Published in Volume
119, Issue 4
(April 1, 2009)J Clin Invest.
Copyright © 2009, American Society for Clinical
Targeted electrode-based modulation of neural circuits for
Department of Psychiatry and Department of Neurology, Emory University
School of Medicine, Atlanta, Georgia, USA.
Address correspondence to: Helen Mayberg, Emory University, Department of
Psychiatry, 101 Woodruff Circle, WMB 4313, Atlanta, Georgia 30322, USA. Phone: (404)
727-6740; Fax: (404) 727-6743; E-mail: firstname.lastname@example.org.
Published April 1, 2009
During the last 20 years of neuroscience research, we have witnessed a fundamental
shift in the conceptualization of psychiatric disorders, with the dominant
psychological and neurochemical theories of the past now complemented by a growing
emphasis on developmental, genetic, molecular, and brain circuit models. Facilitating
this evolving paradigm shift has been the growing contribution of functional
neuroimaging, which provides a versatile platform to characterize brain circuit
dysfunction underlying specific syndromes as well as changes associated with their
successful treatment. Discussed here are converging imaging findings that established
a rationale for testing a targeted neuromodulation strategy, deep brain stimulation,
for treatment-resistant major depression.
Depression affects at least 10% of the world population and is a leading cause of worldwide
disability (1). Major depressive disorder (MDD) is
clinically defined as a multidimensional syndrome, involving disruption of mood, cognition,
sensorimotor functions, and homeostatic/drive functions (including those that control
sleep, appetite, and libido). While depression can be treated in many cases with either
medication or an evidence-based psychotherapy, remission rates in controlled trials using
currently available treatments rarely exceed 30%, and relapse is the rule rather than the
exception (2). For many patients, combinations of
multiple medications and electroconvulsive therapy (ECT) are required. For those who remain
severely depressed despite these aggressive approaches, new strategies are needed (3). This Review describes the development and testing of
a new interventional strategy, deep brain stimulation (DBS), directed at this group of
patients who are otherwise resistant to treatment.
Critical to the development of DBS as a new treatment for intractable MDD has been the
evolving understanding of the brain circuits that mediate normal and abnormal mood states
and the systematic characterization of changes in these circuits that accompany successful
and unsuccessful response to various treatments, measured using functional imaging
(reviewed in refs. 4–8). Based on brain circuit models of depression derived
primarily from PET scan measures of glucose metabolism and blood flow, the first region of
the brain to be targeted with DBS in patients with treatment-resistant depression (TRD) was
the subcallosal cingulate (SCC), the ventral-most segment of the cingulate gyrus (Figure
1). As detailed in the following sections, this
region of the brain was considered a critical node within a putative mood regulatory
circuit, as it showed the most consistent changes in metabolism and blood flow with
clinical recovery, using various well-established antidepressant interventions (9). As such, it was hypothesized that direct stimulation
of the SCC and adjacent white matter would produce modulatory or normalizing changes within
this otherwise unresponsive mood circuit, resulting in antidepressant effects (10). The first clinical results of DBS of the SCC were
encouraging, leading to the initiation of additional clinical studies (11, 12). This
initial clinical success further motivated continued refinement of this depression circuit
model, with goals to optimize surgical targeting, define biomarkers that might effectively
guide patient selection, and increase understanding of DBS mechanisms of action.
Anatomical locations of key brain regions implicated in MDD. Midline, sagittal view of the brain, with subsections of the anterior cingulate
cortex highlighted by coloring. A-Hc, amygdala hippocampus; BS, brainstem; C.
