2 100 102 relative proportion of publications for one
Generalized anxiety –0.961 1.9% 5 253 258 of the 32 common brain disorders listed in
Schizophrenia –0.977 1.1% 67 5768 5835
(A) over the past 25 years, as allocated
Panic disorder –0.986 0.7% 5 713 718
between the top four most highly cited
Alcohol dependence –0.987 0.7% 2 300 302
neurological and psychiatric journals. The
plot shows a kernel density estimate of the
(B)
Publication distribution for prevalent brain disorders distribution of these ratios, and reveals a
sharply bimodal allocation of disorders to
0.8

either psychiatric or neurological domains,

with few disorders appearing in a balanced
ratio of study across disciplines.
0.6
Probability density
0.4
0.2
0

–1 –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8 1

Psychiatric Neurological
Relative proportion of publications

the innate intuitions of childhood, and tend to revert to intuition for unfamiliar scenarios [4]. Thus,
one intriguing possibility is that early failures to identify structural lesions for certain brain
disorders, coupled with an innate human reluctance to ascribe certain mental functions to
the organ itself, allowed two separate disciplines of brain medicine to emerge. This resulted in the
current situation: a Cartesian divide between neurology, for disorders of the ‘wires’, and
psychiatry, for disorders of the ‘psyche’.

‘Where is the Lesion?’ in Psychiatry: New Clues from Neuroimaging

Intuitions of dualism aside, it is now clearer than ever that disorders of the ‘psyche’ are also
disorders of the wiring. Since the 1980s, psychiatric neuropathology became amenable to in

108 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

vivo study, thanks to non-invasive, high-resolution neuroimaging. The structural neuroimaging
technique of voxel-based morphometry (VBM), developed during the late 1990s [5], has been
particularly productive for localizing psychiatric neuropathology. To date, hundreds of ‘first-
wave’ VBM studies have compared gray matter structure in healthy controls versus patients with
psychiatric illnesses.

To sift this wealth of data, researchers have developed quantitative meta-analytic algorithms,
such as activation likelihood estimation (ALE) [6,7], which enable robust statistical inferences
about the spatial consistency of reported abnormalities, across combined samples of hundreds
of patients. Over the past 5 years, nearly 100 ‘second-wave’ VBM meta-analyses have been
reported. Within psychiatry, the first reports appeared for SCZ [8,9], followed swiftly by BD
[10,11], OCD [12,13], autism spectrum disorders (ASD) [14,15], major depression (MDD)
[16,17], attention deficit hyperactivity disorder (ADHD) [8,9], post-traumatic stress disorder
(PTSD) [18,19], panic disorder (PD) [18,20], generalized anxiety disorder (GAD) [20], social
anxiety disorder (SAD) [20], substance dependence disorders, including alcohol [21] and
stimulants [22], and eating disorders, such as anorexia nervosa [23]. As of 2015, this literature
now offers a first-draft map of consistently observed structural abnormalities for almost every
major psychiatric disorder in the Diagnostic and Statistical Manual.

Recently, the VBM literature has begun a ‘third-wave’ phase of integration, by performing
comparative quantitative meta-analyses not only across studies within a disorder, but also
across disorders themselves [20,24,25]. One recent study applied these methods to address
the distinction between neurological and psychiatric disorders directly [24]. The authors sur-
veyed a range of neurological disorders, including several varieties of movement disorder,
Alzheimer's and frontotemporal dementia, amyotrophic lateral sclerosis, dyslexia, and temporal
lobe epilepsy. Not surprisingly, VBM lesions in neurological disorders extended across diverse
brain regions, including sensorimotor cortex, anterior cingulate and insula, striatum, hippocam-
pus, and thalamus. By contrast, psychiatric disorders (SCZ, BD, OCD, PD, PTSD, ADHD, ASD,
and anorexia) showed a more restricted pattern of VBM changes involving the anterior cingulate,
anterior insula, head of the caudate nucleus, putamen, and anterior hippocampus and amyg-
dala. A direct comparison found more involvement of medial prefrontal cortex, anterior and
posterior cingulate, superior frontal gyrus, and occipital cortex in psychiatric versus neurological
disorders (Figure 2A). Thus, the VBM correlates of psychiatric illness appear to be at least
partially distinct from (and certainly a more restricted set of) the more diverse set of areas seen
across neurological conditions.

Regarding common substrates of psychiatric illnesses, one recent study examined 24 VBM
studies of anxiety disorders, surveying GAD, SAD, PD with and without agoraphobia, and
specific phobias [20]. Meta-analytic mapping revealed a pattern of overlapping gray matter
reductions in the bilateral pregenual cingulate cortex, right striatum, and right anterior insula, with
similar reductions in the left striatum and anterior insula also appearing in those patients who
were drug naïve (Figure 2B).

Another recent study reported the remarkable finding of a common neural substrate across
multiple categories of psychiatric illness [25]. Here, the authors used ALE methods to combine
193 studies of mood, anxiety, psychotic, and substance-use disorders in >7000 patients. By
examining different categories of illness separately, the authors identified both common and
distinctive substrates. For example, psychotic disorders involved a pattern of gray matter loss
extending across medial prefrontal regions, insula, thalamus, and amygdala, as well as gray
matter increases in the left and right striatum. Among nonpsychotic disorders, the ‘internalizing’
disorders of OCD, anxiety disorders, and MDD showed greater gray matter loss in hippocampus
and amygdala that were in contrast to ‘externalizing’ disorders, such as substance abuse.

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 109

(A) Areas of gray matter loss in (C) Common areas of loss across VBM meta-analyses
VBM meta-analyses of psychiatric illness
(i)

L L
Across all Across all
psychotic disorders non-psychotic disorders

L R
(ii) Areas of co-activation on functional neuroimaging
(B) Areas of gray matter loss in
VBM meta-analyses of anxiety disorders
(i)

(ii) L L

Meta-analysis of Resting-state
task-based activation functional connectivity

L R

Figure 2. A Common Core of Regions with Structural Abnormalities in Psychiatric Illness. (A) Brain regions
showing consistent loss of gray matter across a selection of voxel-based morphometry (VBM) studies of diverse psychiatric
illnesses, including schizophrenia (SCZ), bipolar disorder (BD), obsessive-compulsive disorder (OCD), panic disorder (PD),
post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and
anorexia. (B) Brain regions showing consistent loss of gray matter across a variety of anxiety disorders [generalized anxiety
disorder (GAD), social anxiety disorder (SAD), PD with and without agoraphobia, and specific phobias], shown in blue,
include the right and left insula and associated regions of the striatum, as well as anterior cingulate cortex. (i) Shows changes
in patients with comorbid depression, while (ii) shows patients who are drug naïve. (C) (i) Brain regions showing a loss of gray
matter across multiple categories of psychotic and nonpsychotic psychiatric disorders. Combining both groups, three
nodes emerge: the left and right anterior insula/frontal operculum, and the dorsal anterior cingulate cortex. (ii) These three
nodes belong to a common network of co-activating brain regions seen in meta-analyses of brain activation across multiple
tasks; on resting-state activity, these nodes belong to a larger common network that also includes a circuit of connected
regions in the striatum, thalamus, subthalamic nucleus, and brainstem. Adapted from [24] (A), [20] (B), and [25] (C).

