Mood disorders cause significant morbidity and mortality, and existing therapies fail 20%–30% of patients. Deep brain stimulation (DBS) is an emerging treatment for refractory mood disorders, but its success depends critically on target selection. DBS focused on known targets within mood-related frontostriatal and limbic circuits has been variably efficacious. Here, we examine the effects of stimulation in orbitofrontal cortex (OFC), a key hub for mood-related circuitry that has not been well characterized as a stimulation target. We studied 25 subjects with epilepsy who were implanted with intracranial electrodes for seizure localization. Baseline depression traits ranged from mild to severe. We serially assayed mood state over several days using a validated questionnaire. Continuous electrocorticography enabled investigation of neurophysiological correlates of mood-state changes. We used implanted electrodes to stimulate OFC and other brain regions while collecting verbal mood reports and questionnaire scores. We found that unilateral stimulation of the lateral OFC produced acute, dose-dependent mood-state improvement in subjects with moderate-to-severe baseline depression. Stimulation suppressed low-frequency power in OFC, mirroring neurophysiological features that were associated with positive mood states during natural mood fluctuation. Stimulation potentiated single-pulse-evoked responses in OFC and modulated activity within distributed structures implicated in mood regulation. Behavioral responses to stimulation did not include hypomania and indicated an acute restoration to non-depressed mood state. Together, these findings indicate that lateral OFC stimulation broadly modulates mood-related circuitry to improve mood state in depressed patients, revealing lateral OFC as a promising new target for therapeutic brain stimulation in mood disorders.

We hypothesized that brain networks involved in emotion processing include regions, like OFC, that represent previously unrecognized stimulation targets for alleviation of neuropsychiatric symptoms. To test this hypothesis, we developed a system for studying mood-related neural activity in subjects with epilepsy who were undergoing intracranial electroencephalography (iEEG) for seizure localization. In addition to direct recording of neural activity, iEEG allows delivery of defined electrical stimulation pulses with high spatiotemporal precision and concurrent measurement of behavioral correlates []. Using serial quantitative mood assessments and continuous iEEG recordings, we investigated the acute effects of OFC stimulation on mood state and characterized corresponding changes in neural activity locally and in distributed brain regions. We found that lateral OFC stimulation acutely improved mood in subjects with baseline depression and that these therapeutic effects correlated with modulation of large-scale brain networks implicated in emotion processing. Our results suggest that lateral OFC stimulation improves mood state at least partly through mechanisms that underlie natural mood variation, and they are consistent with the notion that OFC integrates multiple streams of information relevant to affective cognition.

Residing within prefrontal cortex, the orbitofrontal cortex (OFC) shares reciprocal connections with amygdala, ventral striatum, insula, and cingulate cortex []—areas implicated in emotion regulation []. As such, OFC is anatomically well positioned to regulate mood. Functionally, OFC serves as a nexus for sensory integration and has myriad roles related to emotional experience [], including predicting and evaluating outcomes [], representing reward-driven learning and behavior [], and mediating subjective hedonic experience []. Converging lines of evidence from lesion studies, functional neuroimaging, and intracranial physiology point to a role of OFC in emotion processing []. Clinically depressed individuals have abnormally high levels of activity in OFC as ascertained by functional neuroimaging [], and recovery from depression is associated with decreased OFC activity []. Repetitive transcranial magnetic stimulation (rTMS) of OFC was shown to improve mood in a single-subject case study [] and in a series of patients who otherwise did not respond to rTMS delivered to conventional (non-OFC) targets [], but whether intracranial OFC stimulation can reliably alleviate mood symptoms is not known. Furthermore, OFC is relatively large, and functional distinctions between medial and lateral subregions are known [], raising the possibility that subregions of OFC may play distinct roles in mood regulation []. More generally, it remains poorly understood how direct brain stimulation affects local and network-level neural activity to produce complex emotional responses.

The neural dynamics of reward value and risk coding in the human orbitofrontal cortex.