callosum, corpus callosum; dMF9, dorso-medial frontal cortex BA9; MCC24,
mid-cingulate cortex BA24 (blue); OF11, orbital frontal cortex BA11; pACC24,
pregenual anterior cingulate cortex BA24 (yellow); PCC23, posterior cingulate
cortex BA23; SCC24/25, SCC BA24 and BA25 (red); vMF10, ventro-medial frontal
Neurological depression circuit model: theoretical framework
The development and evolution of a circuit model to explain the many regional brain
abnormalities reported in numerous imaging studies of depressed patients is in keeping
with the classical neurological tradition of symptom localization, using lesion-deficit
correlational analyses. Using this strategy, construction of a depression circuit first
assumes that depression is unlikely to be the result of injury or dysfunction of a
single brain region but rather a system-wide disorder, in which interruption at specific
sites or “nodes” within a defined functional circuit or network
linking many brain regions can result in stereotypic depressive symptoms (9, 13). It is
further hypothesized that a major depressive episode reflects the failure to
appropriately regulate activity in this multi-region circuit, under circumstances of
cognitive, emotional, or somatic stress (6). From
this perspective, a given scan pattern is a readout of both the inciting insult or
provocation and the resulting compensatory processes, influenced by various contributing
factors, including heredity, temperament, early-life experiences, and previous
depressive episodes (14–17). As such, variations in brain scan patterns
among patients would be expected, thus defining distinct depression phenotypes with
potentially predictable responses to different antidepressant treatments (Figure 2). While this premise is purely speculative,
published findings that support this hypothesis are reviewed below, highlighting
disease-, state-, and treatment-specific effects facilitated by pharmacotherapy,
cognitive behavioral therapy (CBT), and DBS.
Theoretical time course of mood circuit changes during a depressive episode. Functional neuroimaging abnormalities are viewed as the net effect of a triggering
event and subsequent intrinsic adaptive or maladaptive responses, in other words,
failure to self-correct. The nature of these compensatory changes is considered
critical for understanding clinical symptom heterogeneity and clinical subtypes of
MDD, providing a potential future framework for the development of brain-based
algorithms for treatment selection based on distinct circuit patterns or brain
phenotypes (indicated here as scan types i–iv). By example, scan type
i, characterized by maladaptive overcorrection of the circuit, might be optimally
treated with CBT. In contrast, failure to initiate or sustain any adaptive
response, as defined here by scan type iv, might require ECT or DBS.
Defining affected brain regions
Structural imaging studies. Structure-function correlations performed in patients developing a depression
syndrome, in the context of either acquired brain lesions (18, 19) or
neurodegenerative disorders (reviewed in ref. 13), provided an early anatomical perspective, consistently identifying clear
abnormalities in both the frontal cortex and basal ganglia. Studies in individuals
with primary depression, on the other hand, have indicated that structural
abnormalities are more subtle, generally necessitating more advanced image
acquisition and analytic approaches. Such studies have identified volume changes in
the amygdala, hippocampus, and anterior cingulate, ventromedial, and prefrontal
cortices but with considerable variability (8,
20–22) (Figure 1). Postmortem
studies further identify glial cell loss in primary depression but the findings are
also not localized to any one brain region (23–26). Unlike
depression following a selective brain lesion or injury, in which causal inferences
can be reasonably asserted, volume changes reported in MDD appear to be more complex,
particularly since acute lesions of the amygdala, hippocampus, cingulate cortex, and
ventromedial frontal cortex do not precipitate depressive symptoms or syndromes
(18, 19). Furthermore, genetic risk factors and environmental stress may further
contribute to some of these reported structural abnormalities, independent of the
presence of depression (27–29). Nonetheless, comparative cytoarchitectural
and anatomical connectivity studies generally confirm the critical involvement of
these regions, most consistently the frontal cortex, cingulate cortex, basal ganglia,
amygdala, and hippocampus in animal models of depression and associated emotional
behaviors (30–34), supporting the hypothesis that even subtle
disruption of pathways linking these regions in humans can result in disturbances in
emotion regulation typical of MDD, namely negative mood coupled with sustained
changes in motivation, motor performance, cognition, and circadian functions. Studies
of regional brain dysfunction with functional imaging further support this
Functional imaging studies.