Yet, there was also a common substrate appearing across every category of disorder: gray
matter volume reductions in the left and right anterior insula, and the dACC (Figure 2C). Although
each illness category also had its own unique neural correlates, these regions appeared
consistently across all psychiatric disorders surveyed. Thus, the emerging picture from structural
neuroimaging is that psychiatric disorders do indeed have ‘organic’ correlates that can be
consistently identified from sufficiently large samples, and that these correlates may be a distinct
subset of regions that are contained within, and do not entirely overlap with, the more diverse set
of areas implicated in neurological illnesses.

A Functional Context for the ‘Common Core’ of Psychiatric Illness

What functions might the psychiatric ‘common core’ regions serve? The functional neuroimag-
ing literature now includes tens of thousands of studies of cognition and behavior in patients and
healthy controls. These studies are catalogued in large databases, amenable to quantitative
meta-analysis techniques similar to those used for structural imaging [26]. Large databases of
resting-state scans in >1000 individuals are also available for interrogation [27,28].

An emerging finding is that brain regions rarely act in isolation, but rather coordinate their activity
into functional networks, each with a distinctive spatial map [29,30]. These networks can be

110 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

extracted from ongoing brain activity, using seed-based or data-driven methods, and are
consistent across individuals in the resting state [31]. Remarkably, a similar set of co-activating
networks emerges from meta-analyses of brain activation during task performance [32], sug-
gesting a common functional architecture during either activation or rest. The exact number of
networks is debated; recent studies across a set of 1000 healthy individuals found peaks of
stability for seven- and 17-network parcellations of cortex [33], with corresponding parcellations
in striatum [27] and cerebellum [34] (Figure 3A, Key Figure).

Some of these functional networks are restricted to low-level sensory or motor areas, such as
primary motor cortex, primary visual cortex, or extra-striate cortex (Figure 3B). Others extend
broadly across multimodal regions of the cortex, suggesting a more integrative role. The best
known and most studied is the default-mode network (DMN) [35]. With nodes in the medial
prefrontal cortex, posterior cingulate cortex, precuneus, and lateral parietal cortex, it has
recognized functions for self-referential thinking [36], recollection and prospection [37], and
mind wandering [38]. Although abnormalities in the structure and dynamics of this network
have been described across a variety of neurological psychiatric illnesses [39–43], it is notable
that the ‘core’ regions from VBM meta-analyses of psychiatric illness lie outside the major foci of
the DMN itself.

Another network appears to act in opposition to the introspective functions of the DMN, during
‘extrospective’ activities, such as task performance [44,45]. The so-called ‘task-positive net-
work’ (TPN) includes several subnetworks, such as the central executive network (CEN) [46] or
frontoparietal network (FPN) [47]. The FPN comprises lateral prefrontal and intraparietal areas.
Active during a variety of external-focus cognitive tasks involving working memory or attention,
the FPN may act to control behavior from external cues, on an event-by-event basis [48].
Importantly, while the FPN is consistently active in a variety of ‘general intelligence’-related tasks
involving rule-based behavioral control using external cues [49,50], its nodes have essentially no
overlap with any of the areas seen in VBM meta-analyses of psychiatric illness.

However, another subnetwork appears to be more closely related. This anterior cingulo-insular
network (aCIN) can be reliably separated from the FPN and appears consistently in seven- and
17-network parcellations of functional activity [33] (Figure 3A,B). Often designated as the
‘salience network’ [51] (Figure 3C), its key nodes overlap almost precisely within the areas
identified as the psychiatric ‘core’: the left and right anterior insula, and the dACC. Its subcortical
components include a larger loop circuit encompassing specific regions of the striatum, globus
pallidus, subthalamic nucleus, and thalamus, as well as the dopamine-rich substantia nigra and
ventral tegmental area in the brainstem, and specific regions of the lateral cerebellum
(Figures 2C, 3C). Thus, the psychiatric ‘common core’ maps strikingly well on to a specific
member of the set of reliably identifiable functional networks of the human brain, the aCIN or
‘salience network’. Therefore, it is worth examining the functions of this network in greater detail.

Common Core Functions: Cognitive Control and Response Selection

Meta-analytic tools (e.g., Neurosynth [52]) are now available to mine databases of thousands of
functional imaging studies for brain regions consistently activated for given cognitive function, or
vice versa. Meta-analytic searches using the term ‘salience network’ reveal a set of areas that
map closely on to the aCIN and the psychiatric ‘common core’, as noted above (Figure 3C). Yet,
the aCIN can also be mapped more specifically on to one of the constructs of the Research
Domain Criteria (RDoC) proposed by the National Institute of Mental Health [53]. The construct of
‘cognitive control’, and specifically the subconstruct of ‘response selection’, map strikingly well
to the aCIN and common core (Figure 3C), suggesting that deficiencies in these functions are a
common element across psychiatric disorders, notwithstanding their differences in other
domains.

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 111

Key Figure
Psychiatric Common Core Regions in the Context of the Functional
Architecture of the Human Brain

(A) Seven-network parcellation 17-Network parcellation

(B) Default mode Frontoparietal Dorsal attention Ventral attention

Visual Somatomotor Limbic Anterior cingulo-insular (aCIN)

(C) (D)
VBM rsFC (i)
Brain regions Whole-brain graph of
(i) Common substrates as graph nodes connections between nodes
of psychiatric illness

(ii) Resting-state aCIN

(iii) Meta-analysis:
‘salience (ii)
network’

(iv) Meta-analysis:
‘cognitive
control’

(v) Meta-analysis: Participation Community

‘response coefficient density
iinhibition’

Low High Low High

L R

Figure 3. (A) Consistent networks can be identified within the activity of the resting brain. Seven- and 17-network
parcellations have been reported as being particularly stable across individuals in data sets of 1000 subjects. (B) Replicable
networks include visual, somatomotor, and limbic networks, as well as a default-mode network (DMN) active during rest or
introspection, two to three frontoparietal networks (FPN) active during cognitive tasks or extrospection, and an anterior
cingulo-insular network (aCIN) or salience network (SN), which closely overlaps the common core areas of structural

112 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

Deficiencies in self-regulation of emotions, thoughts, and behaviors are indeed a hallmark of
psychiatric illness, and are also consistent with what is known about the functions of the dACC and
anterior insula. The dACC stands midway along a hierarchy of medial prefrontal regions (ranging
from the medial frontopolar cortex anteriorly, to supplementary motor area posteriorly) that guide
goal selection, thought selection, and action selection based on internal drives, as opposed to
external cues [54,55]. The dACC itself contains a posterior region for response selection, a middle
region for decision (action) selection, and an anterior region for strategy selection [56]. Consistent
with this role, the dACC region is active when choosing freely between two different cognitive tasks
[57], and during voluntary, internally cued modulation of emotional states [58].