A modern conception of mood disorders holds that the signs and symptoms of emotional dysregulation are manifestations of abnormal activity within large-scale brain networks []. This view, evolved from earlier hypotheses based on chemical imbalances in the brain, has fueled interest in selective neural network modulation with deep brain stimulation (DBS). Although the potential for precise therapeutic intervention with DBS is promising, its efficacy is sensitive to target selection. In treatment-resistant depression (TRD), for example, well-studied targets for DBS include the subgenual cingulate cortex (SCC) [] and subcortical structures [], but the benefits of DBS in these areas are not clearly established []. A major challenge in this regard relates to the fact that clinical manifestations of mood disorders like TRD are heterogeneous and involve dysfunction in cognitive, affective, and reward systems []. Therefore, brain regions that represent a functional confluence of these systems are attractive targets for therapeutic brain stimulation.

Defining biotypes for depression and anxiety based on large-scale circuit dysfunction: a theoretical review of the evidence and future directions for clinical translation.

Affective states arise from a distributed network of brain regions [], and given the effects of OFC stimulation on cortical excitability, we next examined effects on activity in other sites sampled by intracranial electrodes ( Figure 5 A, example subject). Spectral analysis revealed that OFC stimulation suppressed low-frequency power broadly, with greatest effects seen in the theta frequency band in OFC, insula, and dorsal cingulate ( Figure 5 B). No brain areas had significant increases or decreases in the alpha or beta frequency bands, with the exception of an increase in OFC alpha from stim to post-stim periods ( Figure S5 A; OFC alpha, Z = 2.22, p = 0.03). Following offset of stimulation, low-frequency power showed increases that were proportional to the initial decrease across all studied regions ( Figures 5 B and S5 B). By contrast, medial OFC stimulation was not associated with significant changes in theta power in OFC or other studied regions ( Figure S5 C). Although causality cannot be inferred from our data, taken together, these findings suggest that mood-state improvement observed during lateral OFC stimulation may be mediated through a combination of local and network-level changes in neural activity.

(B) Across all subjects, significant changes in power from pre-stim to stim (white bars) and stim to post-stim (black bars) were found in lateral OFC, insula, and cingulate regions in the theta frequency band. Plotting mean time-averaged percent change in power across subjects for both 1 mA and 6 mA stimulation. ∗ indicates significance using a signed-rank test at p < 0.05; error bars indicate ±1 SEM.

(A) Spectrograms from one subject show suppression of low-frequency power in several mood-relevant brain regions sampled by intracranial electrodes. Black and red bars indicate the beginning and end of stimulation, respectively.

To further characterize the neurophysiological effects of OFC stimulation, we probed for changes in cortical excitability by analyzing potentials evoked by current pulses applied immediately before and after continuous stimulation []. Trains of high-amplitude single pulses (see Method Details ) applied to OFC before OFC continuous stimulation evoked local responses within 100 ms of pulse onset ( Figure 4 D). After OFC continuous stimulation, identical trains of single pulses evoked potentiated responses ( Figures 4 D–4F), reflecting increased cortical excitability, as has been described following high-frequency rTMS [], though given the response latencies, we cannot distinguish between increased local excitability and recurrent activation. Continuous stimulation of a site remote to OFC (precentral gyrus) did not potentiate single-pulse-evoked responses in OFC, ruling out a non-specific effect of cortical stimulation on OFC excitability ( Figure S4 ). Of note, abnormal single-pulse responses have been reported as a marker of epileptogenic cortex [], but none of our subjects had seizures arising from OFC ( Table S1 ).