There are now a variety of imaging methods (PET, single photon emission computed
tomography, functional MRI [fMRI], magnetic resonance spectroscopy, EEG,
magnetoencephalography, and optical imaging) capable of quantifying a wide range of
physiological parameters relevant to the study of major depression. In this brief
overview, resting-state blood flow and glucose metabolism measures using PET are
highlighted, as they make up the bulk of the published studies. Functional imaging
studies of primary depression (reviewed in refs. 6–8) commonly report
frontal cortex and cingulate abnormalities, a pattern also seen in neurological
depressions (13). Other limbic-paralimbic
(amygdala, anterior temporal, and insula) and subcortical (basal ganglia and thalamus)
abnormalities have also been identified, but the findings are more variable. Across
studies, the most robust and best-replicated finding is that of decreased prefrontal
cortex function, although normal frontal activity and frontal hyperactivity have also
been reported (35, 36). Localization of abnormalities within the frontal lobe includes
regions of the dorsolateral and ventral-lateral prefrontal cortex (specifically Brodmann
area 9 [BA9], BA46, BA10, and BA47) as well as orbital frontal and ventromedial frontal
cortices (specifically BA11, BA32, and BA10). Findings are generally bilateral, although
asymmetries have been described. Cingulate cortex changes (increases or decreases in
activity) are also commonly seen and consistently involve anterior sectors (in
particular, BA24 and BA25).
Potential sources of scan variability
While there are clearly a highly reproducible set of functional and structural findings
across studies, not all patients show the same pattern. Differences among patient
subgroups (e.g., among those with familial, bipolar, unipolar, neurological, or early
trauma depression) as well as heterogeneous expression of clinical symptoms, such as
illness severity, cognitive impairment, anxiety, anhedonia, mood reactivity, and
psychomotor slowing, are thought to contribute to the described variance, but there is
not yet a consensus. The best-replicated behavioral correlate of a resting-state
abnormality in depression is that of an inverse relationship between the activity of the
prefrontal cortex and the severity of depression. Low prefrontal cortex activity has
also been correlated with slowed reaction times and impairment in cognitive functions
such as attention and working memory; low parietal and parahippocampus activity has been
associated with anxiety; medial frontal and cingulate hypoactivity has been associated
with impairments in performance in error detection and set-shifting tasks; ventral
striatum/nucleus accumbens hypoactivity has been associated with anhedonia; and amygdala
hyperactivity has been associated with cortisol status (37–43). A more complex
ventral-dorsal segregation of frontal lobe functions has also been described, with
anxiety/tension positively correlated with ventral prefrontal cortex activity and
psychomotor and cognitive slowing negatively correlated with dorsolateral prefrontal
cortex activity (40). The prefrontal cortex and
amygdala hyperactivity seen in patients with a more ruminative/anxious clinical
presentation is also consistent with findings described in individuals with primary
anxiety and obsessional disorders (39),
memory-evoked anxiety and fear in healthy subjects and response to the testing
environment due to novelty or state anxiety as well as gene-mediated variability in
emotional reactivity (44). Even with these
considerations, the presence of clinical symptom variability within a given patient
cohort does not appear to fully explain the consistent inconsistencies
in the published imaging literature (6, 17).
One can alternatively consider variable patterns from a systems perspective, as outlined
in Figure 2, in which dysregulated circuit activity
identified in the baseline depressed state is seen to reflect both foci of primary
dysfunction as well as sites of attempted (or failed) adaptation. Such a model would
theoretically accommodate the reported variability among published depression cohorts,
the recognized heterogeneity of depressive symptoms, and purported etiologic risk
factors (15, 16) and is also in keeping with conceptual models of sustained allostatic load
(45). Hypothetically, in the setting of
sustained overactivity of the regulatory circuit (whatever the cause), an exaggerated or
hypersensitive compensatory response may result in an agitated, mood-reactive,
ruminative depressive state in one patient, whereas failure to initiate or maintain an
adequate compensatory response may lead to anergy, psychomotor retardation, apathy, and
mood nonreactivity in a second patient with equally severe depression. In this context,
net circuit activity resulting in a sustained but only partially compensated state would
probably respond equally well to either pharmacological or psychological treatments,
consistent with empirical clinical experience as well as randomized controlled studies
(46). On the other hand, more extreme states
of adaptive changes in the circuit (either overactive or underactive) would require more
specific treatments (i.e., CBT or interpersonal psychotherapy when overactive [ref.