The insula contains multiple functional subregions, each characterized by different patterns of
functional connectivity to the rest of the brain and different functional roles [59,60]. For example,
posterior insula regions link to low-level somatosensory cortices, and have a proposed lower-
level role in ‘interoception’, or visceral sensory perception [61]; ventral anterior insula regions are
active in chemosensory functions and in mediating disgust [62]. One particular insula subregion,
in dorsal anterior insula, maps well on to the aCIN's anterior insular node, appears in VBM meta-
analyses of psychiatric illness [25], and shows functional connectivity to the other aCIN nodes,
including dACC, frontal opercula, anterior putamen, and mediodorsal thalamus [60]. This
subregion has a role in linking external sensory stimuli to their associated emotional states
[61]. Examples include activation for external stimuli that are salient or behaviorally relevant
[63,64], aversive [65], sad [66], or fearful [58].

The RDoC constructs of internally cued cognitive control and response selection may help unify
the variety of more specific functions attributed to the dACC and dorsal anterior insula across the
neuroimaging literature. For the dACC, these include conflict detection and error detection [67],
impulse regulation [68], suppression of prepotent behavior and cognition [69], the capacity for
counterfactual thought that underlies theory of mind [70], and the modulation of emotional
responses to external stimuli [71]. For the anterior insula, these include activation during errors in
task performance [72], visual observations of another person in pain [73], or visually signaled
rejection during social interaction [74]. In broad terms, the dACC and dorsal anterior insula may
serve two sides of the same function. Where the anterior insula may switch cognition and
emotion states based on external sensory inputs, the dACC may serve a similar function based
on internal states and cues.

This division of labor would be consistent with the broader functional architecture of the
prefrontal cortex, in which a hierarchy of lateral regions guides complex behavior using external
cues, while a corresponding and functionally interconnected hierarchy of medial regions serves
analogous functions based on internal cues [75]. Within this hierarchy, the aCIN nodes would
stand in a crossroads or ‘hub’ position, linking multiple networks mediating cognition and
emotion [76], thus having a prominent role across multiple psychiatric disorders.

abnormality across psychiatric disorders. (C) The common neural substrates across multiple psychiatric illnesses on voxel-
based morphometry (VBM) studies comprise a coherent functional network on resting-state functional connectivity (rsFC)
mapping (i), corresponding closely to the aCIN (ii), which in turn corresponds closely to the set of regions emerging from
Neurosynth meta-analyses of activations in neuroimaging studies of the salience network (iii), and more specifically of the
Research Domain Criteria construct ‘cognitive control’ (iv) and response inhibition (v). (D) (i) In graph theoretical analyses of
the functional architecture of the brain, the aCIN regions (shown in purple) stand in a ‘crossroads’ position, connecting to
many other subcommunities. By contrast, other communities, such as low-level visual networks (blue), low-level sensor-
imotor networks (cyan), or even the DMN itself (red), are relatively self contained, tightly integrated within themselves but not
widely connected to other communities. (ii) Quantitative measures of network centrality, such as the participation coefficient
(left) and community density (right), are high in the nodes of the aCIN (dorsal anterior cingulate cortex and anterior insula),
supporting the premise that these regions serve as ‘hubs’ or ‘crossroads’ regions within the functional architecture of the
brain as a whole. Adapted from [33] (A) and [76,78] (D).

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 113

A Neural Crossroads for Psychiatric Illness
It is now possible to analyze network architecture in a rigorous, quantitative way using the
mathematical tools of graph theory [77]. Recent studies have applied graph theory to patterns
of resting-state functional connectivity in the human brain, allowing us to both map the larger
functional architecture of the human brain, and situate the major functional networks within this
architecture [78] (Figure 3D). Some networks, such as primary visual or sensorimotor networks, are
tightly integrated but relatively self contained, having less direct interaction with the other networks
of the brain. The DMN, despite its prominent place in brain function, is relatively self contained;
similar to visual cortex, its nodes interact much more with each other than with other networks.

By contrast, the nodes of the aCIN do interact with a variety of other brain networks, and must be
traversed for many trajectories of information flow over the network as a whole. By this criterion,
the aCIN fulfills the definition of a ‘crossroads’ network [78]. Assessed quantitatively, the aCIN
nodes have a higher participation coefficient and higher community density than the DMN or
other networks, interacting with a broader selection of other brain networks [76] (Figure 3D).
Thus, the aCIN has been proposed to act as a switching system between the FPN and DMN,
activating when brain activity transitions between one and the other [79]. By standing at a
crossroads position between other brain networks, the nodes of the aCIN are better equipped to
integrate the modular functions of the other, more ‘clannish’ networks into a coherent whole.

Functional disruption of the aCIN is apparent in a variety of psychiatric illnesses, including MDD
[80], PTSD [81], and OCD [82]. Conversely, patients with structural lesions of nodes in the aCIN
show impairment across a wider range of neuropsychological functions than do patients with
lesions in the DMN [83]. This observation raises the question of whether treatments that restore
the functioning of the aCIN might have particularly broad-spectrum benefits across psychiatric
disorders, particularly in comorbid cases, by enhancing the general capacity for self-driven
cognitive control and response inhibition.

Targeting the Common Core for Therapeutic Effect

Localizing the neural substrates of psychiatric disease is of limited practical use unless these
substrates can be targeted effectively and selectively; a challenging proposition with medications
or psychotherapy. However, anatomically targeted interventions are now more feasible thanks
to a new, fast-evolving class of treatments: brain stimulation therapies (Box 1). The ‘common
core’ areas in the dACC and anterior insula are notable for being both moderately deep (4–5 cm
from the scalp surface, for both dACC and anterior insula) and moderately focal (2–3 cm in
extent). We consider first the evidence that each technique can successfully engage the target
regions, and then the evidence on whether targeting these areas does show therapeutic efficacy
across a broad spectrum of psychiatric disorders, as predicted.

Convulsive Therapies: ECT and MST

In electroconvulsive therapy (ECT), simulations using finite element modeling (FEM) [84] suggest
that standard bitemporal montages achieve more than adequate penetration of the induced
electrical field throughout the cranium. However, focality with ECT is poor and extends well
beyond the common core areas. A bifrontal montage may more selectively target the anterior
insula bilaterally, and a right unilateral montage may have similar effects unilaterally. Newer
proposed montages [85] and finer titration of the current amplitude [86] may achieve still better
focality over the anterior insula, or potentially the dACC. So far, however, no ECT montage or
parameter set has been optimized specifically to target the cortical components of the ‘core’
brain regions. FEM simulations toward this end may be a fruitful direction for future study.