Having observed that OFC low-frequency power and mood state vary inversely during natural mood fluctuations, we hypothesized that mood improvement would be associated with decreased low-frequency power during OFC stimulation. To test this, we developed an approach to analyze OFC activity during stimulation. Detection of neural responses during electrical stimulation are typically hampered by a stimulus-related artifact that can obscure much or all of the underlying signal. We therefore developed artifact-rejection techniques ( Figure S3 Method Details ) that enabled evaluation of low-frequency neural activity during stimulation. Spectral analysis revealed that OFC stimulation suppresses low-frequency power ( Figure 4 A). This suppression was significant for theta-range frequencies ( Figure 4 B; pre-stim versus stim periods: Z = −2.33, p = 0.02; stim versus post-stim periods: Z = 2.64, p = 0.008), only showed a significant change from stim to post-stim periods in the alpha range ( Figure 4 C; pre-stim versus stim periods: Z = −1.65, p = 0.1; stim versus post-stim periods: Z = 2.22, p = 0.03), and was not significant for beta frequencies (pre-stim versus stim periods: Z = −0.90, p = 0.38; stim versus post-stim periods: Z = −0.26, p = 0.80). Thus, local neurophysiological changes during OFC stimulation (decreased theta and, to a lesser extent, alpha frequency power) are opposite those observed during spontaneous negative mood states ( Figures 3 B and 3C), suggesting that the mood effects of OFC stimulation may involve circuits that mediate natural mood variation. However, OFC power alone does not appear to provide a direct readout of mood state, as Pearson correlation analysis revealed that percent-change in CMS is not significantly correlated to percent-change in OFC theta power from pre-stim to stim periods (r = 0.41, p = 0.16).

(F) Across four subjects, peak amplitude of evoked potentials increased after continuous stimulation. Each circle represents evoked potential from an individual pulse of SPS. Black bars show mean across SPS pulses.

(E) Lateral OFC SPS before (green) and after (magenta) lateral OFC continuous stimulation in a representative subject (EC153), showing that evoked potentials increase after continuous stimulation. Solid lines are mean across 20 SPS pulses; shading shows ±1 SEM.

(D) Single-pulse stimulation (SPS) in lateral OFC before and after lateral OFC continuous stimulation to assess changes in cortical excitability.

(B) Percent change in lateral OFC power (average of 1 mA and 6 mA responses) from pre-stim to stim (left) and stim to post-stim (right). Theta power significantly decreased from pre-stim to stim and significantly increased from stim to post-stim. Gray lines indicate percent change for each subject; black line indicates group mean.

(A) Low-frequency power is suppressed during lateral OFC stimulation. Individual subject (EC125) example shown for 1 mA (left) and 6 mA (right) stimulation. Stimulation onset (black line) and offset (red line).

To further understand how OFC stimulation might have this effect, we asked how changes in mood state are reflected in neurophysiology, especially in OFC. Subjects serially reported their mood state using the IMS at variable intervals in the days prior to stimulation studies ( Figure 1 A; Table S1 ; mean total number of IMS data points per subject ± SD = 13.2 ± 10.5; mean number of IMS data points per day ± SD = 2.3 ± 2.4). Variability in IMS scores within subjects ( Figure S2 A) facilitated regression analysis with features of neural activity. We extracted segments of iEEG activity surrounding each IMS data point and examined first-order neural features during this natural (spontaneous) fluctuation in mood ( Figure 3 A). Normalized OFC power negatively correlated with IMS in theta and alpha frequency bands but not in higher frequencies ( Figures 3 B, 3C, and S2 B). In contrast, the correlation coefficient for the beta band was not significantly different from zero (two-sided z test, p = 0.11). This frequency-specific inverse relationship between mood state and OFC power was seen only in subjects with moderate-to-severe baseline mood traits ( Figures 3 B and 3C). Moreover, we found that for low frequencies, the correlation coefficient was significantly different from zero (two-sided z test, p = 0.0092 and p = 0.018 for theta and alpha bands, respectively, among n = 9 subjects who had at least 10 IMS data points).

(C) In patients with moderate-to-severe depression, theta and alpha lateral OFC powers exhibited negative correlations with IMS. R, p, black line, and shaded area same as above. Number of IMS data points used in correlations for each subject: EC81 (3), EC82 (16), EC84 (16), EC87 (12), EC91 (2), EC92 (3), EC96 (2), EC99 (3), EC108 (12), EC113 (5), EC122 (13), EC125 (12), EC129 (8), EC133 (6), EC137 (18), EC139 (3), EC142 (9), EC150 (20), EC152 (7), EC153 (3), EC162 (11), EC175 (7).