47] and medication augmentation or ECT, vagus
nerve stimulation, or repetitive transcranial magnetic stimulation when underactive
[refs. 2, 48–51]), with failure of
the circuit to initiate an adaptive response defining patients with TRD and a need for
more aggressive interventions such as DBS (11,
12, 52–54). Such hypotheses lay the foundation for a related goal, namely
to define a specific brain circuit signature that could eventually provide a therapeutic
road map for optimal treatment selection in individual depressed patients —
if baseline variability and associated change patterns with different treatment
interventions can be fully characterized (6).
While important insights have been made using group-based analyses, as described in the
following sections, practically speaking, fMRI may prove a more agile technology to
achieve this goal, since circuit patterns, commonly termed “functional
connectivity”, are testable in individual subjects. Such strategies
emphasize not merely the absolute state of regional activity, but rather, the way in
which activities in different locales influence one another as indexed using
region-region correlations or covariances (55–57).
Scan variability as a biomarker of response likelihood
In an attempt to define a neural signature that could indicate the treatment most likely
to be effective in a given patient, several groups have already identified pretreatment
scan patterns that differentiate response-specific subtypes to various treatments (58–67). Retrospective analyses of resting-state PET studies and, more recently,
fMRI studies using behavioral tasks have consistently reported that increased
pretreatment activity in the pregenual anterior cingulate cortex (pACC; BA24)
distinguishes responders to several different antidepressant interventions from
nonresponders (58, 59, 63, 67). However, prospective testing has not been done to indicate
whether this pattern differentially predicts response to a specific treatment class.
Using similar methods, SCC (specifically BA25) hyperactivity has been shown to predict
response to sleep deprivation (64) and
cingulotomy (66) in patients who had previously
not responded to medication treatment, identifying a potential marker of treatment
resistance (11, 62, 68). Systematic characterization
of these potential predictive patterns alone or in combination with genetic markers
(69) has important therapeutic implications in
light of increasing evidence that the presence of residual symptoms places patients at
increased risk for future relapse or recurrence (48).
Brain targets of antidepressant treatments
As seen in studies of the baseline depressed state, PET measures of regional cerebral
glucose metabolism and blood flow, and, more recently, resting-state and task fMRI have
also proven to be sensitive indices of changing brain function following various
treatments. Changes in cortical, limbic-paralimbic, and subcortical regions have been
described following treatments as diverse as medication, psychotherapy, sleep
deprivation, ECT, repetitive transcranial magnetic stimulation, vagus nerve stimulation,
ablative surgery, and DBS (6, 7, 10–12, 62, 70–78). While
normalization of frontal abnormalities is the best-replicated finding, other regional
effects are reported with variable patterns with different treatments. The nature of the
specific imaging strategy and the behavior provocation or task used to test the effect
of treatment contribute to variability. Despite this caveat, modality-specific effects
are consistent with the hypothesis that different interventions modulate specific
regional targets, resulting in a variety of complementary, adaptive chemical, and
molecular changes sufficient to reestablish a euthymic, remitted state.
Medication. Across studies of chronic antidepressant treatment using commonly prescribed
medications, prefrontal cortical changes are the most consistently reported, with
normalization of frontal cortex overactivity and underactivity both described (62, 70–72). Additionally,
changes are also seen in limbic and subcortical regions, including the subgenual
cingulate, amygdala, hippocampus, posterior cingulate cortex, and insula, with
decreased activity most commonly observed (70,
71, 74–77). The time course
of these medication effects and differences between responders and nonresponders have
provided additional localizing clues as to critical brain changes
mediating depression remission. In one such experiment (70), responders and nonresponders to the selective serotonin
reuptake inhibitor (SSRI) fluoxetine were differentiated by their pattern of glucose
metabolism observed six weeks after the initiation of therapy, with clinical
improvement associated with limbic-paralimbic and striatal decreases and dorsal
cortical increase in glucose metabolism. Failed response was associated with
persistence of the pattern of glucose metabolism observed one week after the
initiation of therapy (when the same pattern was seen in both groups) and absence of
either SCC (specifically BA25) or prefrontal cortex changes. This combination of
reciprocal dorsal cortical and ventral limbic changes appears to be a common pattern
in individuals that respond to treatment with SSRIs (72), placebo medication (79), and
combination serotonin-norepinephrine reuptake inhibitors (SNRIs) (62). The change in the glucose metabolism pattern
in only those patients who showed clinical improvement suggests a process of neural
plasticity or adaptation in specific brain regions with chronic treatment. These
responder-nonresponder differences are also consistent with the time course and
location of changes identified in animal studies of antidepressant medications, which
emphasize early brainstem and hippocampal changes and late cortical effects,
involving presynaptic autoregulatory desensitization, up- and downregulation of
multiple postsynaptic receptor sites, and receptor-mediated second messenger and
neurotrophic intracellular signaling effects (80, 81).