FEM simulations of magnetic seizure therapy (MST) [84,86] suggest a desirable combination of
moderate depth and moderate focality, in a favorable three-lobed ‘left-centre-right’ spatial

114 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

 Box 1. Non-Invasive Brain Stimulation Therapies
Non-invasive brain stimulation techniques for treating psychiatric illness include older approaches, such as electro-
convulsive therapy (ECT), as well as more recently approved methods, such as repetitive transcranial magnetic
stimulation (rTMS), hybrid methods, such as magnetic seizure therapy (MST), and emerging methods, such as
transcranial direct current stimulation (tDCS). Their more invasive counterparts include deep brain stimulation (DBS)
and epidural cortical stimulation (EpCS). All are being used to treat an increasingly wide range of psychiatric illnesses,
from mood and anxiety disorders to substance dependence, psychotic illness, OCD, and eating disorders

ECT applies pulsed electrical currents of approximately 800 mA to the brain to induce a therapeutic generalized tonic-
clonic seizure. The technique is performed under brief general anesthesia, with muscle relaxation to avoid injury from
convulsive movements. Common montages include bilateral stimulation over the temporal poles, right unilateral
stimulation over the right parietal cortex and right temporal pole, or bifrontal stimulation with both electrodes over
the frontal pole. In all cases, stimulation is fairly nonfocal and extends across much of the cerebrum; medial temporal
stimulation is thought to be responsible for the retrograde amnesia that is a common ECT side effect. MST induces the
seizures via a pair of large circular rTMS coils placed over the vertex or the frontal lobes; stimulation is more focal and
penetrates approximately 5 cm from the scalp surface, sparing the medial temporal lobes.

rTMS uses powerful, focused magnetic field pulses to induce lasting changes in brain activity. Stimulation coils may have
a circular or figure of eight shape; ‘deep TMS’ coils use a helmet-shaped array of windings to reach structures >5 cm from
the scalp surface. A typical course involves 20–30 sessions of stimulation. The dorsolateral prefrontal cortex (DLPFC) is
the most common target in the literature to date, with therapeutic effects seen in MDD [88,89]. Other psychiatric
indications under exploration include anxiety disorders, such as PTSD [90], OCD [93], substance dependence [97],
eating disorders [91], and some symptoms of SCZ [122].

tDCS [and its variants, such as transcranial alternating current or random noise stimulation (tACS/tRNS)] use current
amplitudes that are more than 100 times weaker than ECT, and do not produce action potentials. Anodal stimulation is
considered excitatory; cathodal stimulation is considered inhibitory. A limited number of large trials of tDCS suggest some
efficacy in MDD [123,124]; to date, these have exclusively targeted the DLPFC, with left anodal and right cathodal stimulation.

distribution. In particular, a double-cone inductor placed over the lateral frontal lobes may be well
situated to stimulate the dorsomedial prefrontal region encompassing the dACC. The MST
literature to date is sparse, and the comparative efficacy of different MST montages has not yet
assessed; neither has the full range of potential indications for MST been explored. However, the
good concordance of MST fields with the ‘common core’ brain regions suggests that MST
should be studied across a wider range of indications than is usual for ECT, such as SCZ. In
general, ECT and MST montages optimized for the aCIN could theoretically prove helpful for
other severe, debilitating psychiatric illnesses that are presently poor indications for convulsive
therapies, such as refractory OCD, PTSD, or anxiety disorders.

Nonconvulsive Therapies: rTMS

Most therapeutic repetitive transcranial magnetic stimulation (rTMS) studies to date, regardless
of indication, have targeted dorsolateral prefrontal cortex (DLPFC) [87]. While DLPFC-rTMS
achieves fair efficacy for MDD [88,89], efficacy in other psychiatric disorders is more modest [90–
93]. DLPFC regions do occur in aCIN/salience network maps (Figure 3), albeit less consistently
than dACC and anterior insula (Figure 3C). Therefore, future rTMS studies might explore whether
targeting these other aCIN nodes might boost remission rates across a wider range of
psychiatric disorders.

The electromagnetic fields of rTMS are subject to a trade-off between depth and focality [94], so
designing a coil to stimulate the dACC and anterior insula selectively is challenging. However,
FEM simulations suggest that stimulation to the 4–5 cm depth of the dACC and anterior insula is
feasible with commercially available double-cone [95] and helmet-shaped ‘deep TMS’ systems
[96,97], assuming that some stimulation of neighboring regions is acceptable.

Several lines of evidence suggest that stimulation of the dACC is feasible. Double-cone rTMS
can elicit lower limb movements when used to target primary motor cortex for the lower
extremity, 4–5-cm from the scalp surface [98]. Dorsomedial prefrontal rTMS has also been

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 115

shown directly to activate the dACC on positron emission tomography (PET) [99], to influence
performance on the Stroop task, which recruits this area [100], and to reduce impulsivity on the
delay-discounting task [101].

Although the most common target for therapeutic rTMS is the DLPFC, a series of recent studies
has begun to demonstrate therapeutic efficacy for dorsomedial rTMS for MDD and BP
[102,103], OCD [104], refractory alcohol dependence [105], ASD [106], binge and purge
behaviors in eating disorders [107], and PTSD [108]. These diverse effects are in keeping with
the involvement of the dACC across multiple categories of psychiatric illness.

Fewer rTMS studies have attempted to target the insula. Double-cone rTMS has been shown to
alter the perception of cold stimuli when applied to the posterior insula [109], suggesting
feasibility. rTMS has also recently been used to target the anterior insular node of the aCIN
specifically, with changes observed in the resting-state functional connectivity of this network
both within itself and to the FPN [110,111]. Deep TMS of the frontal operculum and anterior
insula, using a helmet-shaped coil, has recently shown efficacy for nicotine dependence, when
applied at high but not low frequency [97] (see Outstanding Questions).

Nonconvulsive Therapies: tDCS

Despite its relatively low field strength, there is evidence that transcranial direct current stimula-
tion (tDCS) may be capable of altering the excitability of structures at the depth of the dACC and
anterior insula. For example, anodal tDCS targeting lower limb motor cortex (equivalent to the
depth of dACC) has been shown to potentiate TMS-induced lower limb movements [112].
Anodal tDCS of the dorsomedial prefrontal cortex, neighboring the dACC, has recently been
shown to improve inhibitory control of behavior [113], and to reduce implicit negative bias
towards racial outgroups [114]. Both findings suggest potential therapeutic utility for enhancing
self regulation of cognition, emotion, and behavior.

Thus far, there is little proof-of-concept evidence available regarding the feasibility of anterior
insular tDCS. FEM simulations support the potential feasibility of stimulating regions of equivalent
or greater depth [115], particularly using the multielectrode montages of high-definition tDCS
[116]. Therapeutically, few studies of dACC-tDCS or anterior insular tDCS have been reported.
However, tDCS targeting the nearby supplementary motor area has recently been reported to
modulate OCD symptoms, with worsening symptoms after a course of cathodal stimulation and
improvement of symptoms after anodal stimulation [117]. Given the favorable safety and
tolerability profile of tDCS, future studies targeting the dACC and anterior insula in psychiatric
illness should be given high priority.

Neurosurgical Approaches to Brain Stimulation: EpCS and DBS

Epidural cortical stimulation (EpCS) is well suited to targeting the dACC and anterior insula focally
and selectively, since the stimulation contacts can be placed directly upon the cortical surfaces
of these targets. To date, this technique has not been applied to the anterior insula. However,
EpCS has shown therapeutic effect when applied to the medial prefrontal cortex, just anterior to
the dACC, in patients with MDD [118]. However, this study also applied EpCS electrodes to
DLPFC. Since the efficacy of EpCS for refractory MDD has been called into question [119], the
most important implication vis à vis the ‘core’ for this technique might be in encouraging
exploration of evidence-based targets other than the DLPFC, before dismissal of its therapeutic
value in MDD [120].