(B) Across all IMS data points in subjects with minimal-to-mild depression, there were no significant correlations between IMS and lateral OFC power. R is the correlation coefficient; p is the p value of the correlation coefficient; black lines show the least-squares linear fit; shaded area is the 95% confidence interval of the least-squares linear fit.

(A) 4 min of iEEG were extracted surrounding each IMS data point. Time-averaged log power (z-scored within subjects) in lateral OFC was calculated for each iEEG segment and correlated with z-scored IMS in order to compare variations in lateral OFC power with variations in IMS. Lower IMS indicates more negative mood state.

Speech rate during verbal report did not suggest mania during OFC stimulation ( Figures S1 E and S1F), though stimulation did specifically elevate speech rate in trait-depressed subjects, resulting in a level similar to that of the non-depressed subjects. Subjects did not display hyperactivity, grandiosity, distractibility, or other symptoms of mania. This indicates that the acute intervention did not produce a supraphysiological mood state, as has been observed with DBS of other brain regions []. Furthermore, OFC stimulation generally did not affect CMS of individuals who did not report low mood symptoms during the baseline sham period, suggesting that OFC stimulation normalizes mood state and does not produce non-specific mood elevation.

Stimulation of other limbic and paralimbic regions generally did not result in such robust mood-state improvement. However, in line with previous studies [], cingulate cortex stimulation did improve mood state ( Figure S1 D), though the effect was more variable than with OFC stimulation. Electrode locations typically permitted stimulation of lateral portions of OFC ( Figure 1 C, red markers), but we occasionally had the opportunity to stimulate medial OFC as well ( Figure 1 C, yellow makers). Stimulation of lateral OFC was more effective for mood improvement than medial OFC ( Figure S1 D), likely due to distinct functions of these subregions []. Accordingly, OFC stimulation hereafter refers to lateral OFC stimulation unless otherwise specified.

Subjects had baseline trait depression that ranged from minimal to severe ( Figure 2 A). Across multiple brain regions and over a wide range of stimulation parameters (0.2–100 Hz, pulse width 100–1,000 μs, 1–10 mA, duration 1–200 s), subjects generally did not report acute stimulation-induced changes in mood state, though stimulation of amygdala occasionally evoked dysphoria or other unpleasant symptoms, as previously described []. By contrast, during lateral OFC stimulation (100 Hz, 100 μs pulse width, 1 or 6 mA, duration 100–200 s; hereafter referred to as continuous stimulation), subjects’ verbal reports often reflected marked mood improvement ( Table S2 ). For example, one subject (EC84) used mostly negative words to describe their mood state during sham (0 mA) stimulation (“on the sad side,” “a little bit nervous”) but, during lateral OFC stimulation (6 mA), used mostly positive words (“calm, cool, and collected,” “a lot better”). CMS measures reflected such changes, increasing relative to baseline levels recorded during sham stimulation in nearly all subjects ( Figure S1 A). This effect was driven largely by the word-valence component of CMS, as changes in the quantified self-report component of CMS (immediate mood scaler, IMS []; see Method Details ) approached but did not reach statistical significance (p = 0.06; Figures S1 B and S1C). Increase in CMS (i.e., mood improvement) with lateral OFC stimulation was significant in subjects with moderate or severe trait depression, and higher stimulation current was more effective than lower current ( Figure 2 B, left; 1 mA: Z = 2.20, p = 0.03; 6 mA: Z = 2.52, p = 0.01; 1 mA versus 6 mA: Z = −1.9, p = 0.05). In contrast, we observed no significant change in mood in subjects with minimal or mild baseline mood traits ( Figure 2 B, right; 1 mA: Z = 0.45, p = 0.65; 6 mA: Z = 1.82, p = 0.07; 1 mA versus 6 mA: Z = −0.65, p = 0.51). This finding is consistent with previous work on TRD showing that patient-specific factors, including measures of disease severity, predict response to brain stimulation [].