In contrast to pharmacological treatments, CBT is thought to retrain brain activity by
modifying attention and memory functions involved in the mediation of
depression-relevant explicit cognitions, affective bias, and maladaptive information
processing, all of which are putatively localized to orbital, medial frontal,
prefrontal, and anterior cingulate regions of the cortex (82, 83). Imaging studies
examining brain changes following interpersonal psychotherapy and CBT report substantial
regional effects — most prominently decreased glucose metabolism and blood
flow in the prefrontal cortex (62, 71, 84, 85), but with differential non–frontal
cortex changes depending on the specific therapeutic intervention employed. For example,
using CBT, remission was associated with not only prefrontal cortex changes but also
decreased metabolism in posterior cingulate, dorsomedial frontal, and orbital frontal
cortices as well as increased metabolism in anterior mid-cingulate cortex and
parahippocampal regions (71). This CBT-specific
change pattern was generally replicated in a follow-up, randomized study comparing
treatment with CBT and the SNRI venlafaxine (62).
Interestingly, this second study identified both a common decrease in dorsomedial
frontal cortical activity with both treatments as well as reciprocal changes in
subgenual cingulate cortex activity (increased with CBT, decreased, as seen previously,
with medication), further suggesting a critical role for this region in mediating
remission from depression across treatments.
Critical role for the SCC
Among the series of treatment studies surveyed, the involvement of the SCC is especially
prominent (Figure 3, A–E). Not only do
changes in this region appear critical for antidepressant response to active and placebo
pharmacotherapy, ECT, and CBT (62, 70, 73, 79), but functional hyperactivity of this region
best characterizes more treatment-resistant patients (Figure 3, F–I) (11, 62, 65, 66, 68).
Furthermore, anatomical changes on structural MRI scans as well as postmortem
identification of glial cell abnormalities (21,
23) are reported in depressed patient samples.
In addition, structural and functional variability in this region has been linked to a
normal polymorphism in the serotonin transporter, an emerging risk factor for depression
(28). These converging anatomical findings
complement a large functional imaging literature, linking the SCC to the regulation of
negative emotional states, as illustrated by increased activity in this region with the
provocation of sad mood, using either autobiographical memory (Figure 3J) (10) or a
pharmacological challenge, such as tryptophan depletion (86), as well as passive exposure to sad, negative, or unpleasant pictures and
words (61, 87).
Converging evidence implicating the SCC region in MDD. (A–E) Common pattern of changes in glucose
metabolism or blood flow in the SCC with antidepressant response to various
interventions. Images demonstrate group change patterns relative to the baseline
depressed state for each treatment: (A) metabolic decreases with the
selective serotonin reuptake inhibitor (SSRI) fluoxetine; (B)
metabolic decreases with a placebo pill; (C) metabolic decreases with
the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine;
(D) blood flow decreases with ECT; and (E) metabolic
increases with CBT. (F–J) Images demonstrate
elevated resting-state SCC25 activity in various groups of patients with TRD:
(F) metabolic increases in CBT and venlafaxine (V) nonresponders
(NRs) relative to both healthy subjects and similarly depressed patients who
responded to either treatment; (G) resting-state fMRI increases in
pharmacotherapy (Med) nonresponders relative to healthy controls; (H)
glucose metabolic increases in patients with TRD who later responded to
cingulotomy (CGT) relative to those that failed to respond; (I) blood
flow increases in patients with TRD, enrolled in a DBS treatment trial relative to
healthy controls; (J) SCC blood flow increases with induction of
transient sadness induced by recollection of a personal sad memory in healthy
subjects, a pattern similar to that seen in patients with TRD. Red indicates
increased activity (white arrows) and blue indicates decreased activity (black
arrows). Images are courtesy of Mitch Nobler (D), Michael Greicius
(G), and Darin Dougherty (H). Panels A
and J are generated from data published in American Journal
of Psychiatry (10). Panels
B and D are adapted with permission from
American Journal of Psychiatry (refs. 79 and 73,
respectively). Panel I is adapted with permission from
Neuron (11). Panels
C and E are adapted with permission from
American Journal of Psychiatry (62). Panel F is generated from data published in
American Journal of Psychiatry (62). Panel G is adapted with permission from
Biological Psychiatry (68). Panel H is adapted with permission from Journal
of Neurosurgery (66).