Deep brain stimulation (DBS) may be better suited to targeting the subcortical components of
the aCIN circuit rather than the dACC and anterior insula directly. As with its approved use in
movement disorders, DBS electrodes targeting the striatum, globus pallidus, or thalamus would

116 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

be expected to modulate the entire cortico-striatal-pallidal-thalamic loop through the target Outstanding Questions
region, to therapeutic effect [121]. With accurate implantation, one would hypothesize broad- Do lesion studies confirm VBM meta-
spectrum effects across a variety of psychiatric symptom categories. Maps of resting and task- analyses in implicating the aCIN, or
other functional networks, in psychiat-
based functional connectivity through the aCIN may offer suggestions for novel DBS implanta- ric illness? Large registries of patients
tion targets in severe psychiatric disease. with focal brain lesions (e.g., the Viet-
nam Head Injury Study registry) may be
informative in bolstering evidence for a
Concluding Remarks
robust link between aCIN pathology
The Cartesian divide between the ‘functional’ disorders of psychiatry and the ‘organic’ disorders and psychiatric symptomatology.
of neurology may soon be ending. Quantitative meta-analyses, applied to growing repositories
of neuroimaging data, are helping to localize the neuroanatomical substrates of psychiatric Which brain stimulation techniques can
offer reliable and focal stimulation of the
illness. Strikingly, a common circuit seems to unify most psychiatric disorders, and this circuit
dACC and anterior insula? Although
maps fairly neatly on to a specific network of brain regions: the aCIN. This network occupies a focal stimulation of these areas (or their
critical ‘hub’ position within the functional architecture of the brain, which may account for its subcortical partners) may be possible
prominence in complex functions involving cognition, emotion, behavioral regulation, social with invasive techniques, such as DBS
or EpCS, further research will be helpful
behavior, and theory of mind. When this hub network fails, the corollary could be severely
to clarify how reliably and how selec-
disabling illness, even if the basic component functions of sensory perception and motor control tively these areas can be stimulated
remain intact. with non-invasive techniques, such
as tDCS, rTMS, MST, and ECT.

The notion of psychiatric dysfunction as an organic ‘illness’ may challenge our intuitions. Which psychiatric illnesses will respond
However, it need not challenge our progress in developing new treatments. The identification to stimulation of the dACC and anterior
of a discrete set of neural substrates for psychiatric illness arrives at a fortuitous time, just as insula? Although promising results are
anatomically targeted brain stimulation therapies are making the leap from the lab to the clinic. emerging for some disorders, such as
MDD, PTSD, OCD, and substance
Optimizing the efficacy of brain stimulation therapies requires that we engage the correct targets. abuse, there remains a need for large,
As a result of a confluence of progress in neuroimaging and brain stimulation, we may soon be multicenter, randomized controlled tri-
on the cusp of a new generation of more effective therapies in one of the most challenging, yet als to better establish the range of dis-
orders for which ‘common core’
most exciting fields of modern medicine.
stimulation will prove to have therapeu-
tic efficacy.
Acknowledgments
J.D. has received research support from the Canadian Institutes of Health Research (CIHR), Brain Canada, the National Which biomarkers are best suited for
Institutes of Health (NIH), the Klarman Family Foundation, the Edgestone Foundation, and the Toronto General and demonstrating engagement of the
Western Hospital Foundation, as well as travel stipends from Lundbeck and ANT Neuro, and in-kind equipment support dACC and anterior insula targets dur-
ing therapeutic brain stimulation? Neu-
for an investigator-initiated study from MagVenture. D.M.B. receives research support from the CIHR, NIH, Brain Canada,
roimaging, electrophysiological,
Temerty Family through the Centre for Addiction and Mental Health (CAMH) Foundation, and the Campbell Family cognitive, behavioral, or clinical-symp-
Research Institute. He receives nonsalary operating funds and in-kind equipment support from Brain Research and tomatic measures may all be useful for
Development Services Ltd for an investigator-initiated study. He is the site principal investigator for several sponsor- demonstrating modulation of the target
initiated clinical trials from Brain Research and Development Services Ltd. He receives in-kind equipment support from regions during treatment.
Tonika/Magventure for an investigator-initiated study. Z.J.D. has over the past 5 years received research and equipment
Can clinically useful biomarkers be
in-kind support for an investigator-initiated study through Brain Research and Development Services Ltd. He has also
developed for predicting and tracking
served on the advisory board for Hoffmann-La Roche Limited and Merck and received speaker support from Sepracor
treatment outcome in individual
and Eli Lilly. This work was supported by the Ontario Mental Health Foundation (OMHF), the CIHR, Brain Canada, the patients? Given that brain stimulation
Brain and Behaviour Research Foundation and the Temerty Family and Grant Family and through the CAMH Foundation, techniques themselves may be hetero-
and the Campbell Institute. geneous in their effects on individual
patients, there is a need for biomarkers
that can reliably predict and track treat-
References
1. Price, B.H. et al. (2000) Neurology and psychiatry: closing the 6. Laird, A.R. et al. (2005) ALE meta-analysis: controlling the false
ment outcomes. To be clinically useful,
great divide. Neurology 54, 8–14 discovery rate and performing statistical contrasts. Hum. Brain these biomarkers must achieve ade-
2. Martin, J.B. (2002) The integration of neurology, psychiatry, Map. 25, 155–164 quate predictive accuracy (generally
and neuroscience in the 21st century. Am. J. Psychiatry 159, 7. Turkeltaub, P.E. et al. (2002) Meta-analysis of the functional >85%) in individual patients, rather than
695–704 neuroanatomy of single-word reading: method and validation. simply correlating with outcomes
3. Johnson, C.N. (1990) If you had my brain, where would I be? Neuroimage 16, 765–780 across a sample of patients overall.
Children's understanding of the brain and identity. Child Dev. 61, 8. Glahn, D.C. et al. (2008) Meta-analysis of gray matter anomalies
962–972 in schizophrenia: application of anatomic likelihood estimation
4. Bloom, P. and Weisberg, D.S. (2007) Childhood origins of adult and network analysis. Biol. Psychiatry 64, 774–781
resistance to science. Science 316, 996–997 9. Fornito, A. et al. (2009) Mapping grey matter reductions in schizo-
5. Ashburner, J. and Friston, K.J. (2000) Voxel-based morphome- phrenia: an anatomical likelihood estimation analysis of voxel-
try: the methods. Neuroimage 11, 805–821 based morphometry studies. Schizophr. Res. 108, 104–113