(B) Mood-improving effects of lateral OFC stimulation were specific to subjects with Mod-Severe trait depression. Bars show mean change in CMS with stimulation relative to sham (0 mA) ± 1 SEM. Significance assessed by signed-rank and rank-sum tests (p values shown in graph).

Electrical Stimulations of the Human Insula: Their Contribution to the Ictal Semiology of Insular Seizures.

A modular experimental design ( Figures 1 A and 1B ) and extensive electrode coverage in all subjects ( Figures 1 C and 1D; Table S1 ) allowed us to assess the effects of stimulation in numerous brain regions, including limbic and paralimbic structures implicated in mood regulation, with respect to both mood state and mood trait. To assess acute stimulation effects on current mood state, we employed a combination of quantified self-report and word-valence metrics (composite mood score, CMS; lower CMS indicates more negative mood state; see Method Details ). To assess stimulation effects with respect to baseline mood trait, we utilized Beck Depression Inventory (BDI) scores obtained prior to surgery.

(D) MNI template brain with all recording electrodes across study subjects. Colored markers indicate electrodes that were verified to be located within the indicated regions based on review of co-registered CT and MRI, while gray markers indicate electrodes outside the indicated regions. Green, orbitofrontal cortex (OFC); magenta, cingulate; blue, insula; cyan, amygdala; yellow, hippocampus.

(C) Montreal Neurological Institute (MNI) template brain with all tested stimulation electrodes across study subjects. Lateral OFC sites shown by red markers, medial OFC sites shown by yellow markers, non-OFC sites shown by white markers.

(B) Overview of stimulation experiments. iEEG was continuously recorded while stimulation was delivered at different sites. For each stimulation site, verbal report and IMS score were combined to provide a composite mood score (CMS) as a measure of current mood state (see Method Details ). Bipolar stimulation was delivered in charge-balanced biphasic pulses of 100 μS pulse width, 100 Hz frequency, and amplitudes of 1 or 6 mA.

(A) Experimental timeline: Subjects completed the Beck Depression Inventory II (BDI) to assay trait depression prior to electrode implantation for seizure monitoring. Mood was assessed during continuous intracranial electroencephalography (iEEG) using the Immediate Mood Scaler (IMS). Stimulation studies were conducted, and electrodes were then explanted.

Discussion

Here, we show that human lateral OFC is a promising target for brain stimulation to alleviate mood symptoms. Unilateral stimulation of lateral OFC consistently produced acute, dose-dependent mood-state improvement across subjects with baseline depression traits. Locally, lateral OFC stimulation increased cortical excitability and suppressed low-frequency power, a feature we found to be negatively correlated with mood state. At the network level, lateral OFC stimulation modulated activity within a network of limbic and paralimbic structures implicated in mood regulation.

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Downar J. 1Hz rTMS of the right orbitofrontal cortex for major depression: Safety, tolerability and clinical outcomes. Relief of mood symptoms afforded by lateral OFC stimulation may arise from OFC acting as a hub within brain networks that mediate affective cognition. Previous studies identify OFC as a key node within an emotional salience network activated by anticipation of aversive events []. Within this network, OFC is thought to integrate multimodal sensory information and guide emotion-related decisions by evaluating expected outcomes []. Stimulation of other brain regions that encode value information, such as SCC [] and ventral striatum [], has also been found to improve mood, highlighting the relevance of reward circuits to mood state. Here, using iEEG, we extend previous studies that employed indirect imaging biomarkers, such as glucose metabolism or blood oxygen level [], to show that direct OFC stimulation modulates neural activity within a distributed network of brain regions. Our finding that lateral OFC stimulation was more effective than medial OFC stimulation for mood symptom relief advances the idea that these regions have differential contributions to depression, likely due to differences in network connectivity []. We did not observe consistent differences based on laterality of stimulation [], but future studies powered to discern such differences may reveal additional layers of specificity.