The foundation for a more specific role of the SCC in the autonomic and circadian
aspects of emotion regulation, as occurs with both stress and depression, including
alterations in sleep, appetite, libido, and endocrine functioning, is also suggested by
the predominant afferent and efferent connections of the SCC to the insula, brainstem,
and hypothalamus (34, 88–91).
Reciprocal pathways linking SCC BA25 to orbitofrontal, medial frontal, and dorsal
prefrontal cortices, the anterior and posterior cingulate cortices, and to the amygdala,
hippocampus, and nucleus accumbens further identify plausible pathways by which
interceptive and homeostatic processes might influence aspects of learning, memory,
reward, and reinforcement (34, 91–94), which are core behaviors impaired in depressed patients. Interestingly,
these various connections show considerable overlap with the pattern of regional changes
seen with both CBT and pharmacotherapy treatment described above, providing strong
evidence to pursue strategies that might effectively alter SCC
connectivity in individuals with TRD, rather than focusing on merely
correcting absolute activity in SCC in isolation.
Testing the model: targeting the SCC with DBS
The repeated observations of increased activity in the SCC in studies of acute negative
affective states (sadness), cellular abnormalities in this region in depressed patients
postmortem, and predictable decreases in activity with a variety of pharmacological and
somatic antidepressant treatments provided the critical foundation to test the use of
direct modulation of SCC (BA25), using high frequency DBS as a novel treatment strategy
for individuals with otherwise treatment-resistant MDD. Based on the well-established
evidence in Parkinson disease (PD), demonstrating that chronic, high frequency DBS in
pathologically overactive motor circuits produces profound clinical benefits (95), it was hypothesized that focal stimulation of
the SCC and adjacent white matter would not only reduce chronically elevated SCC
activity but would also normalize aberrant activity throughout the depression circuit,
with resulting clinical benefit.
In a proof-of-principle study, six patients with refractory MDD who had failed to
respond to multiple medications as well as psychotherapy and ECT were implanted with two
DBS electrodes (one in each hemisphere) under local anesthesia, using MRI guidance and
stereotaxic surgical procedures routinely used in the treatment of PD. A protocol
similar to that used in evaluating stimulation thresholds for efficacy and adverse
effects for PD was also adopted for use in the patients with TRD, with stimulation
settings programmed via an implanted pulse generator inserted in the subcutaneous chest
wall. Chronic bilateral stimulation (pulse width = 90 μs; frequency = 130
Hz; voltage ≅ 4 V) of the white matter tracts adjacent
to the SCC produced a sustained remission of depressive symptoms in four of the six
patients in the pilot study (11). Consistent with
the circuit hypothesis stated above, clinical antidepressant effects were associated
with a marked reduction in SCC blood flow as well as changes in downstream limbic and
cortical sites (decreased activity in the hypothalamus, ventral striatum, and orbital
and medial frontal cortices and increased activity in the dorsolateral prefrontal,
parietal, mid-cingulate, and posterior cingulate cortices) measured using PET (Figure
4). While it is not yet clear which of these
remote changes is most critical to the sustained antidepressant effects, the clinical
and imaging findings have now been replicated in an additional 14 patients, with an
overall six-month response rate of 60% and with sustained response exceeding one year
(12). Placebo-controlled trials extending
these first studies are now underway, examining both clinical efficacy and mechanisms as
well as potential clinical or imaging biomarkers that might identify the patients with
TRD most likely to benefit from this intervention.