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 117

10. Ellison-Wright, I. and Bullmore, E. (2010) Anatomy of bipolar
disorder and schizophrenia: a meta-analysis. Schizophr. Res.
117, 1–12
11. Bora, E. et al. (2010) Voxelwise meta-analysis of gray matter
abnormalities in bipolar disorder. Biol. Psychiatry 67, 1097–1105
12. Radua, J. and Mataix-Cols, D. (2009) Voxel-wise meta-analysis
of grey matter changes in obsessive-compulsive disorder. Br. J.
Psychiatry 195, 393–402
13. Rotge, J.Y. et al. (2010) Gray matter alterations in obsessive-
compulsive disorder: an anatomic likelihood estimation meta-
analysis. Neuropsychopharmacology 35, 686–691
14. Yu, K.K. et al. (2011) Can Asperger syndrome be distinguished
from autism? An anatomic likelihood meta-analysis of MRI stud-
ies. J. Psychiatry Neurosci. 36, 412–421
15. Via, E. et al. (2011) Meta-analysis of gray matter abnormalities in
autism spectrum disorder: should Asperger disorder be sub-
sumed under a broader umbrella of autistic spectrum disorder?
Arch. Gen. Psychiatry 68, 409–418
16. Bora, E. et al. (2012) Gray matter abnormalities in Major Depres-
sive Disorder: a meta-analysis of voxel based morphometry
studies. J. Affect. Disord. 138, 9–18
17. Du, M.Y. et al. (2012) Voxelwise meta-analysis of gray matter
reduction in major depressive disorder. Prog. Neuropsychophar-
macol. Biol. Psychiatry 36, 11–16
18. Radua, J. et al. (2010) Meta-analytical comparison of voxel-
based morphometry studies in obsessive-compulsive disorder
vs other anxiety disorders. Arch. Gen. Psychiatry 67, 701–711
19. Kuhn, S. and Gallinat, J. (2013) Gray matter correlates of post-
traumatic stress disorder: a quantitative meta-analysis. Biol.
Psychiatry 73, 70–74
20. Shang, J. et al. (2014) The common traits of the ACC and PFC in
anxiety disorders in the DSM-5: meta-analysis of voxel-based
morphometry studies. PLoS ONE 9, e93432
21. Xiao, P. et al. (2015) Regional gray matter deficits in alcohol
dependence: a meta-analysis of voxel-based morphometry
studies. Drug Alcohol. Depend. 153, 22–28
22. Hall, M.G. et al. (2015) Gray matter abnormalities in cocaine
versus methamphetamine-dependent patients: a neuroimaging
meta-analysis. Am. J. Drug Alcohol Abuse 41, 1–10
23. Titova, O.E. et al. (2013) Anorexia nervosa is linked to reduced
brain structure in reward and somatosensory regions: a meta-
analysis of VBM studies. BMC Psychiatry 13, 110
24. Crossley, N.A. et al. (2015) Neuroimaging distinction between
neurological and psychiatric disorders. Br. J. Psychiatry 207,
429–434
25. Goodkind, M. et al. (2015) Identification of a common neurobi-
ological substrate for mental illness. JAMA Psychiatry 72,
305–315
26. Laird, A.R. et al. (2011) The BrainMap strategy for standardiza-
tion, sharing, and meta–analysis of neuroimaging data. BMC
Res. Notes 4, 349
27. Choi, E.Y. et al. (2012) The organization of the human striatum
estimated by intrinsic functional connectivity. J. Neurophysiol.
108, 2242–2263
28. Biswal, B.B. et al. (2010) Toward discovery science of
human brain function. Proc. Natl. Acad. Sci. U.S.A. 107,
4734–4739
29. Beckmann, C.F. et al. (2005) Investigations into resting-state
connectivity using independent component analysis. Philos.
Trans. R. Soc. Lond. B: Biol. Sci. 360, 1001–1013
30. van den Heuvel, M.P. and Hulshoff Pol, H.E. (2010) Exploring the
brain network: a review on resting-state fMRI functional connec-
tivity. Eur. Neuropsychopharmacol. 20, 519–534
31. Damoiseaux, J.S. et al. (2006) Consistent resting-state networks
across healthy subjects. Proc. Natl. Acad. Sci. U.S.A. 103,
13848–13853
32. Smith, S.M. et al. (2009) Correspondence of the brain's func-
tional architecture during activation and rest. Proc. Natl. Acad.
Sci. U.S.A. 106, 13040–13045
33. Yeo, B.T. et al. (2011) The organization of the human Cereb.
Cortex estimated by intrinsic functional connectivity. J. Neuro-
physiol. 106, 1125–1165
118 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2
34. Buckner, R.L. et al. (2011) The organization of the human cere-
bellum estimated by intrinsic functional connectivity. J. Neuro-
physiol. 106, 2322–2345
35. Raichle, M.E. et al. (2001) A default mode of brain function. Proc.
Natl. Acad. Sci. U.S.A. 98, 676–682
36. Gusnard, D.A. et al. (2001) Medial prefrontal cortex and self-
referential mental activity: relation to a default mode of brain
function. Proc. Natl. Acad. Sci. U.S.A. 98, 4259–4264
37. Spreng, R.N. and Grady, C.L. (2010) Patterns of brain activity
supporting autobiographical memory, prospection, and theory of
mind, and their relationship to the default mode network. J.
Cogn. Neurosci. 22, 1112–1123
38. Fox, K.C. et al. (2015) The wandering brain: meta-analysis of
functional neuroimaging studies of mind-wandering and related
spontaneous thought processes. Neuroimage 111, 611–621
39. Kaiser, R.H. et al. (2015) Large-scale network dysfunction in
major depressive disorder: a meta-analysis of resting-state func-
tional connectivity. JAMA Psychiatry 72, 603–611
40. Chen, A.C. and Etkin, A. (2013) Hippocampal network connec-
tivity and activation differentiates post-traumatic stress disorder
from generalized anxiety disorder. Neuropsychopharmacology
38, 1889–1898
41. Whitfield-Gabrieli, S. and Ford, J.M. (2012) Default mode net-
work activity and connectivity in psychopathology. Annu. Rev.
Clin. Psychol. 8, 49–76
42. Beucke, J.C. et al. (2014) Default mode network subsystem
alterations in obsessive-compulsive disorder. Br. J. Psychiatry
205, 376–382
43. Weiland, B.J. et al. (2015) Reduced executive and default net-
work functional connectivity in cigarette smokers. Hum. Brain
Mapp. 36, 872–882
44. Fransson, P. (2005) Spontaneous low-frequency BOLD signal
fluctuations: an fMRI investigation of the resting-state default
mode of brain function hypothesis. Hum. Brain Mapp. 26, 15–29
45. Fox, M.D. et al. (2005) The human brain is intrinsically organized
into dynamic, anticorrelated functional networks. Proc. Natl.
Acad. Sci. U.S.A. 102, 9673–9678
46. Dosenbach, N.U. et al. (2006) A core system for the implemen-
tation of task sets. Neuron 50, 799–812
47. Seeley, W.W. et al. (2007) Dissociable intrinsic connectivity net-
works for salience processing and executive control. J. Neurosci.
27, 2349–2356
48. Dosenbach, N.U. et al. (2007) Distinct brain networks for adap-
tive and stable task control in humans. Proc. Natl. Acad. Sci. U.S.
A. 104, 11073–11078