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Shahlaie K. Acute Frequency-Dependent Hypomania Induced by Ventral Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease: A Case Report. Although few behavioral variables have been identified to predict which individuals will respond to stimulation of a given target for depression, we found that only patients with significant trait depression experienced mood-state improvement with lateral OFC stimulation. Based on speech-rate analysis, lateral OFC stimulation did not produce supraphysiological mood states, as can be seen with stimulation of other targets [], but did specifically elevate speech rate in trait-depressed subjects, resulting in a level similar to that of the non-depressed subjects. Local neurophysiological changes induced by stimulation were opposite of those observed during spontaneous negative mood states. Taken together, these findings suggest that the effect of lateral OFC stimulation is to normalize or suppress pathological activity in circuits that mediate natural mood variation.

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Vanneste S. State of the Art: Novel Applications for Cortical Stimulation. Our results have potential implications for interventional treatments for psychiatric disorders like TRD and anxiety. DBS efficacy for TRD is inconsistent [], and a major thrust of the field has been to understand and circumvent inter-subject variability []. For example, the heterogeneous responses seen with SCC stimulation may relate to laterality [] and precise anatomic electrode position []. In our study, positive mood responses were induced by unilateral stimulation of the OFC in either hemisphere, and although stimulation of lateral OFC improved mood more than stimulation of medial OFC, we observed mood improvement with stimulation across lateral OFC and did not see evidence of fine subregion specificity. These findings suggest that lateral OFC may be a more forgiving site for therapeutic stimulation than previously reported targets []. Another practical advantage of OFC relative to other targets is that the cortical surface is generally more surgically accessible than deep brain targets and that the ability to forego parenchymal penetration may impart lower risk during electrode implantation. Although seizures are a theoretical risk with any cortical stimulation, this risk is thought to be acceptably low [], and we did not observe seizures during OFC stimulation.

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Downar J. Neural correlates of successful orbitofrontal 1 Hz rTMS following unsuccessful dorsolateral and dorsomedial prefrontal rTMS in major depression: A case report. Despite the widespread use of DBS in clinical and research applications, the mechanisms by which focal brain stimulation modulates network activity to produce complex behavioral changes remain largely unknown. The effects of stimulation are not limited to the targeted region, and stimulation-induced activity can propagate through anatomical connections to influence distributed networks in the brain. Previous studies have shown that target connectivity may determine likelihood of response to DBS []. Deciphering the precise mechanism of mood improvement with OFC stimulation requires future study, but our observation that stimulation suppresses low-frequency activity broadly across multiple sites suggests a possible local inhibitory effect that reverberates through connected brain regions. Consistent with this, inhibitory transcranial magnetic stimulation of OFC was recently reported to improve mood in one depressed patient []. Since the OFC is relatively large and bilateral, it is possible that the mood effects we observed could be improved by more widespread stimulation.

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Coenen V.A. Rapid effects of deep brain stimulation for treatment-resistant major depression. Our study has limitations. The sample size was relatively small, reflecting the rare opportunity to directly and precisely target brain stimulation in human subjects. Although electrode coverage was generally extensive in our subjects, basal ganglia structures known to be important for mood [] are not typically implanted with electrodes for the purposes of seizure localization. Subjective self-report of mood has intrinsic limitations but remains the best instrument available to measure internal experience []. Our subjects, who had medically refractory epilepsy, may not be representative of all patients with mood disorders. While we cannot rule out the possibility that mood symptoms in our subjects had a seizure-specific etiology, the observed effects of lateral OFC stimulation were robust in a patient group with diverse underlying seizure pathology ( Table S1 ). To establish generalizability, our findings will need to be replicated in other cohorts. Finally, it is possible that the acute effects of stimulation we observed may not translate into chronic efficacy for mood disorders in clinical settings []. Indeed, rapid mood changes have been previously reported in TRD patients treated with bilateral DBS of SCC [] and subcortical targets []. Whether chronic OFC stimulation can produce durable mood improvement is an important question for future study, ideally under controlled clinical trial conditions with appropriate monitoring of relevant outcomes and adverse events.