Selective targeting of the depression circuit with DBS in patients with TRD. (A) Preoperative (pre-op) MRI demonstrating the intended anatomical
location for the DBS electrode within the SCC white matter. The four individual
contacts on the electrode (numbered 1–4) can be independently
stimulated using a programmable implanted pulse generator. (B)
Preoperative blood flow PET scan demonstrating baseline hyperactivity of the SCC
in the TRD study group (n = 6) relative to healthy controls.
(C) The postoperative (post-op) MRI with the electrodes in place
within the SCC white matter. (D) Six-month blood flow change relative
to preoperative baseline associated with chronic DBS of the optimal SCC contact in
four DBS responders. Red indicates increased blood flow and blue indicates
decreased blood flow. hth, hypothalamus; MCC, mid-cingulate cortex; sn, substantia
nigra; vCd, ventral caudate (adapted with permission from Neuron
In addition to the apparent sustained rate of clinical recovery in the first
experimental group treated with DBS was the intriguing observation that the precise
target of stimulation was extremely critical, with variable clinical effects seen with
stimulation of adjacent contacts separated by mere millimeters along the same electrode
(Figure 4, left panel). Similarly, with patients
awake in the operating room, immediate behavioral effects were often seen with acute
stimulation of some but not all the individual contacts. Such acute effects often
predicted future sustained antidepressant response with chronic stimulation at the same
contact. Among spontaneous patient reports, “a lifting of the
void” or resolution of dread were most common, with heightened interest and
a sense of “connectedness” as well as increased motor speed,
increased volume and rate of spontaneous speech, and improved prosody also observed
(11). These provocative findings have not been
systematically characterized either clinically or with appropriate imaging strategies
but are the focus of current experiments. New studies have also implemented diffusion
imaging and probabilistic tractography analyses and are now examining the specific white
matter tracts affected by focal stimulation of adjacent individual contacts to further
delineate which pathways mediate these potentially critical acute stimulation effects
(96, 97). Such studies combined with real-time electrophysiological recordings in
animals will provide new models that inform on system-level dynamics, mediating the
transition from acute to sustained antidepressant effects at the cellular, local
circuit, and network level.
Unifying depression circuit model
To help summarize converging findings and facilitate future experiments, an expanded
version of a previously proposed and evolving multi-node circuit model of depression
has been constructed from the various studies discussed in the previous sections (Figure
5). Regions within this model are clustered into
four main functional compartments, based on reproducible patterns across various
experiments, and informed by comparative anatomical, electrophysiological, and
tract-tracing experiments in nonhuman primates and rodents (34, 88–94, 98). Such
compartmental groupings aim to accommodate the major defining symptoms of MDD (sustained
mood, motor, cognitive, and circadian dysfunction) and changes in these behaviors
accompanying treatment and recovery. The model further attempts to capture basic
cognitive (exteroceptive) and visceral-motor (interoceptive) processes mediating normal
responses to novel overt and covert emotional stimuli (34, 38, 44, 99–108), recognizing that the complexities and nuances
of brain mechanisms mediating these behaviors are grossly oversimplified by this model.
With this caveat, consistent functional interactions and region-region correlations are
emphasized in the assignment of a particular region to a specific compartment, with
explicit anatomical connections linking individual regions both within and across
compartments critical to the core model construct.
Circuit model of MDD. Regions with known anatomical interconnections that show consistent changes across
converging imaging experiments form the basis of this model. Regions are grouped
into four main compartments, reflecting general behavioral dimensions of MDD and
regional targets of various antidepressant treatments. Regions within a
compartment all have strong anatomical connections to one another. Black arrows
identify cross-compartment anatomical connections. Solid colored arrows identify
putative connections between compartments mediating a specific treatment: green
indicates CBT; blue indicates pharmacotherapy; red indicates SCC DBS. a-ins,
anterior insula; amg, amygdala; dm-Th, dorsomedial thalamus; dp-Hc,
dorsal-posterior hippocampus; mb-vta, midbrain-ventral tegmental area; mF10/9,
medial frontal cortex BA10 and BA9; mOF11, medial orbital frontal cortex BA11;
Par40, parietal cortex BA40; PF46/9, prefrontal cortex BA46 and BA9; PM6, premotor
cortex BA6; va-HC, ventral-anterior hippocampus; vst-cd, ventral
While earlier versions of this model implicated a more limited set of brain regions
what has remained consistent across models are the reciprocal interactions between
ventral limbic (interoceptive) regions and dorsal cortical (exteroceptive) regions as a
hallmark of a negative mood state (increased limbic activity and decreased cortical
activity), occurring either transiently — such as with an acute emotional
provocation — or when sustained, as seen during a major depressive episode.