49. Duncan, J. et al. (2000) A neural basis for general intelligence.
Science 289, 457–460
50. Lee, K.H. et al. (2006) Neural correlates of superior intelligence:
stronger recruitment of posterior parietal cortex. Neuroimage 29,
578–586
51. Menon, V. (2011) Large-scale brain networks and psychopa-
thology: a unifying triple network model. Trends Cogn. Sci. 15,
483–506
52. Yarkoni, T. et al. (2011) Large-scale automated synthesis of
human functional neuroimaging data. Nat. Methods 8, 665–670
53. Morris, S.E. and Cuthbert, B.N. (2012) Research Domain Criteria:
cognitive systems, neural circuits, and dimensions of behavior.
Dialogues Clin. Neurosci. 14, 29–37
54. Kouneiher, F. et al. (2009) Motivation and cognitive control in the
human prefrontal cortex. Nat. Neurosci. 12, 939–945
55. Koechlin, E. et al. (2000) Dissociating the role of the medial and
lateral anterior prefrontal cortex in human planning. Proc. Natl.
Acad. Sci. U.S.A. 97, 7651–7656
56. Venkatraman, V. et al. (2009) Resolving response, decision, and
strategic control: evidence for a functional topography in dorso-
medial prefrontal cortex. J. Neurosci. 29, 13158–13164
57. Bengtsson, S.L. et al. (2009) The representation of abstract task
rules in the human prefrontal cortex. Cereb. Cortex 19, 1929–1936
58. Veit, R. et al. (2012) Using real-time fMRI to learn voluntary
regulation of the anterior insula in the presence of threat-related
stimuli. Soc. Cogn. Affect. Neurosci. 7, 623–634
59. Cauda, F. et al. (2011) Functional connectivity of the insula in the
resting brain. Neuroimage 55, 8–23
60. Chang, L.J. et al. (2013) Decoding the role of the insula in human
cognition: functional parcellation and large-scale reverse infer-
ence. Cereb. Cortex 23, 739–749
61. Craig, A.D. (2003) Interoception: the sense of the physiological
condition of the body. Curr. Opin. Neurobiol. 13, 500–505
62. Pritchard, T.C. et al. (1999) Taste perception in patients with
insular cortex lesions. Behav. Neurosci. 113, 663–671
63. Downar, J. et al. (2000) A multimodal cortical network for the
detection of changes in the sensory environment. Nat. Neurosci.
3, 277–283
64. Menon, V. and Uddin, L.Q. (2010) Saliency, switching, attention
and control: a network model of insula function. Brain Struct.
Funct. 214, 655–667
65. Wicker, B. et al. (2003) Both of us disgusted in my insula: the
common neural basis of seeing and feeling disgust. Neuron 40,
655–664
66. Liotti, M. et al. (2000) Differential limbic–cortical correlates of
sadness and anxiety in healthy subjects: implications for affective
disorders. Biol. Psychiatry 48, 30–42
67. Koban, L. and Pourtois, G. (2014) Brain systems underlying the
affective and social monitoring of actions: an integrative review.
Neurosci. Biobehav. Rev. 46, 71–84
68. Cho, S.S. et al. (2013) Morphometric correlation of impulsivity in
medial prefrontal cortex. Brain Topogr. 26, 479–487
69. Haggard, P. (2008) Human volition: towards a neuroscience of
will. Nat. Rev. Neurosci. 9, 934–946
70. Denny, B.T. et al. (2012) A meta-analysis of functional neuroim-
aging studies of self- and other judgments reveals a spatial
gradient for mentalizing in medial prefrontal cortex. J. Cogn.
Neurosci. 24, 1742–1752
71. Wager, T.D. et al. (2008) Prefrontal-subcortical pathways
mediating successful emotion regulation. Neuron 59,
1037–1050
72. Klein, T.A. et al. (2007) Neural correlates of error awareness.
Neuroimage 34, 1774–1781
73. Singer, T. et al. (2004) Empathy for pain involves the affective but
not sensory components of pain. Science 303, 1157–1162
74. Cacioppo, S. et al. (2013) A quantitative meta-analysis of func-
tional imaging studies of social rejection. Sci. Rep. 3, 2027
75. Taren, A.A. et al. (2011) A parallel functional topography between
medial and lateral prefrontal cortex: evidence and implications for
cognitive control. J. Neurosci. 31, 5026–5031
76. Power, J.D. et al. (2013) Evidence for hubs in human functional
brain networks. Neuron 79, 798–813
77. Bullmore, E. and Sporns, O. (2009) Complex brain networks:
graph theoretical analysis of structural and functional systems.
Nat. Rev. Neurosci. 10, 186–198
78. Power, J.D. et al. (2011) Functional network organization of the
human brain. Neuron 72, 665–678
79. Sridharan, D. et al. (2008) A critical role for the right fronto-
insular cortex in switching between central-executive and
default-mode networks. Proc. Natl. Acad. Sci. U.S.A. 105,
12569–12574
80. Manoliu, A. et al. (2013) Insular dysfunction within the salience
network is associated with severity of symptoms and aberrant
inter-network connectivity in major depressive disorder. Front.
Hum. Neurosci. 7, 930
81. Lei, D. et al. (2015) Disrupted functional brain connectome in
patients with posttraumatic stress disorder. Radiology 276, 818–
827
82. Fitzgerald, K.D. et al. (2010) Altered function and connectivity of
the medial frontal cortex in pediatric obsessive-compulsive dis-
order. Biol. Psychiatry 68, 1039–1047
83. Warren, D.E. et al. (2014) Network measures predict neuropsy-
chological outcome after brain injury. Proc. Natl. Acad. Sci. U.S.
A. 111, 14247–14252
84. Deng, Z.D. et al. (2011) Electric field strength and focality in
electroconvulsive therapy and magnetic seizure therapy: a finite
element simulation study. J. Neural Eng. 8, 016007
85. Nahas, Z. et al. (2013) A feasibility study of a new method for
electrically producing seizures in man: focal electrically adminis-
tered seizure therapy [FEAST]. Brain Stimul. 6, 403–408
86. Deng, Z.D. et al. (2013) Controlling stimulation strength and
focality in electroconvulsive therapy via current amplitude and
electrode size and spacing: comparison with magnetic seizure
therapy. J. ECT 29, 325–335
87. Downar, J. and Daskalakis, Z.J. (2013) New targets for rTMS in
depression: a review of convergent evidence. Brain Stimul. 6,
231–240
88. Berlim, M.T. et al. (2014) Response, remission and drop-out
rates following high-frequency repetitive transcranial magnetic
stimulation (rTMS) for treating major depression: a systematic
review and meta-analysis of randomized, double-blind and
sham-controlled trials. Psychol. Med. 44, 225–239
89. Lam, R.W. et al. (2008) Repetitive transcranial magnetic stimula-
tion for treatment-resistant depression: a systematic review and
metaanalysis. Can. J. Psychiatry 53, 621–631
90. Berlim, M.T. and Van Den Eynde, F. (2014) Repetitive transcranial
magnetic stimulation over the dorsolateral prefrontal cortex for
treating posttraumatic stress disorder: an exploratory meta-anal-
ysis of randomized, double-blind and sham-controlled trials.
Can. J. Psychiatry 59, 487–496
91. Walpoth, M. et al. (2008) Repetitive transcranial magnetic stimu-
lation in bulimia nervosa: preliminary results of a single-centre,
randomised, double-blind, sham-controlled trial in female out-
patients. Psychother. Psychosom. 77, 57–60
92. Mansur, C.G. et al. (2011) Placebo effect after prefrontal mag-
netic stimulation in the treatment of resistant obsessive-compul-
sive disorder: a randomized controlled trial. Int. J.
Neuropsychopharmacol. 14, 1389–1397
93. Berlim, M.T. et al. (2013) Repetitive transcranial magnetic stimu-
lation (rTMS) for obsessive-compulsive disorder (OCD): an
exploratory meta-analysis of randomized and sham-controlled
trials. J. Psychiatr. Res. 47, 999–1006
94. Deng, Z.D. et al. (2013) Electric field depth-focality tradeoff in
transcranial magnetic stimulation: simulation comparison of 50
coil designs. Brain Stimul. 6, 1–13
95. Deng, Z.D. et al. (2014) Coil design considerations for deep trans-
cranial magnetic stimulation. Clin. Neurophysiol. 125, 1202–1212
96. Levkovitz, Y. et al. (2009) Deep transcranial magnetic stimu-
lation over the prefrontal cortex: evaluation of antidepressant
and cognitive effects in depressive patients. Brain Stimul. 2,
188–200
97. Dinur-Klein, L. et al. (2014) Smoking cessation induced by deep
repetitive transcranial magnetic stimulation of the prefrontal and
insular cortices: a prospective, randomized controlled trial. Biol.
Psychiatry 76, 742–749
98. Terao, Y. et al. (2000) Predominant activation of I1-waves from
the leg motor area by transcranial magnetic stimulation. Brain
Res. 859, 137–146
99. Hayward, G. et al. (2007) Exploring the physiological effects of
double-cone coil TMS over the medial frontal cortex on the
anterior cingulate cortex: an H2(15)O PET study. Eur. J. Neuro-
sci. 25, 2224–2233
100. Hayward, G. et al. (2004) The role of the anterior cingulate
cortex in the counting Stroop task. Exp. Brain Res. 154,
355–358
101. Cho, S.S. et al. (2015) Investing in the future: stimulation of the
medial prefrontal cortex reduces discounting of delayed rewards.
Neuropsychopharmacology 40, 546–553
102. Kreuzer, P.M. et al. (2015) The ACDC pilot trial: targeting the
anterior cingulate by double cone coil rTMS for the treatment of
depression. Brain Stimul. 8, 240–246
103. Downar, J. et al. (2014) Anhedonia and reward-circuit connec-
tivity distinguish nonresponders from responders to dorsomedial
prefrontal repetitive transcranial magnetic stimulation in major
depression. Biol. Psychiatry 76, 176–185
104. Mantovani, A. et al. (2010) Randomized sham-controlled trial of
repetitive transcranial magnetic stimulation in treatment-resistant
obsessive-compulsive disorder. Int. J. Neuropsychopharmacol.
13, 217–227
Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 119
105. De Ridder, D. et al. (2011) Transient alcohol craving suppression
by rTMS of dorsal anterior cingulate: an fMRI and LORETA EEG
study. Neurosci. Lett. 496, 5–10
106. Enticott, P.G. et al. (2014) A double-blind, randomized trial of
deep repetitive transcranial magnetic stimulation (rTMS) for
autism spectrum disorder. Brain Stimul. 7, 206–211
107. Downar, J. et al. (2012) Unanticipated rapid remission of refrac-
tory bulimia nervosa, during high-dose repetitive transcranial
magnetic stimulation of the dorsomedial prefrontal cortex: a case
report. Front. Psychiatry 3, 30
108. Isserles, M. et al. (2013) Effectiveness of deep transcranial magnetic
stimulation combined with a brief exposure procedure in post-
traumatic stress disorder–a pilot study. Brain Stimul. 6, 377–383
109. Ciampi de Andrade, D. et al. (2012) Into the island: a new
technique of non-invasive cortical stimulation of the insula. Clin.
Neurophysiol. 42, 363–368
110. Gratton, C. et al. (2014) Perfusion MRI indexes variability in the
functional brain effects of theta-burst transcranial magnetic stim-
ulation. PLoS ONE 9, e101430
111. Gratton, C. et al. (2013) The effect of theta-burst TMS on cogni-
tive control networks measured with resting state fMRI. Front.
Syst. Neurosci. 7, 124
112. Jeffery, D.T. et al. (2007) Effects of transcranial direct current
stimulation on the excitability of the leg motor cortex. Exp. Brain
Res. 182, 281–287
113. Hsu, T.Y. et al. (2011) Modulating inhibitory control with direct
current stimulation of the superior medial frontal cortex. Neuro-
image 56, 2249–2257
114. Sellaro, R. et al. (2015) Reducing prejudice through brain stimu-
lation. Brain Stimul. 8, 891–897
115. Sadleir, R.J. et al. (2012) Target optimization in transcranial direct
current stimulation. Front. Psychiatry 3, 90
120 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2
116. Edwards, D. et al. (2013) Physiological and modeling evi-
dence for focal transcranial electrical brain stimulation in
humans: a basis for high-definition tDCS. Neuroimage 74,
266–275
117. D’Urso, G. et al. (2015) Polarity-dependent effects of transcranial
direct current stimulation in obsessive-compulsive disorder. Neu-
rocase 14, 1–5
118. Hajcak, G. et al. (2010) Dorsolateral prefrontal cortex stimu-
lation modulates electrocortical measures of visual attention:
evidence from direct bilateral epidural cortical stimulation in
treatment-resistant mood disorder. Neuroscience 170,
281–288
119. Spielmans, G.I. (2012) Unimpressive efficacy and unclear
safety assessment of epidural cortical stimulation for refractory
major depressive disorder. Neurosurgery 70, E268–E269 author
reply E269
120. Pathak, Y. et al. (2013) The role of electrode location and stimu-
lation polarity in patient response to cortical stimulation for major
depressive disorder. Brain Stimul. 6, 254–260
121. Boertien, T. et al. (2011) Functional imaging of subthalamic
nucleus deep brain stimulation in Parkinson's disease. Mov.
Disord. 26, 1835–1843
122. Barr, M.S. et al. (2013) Can repetitive magnetic stimulation
improve cognition in schizophrenia? Pilot data from a random-
ized controlled trial. Biol. Psychiatry 73, 510–517
123. Brunoni, A.R. et al. (2013) The sertraline vs. electrical current
therapy for treating depression clinical study: results from a
factorial, randomized, controlled trial. JAMA Psychiatry 70,
383–391
124. Loo, C.K. et al. (2012) Transcranial direct current stimulation for
depression: 3-week, randomised, sham-controlled trial. Br. J.
Psychiatry 200, 52–59