Similarly, reversal of this pattern (decreased limbic activity and increased cortical
activity) characterizes mood improvement, with depression remission (10, 11).
Medial frontal cortical regions have been assigned a distinct compartment in the model,
as these regions appear most critical to active cognitive control and overt regulation
of emotional and affective state (37, 103–106, 109). Similarly, a set of
subcortical regions, including the amygdala, basal ganglia, and thalamus, which have
been consistently implicated in primary and often covert processing of novel emotional
and nonemotional stimuli (37), have been grouped
together to emphasize their more general role in evaluating salience (107) and in mediating reinforcement, learning, and
habit (38, 44, 108, 110–112).
Ventral (subcallosal SCC BA25), rostral (pACC BA24), and dorsal (supragenual or
mid-cingulate cortex BA24) subregions of the anterior cingulate cortex (also shown in
Figure 1) have been similarly segregated, in
keeping with their differential anatomical connections within and between compartments
(34, 88, 94, 98). Within this framework, synchronized changes within and across
compartments are considered critical for illness remission, regardless of treatment
modality, accommodating the described pharmacotherapy as well as cognitive and surgical
interventions. That said, it is not yet clear if the specific balance between regions or
compartments is differentially sensitive to a particular treatment, as postulated in
Figure 2, but this remains an important focus of
Multicenter, randomized, placebo-controlled trials are ultimately necessary to determine
the clinical efficacy of DBS for TRD, using modulation of the SCC as described here
(11, 12) or modulation of other brain regions currently being testing, including the
anterior limb of the internal capsule, the nucleus accumbens, and the inferior thalamic
peduncle (52–54). That said, complementary research studies in patients
undergoing these procedures offer unique opportunities to examine both disease and
treatment mechanisms from new perspectives. Such studies will optimally benefit from a
flexible research infrastructure that can take best advantage of ongoing advances in
multimodal imaging and computational modeling of complex circuits (109, 113–116) as well as new animal models (30–32, 117–119). As has proven to be the case with DBS for the
treatment of PD (120–124), such platforms facilitate the necessary
translational studies needed to fully characterize DBS effects at the cellular,
molecular, and network levels. It is further expected that continued refinement of
brain-based circuit models for depression and other neuropsychiatric disorders will have
a growing role not only in the development of novel therapies but in defining a new
depression nosology, a critical step toward the eventual use of evidence-based brain
biomarkers to optimize treatment selection in individual patients.
I thank my many colleagues who contributed to these many studies, including Robert
Robinson, Sergio Starkstein, Stephen Brannan, Mario Liotti, Sidney Kennedy, Zindel
Segal, Andres Lozano, Paul Holtzheimer, and Cameron Craddock. Past and current work is
supported by grants from the National Institute of Mental Health (NIMH), Canadian
Institute for Health Research (CIHR), National Alliance for Research on Schizophrenia
and Depression (NARSAD), Dana Foundation, Stanley Medical Research Institute, and the
Conflict of interest: The author consults with Advanced Neuromodulation
Systems (ANS, a division of St. Jude Medical [SJM]) and has intellectual property
rights on a deep brain stimulation technology for treating depression that has been
licensed to ANS/SJM.
Nonstandard abbreviations used: BA, Brodmann area; CBT, cognitive
behavioral therapy; DBS, deep brain stimulation; ECT, electroconvulsive therapy;
fMRI, functional MRI; MDD, major depressive disorder; PD, Parkinson disease; SCC,
subcallosal cingulate; TRD, treatment-resistant depression.
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