OFC, Brain Stimulation for Depression – Janice Wood * Direct Electrical Stimulation of Lateral OFC Acutely Improves Mood.

“You could see the improvements in patients’ body language. They smiled, they sat up straighter, they started to speak more quickly and naturally. They said things like ‘Wow, I feel better,’ ‘I feel less anxious,’ ‘I feel calm, cool and collected.”

An important step toward developing a therapy for people with treatment-resistant depression.

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.

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.

Unilateral stimulation of lateral OFC consistently produced acute, dose-dependent mood-state improvement across subjects with baseline depression traits.

In a new study, patients with moderate to severe depression reported significant improvements in mood when researchers stimulated the orbitofrontal cortex (OFC).

The orbitofrontal cortex (OFC) is a prefrontal cortex region in the frontal lobes in the brain, which is involved in the cognitive processing of decision-making.

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Researchers at the University of California San Francisco say the study’s findings are “an important step toward developing a therapy for people with treatment-resistant depression, which affects as many as 30 percent of depression patients.”

Using electrical current to directly stimulate affected regions of the brain has proven to be an effective therapy for treating certain forms of epilepsy and Parkinson’s disease, but efforts to develop therapeutic brain stimulation for depression have so far been inconclusive, according to the researchers.

“The OFC has been called one of the least understood regions in the brain, but it is richly connected to various brain structures linked to mood, depression, and decision making, making it very well positioned to coordinate activity between emotion and cognition.”

Two additional observations suggested that OFC stimulation could have therapeutic potential.

First, the researchers found that applying current to the lateral OFC triggered wide-spread patterns of brain activity that resembled what had naturally occurred in volunteers’ brains during positive moods in the days before brain stimulation. Equally promising was the fact that stimulation only improved mood in patients with moderate to severe depression symptoms but had no effect on those with milder symptoms.

“These two observations suggest that stimulation was helping patients with serious depression experience something like a naturally positive mood state, rather than artificially boosting mood in everyone.

This is in line with previous observations that OFC activity is elevated in patients with severe depression and suggests electrical stimulation may affect the brain in a way that removes an impediment to positive mood that occurs in people with depression.”

Psych Central

Direct Electrical Stimulation of Lateral Orbitofrontal Cortex Acutely Improves Mood in Individuals with Symptoms of Depression

Vikram R. Rao, Kristin K. Sellers, Deanna L. Wallace, Maryam M. Shanechi, Heather E. Dawes, Edward F. Chang.

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.

Experimental Design and Locations of Stimulated Sites

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Introduction

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.

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.

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.

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.

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.

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.

Our observations provide potential clues about how lateral OFC stimulation may impact mood. Although functional imaging biomarkers of depression are not firmly established, increased activity in lateral OFC is seen in patients with depression and normalizes with effective antidepressant treatment, and lateral OFC hyperactivity has been proposed as a mood-state marker of depression.

Thus, a speculative possibility is that our stimulation paradigm works by decreasing OFC theta power in a way that may impact baseline hyperactivity. We cannot exclude the possibility that the mechanisms underlying mood improvement with lateral OFC stimulation involve multiple regions and may at least partially overlap with mechanisms responsible for mood improvement with stimulation of SCC. In fact, based on anatomic and functional connectivity between these regions, and the constellation of white matter tracts likely affected by stimulation of these sites, some mechanistic overlap seems probable.

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.

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.

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. 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.

The clinical heterogeneity of mood disorders suggests that brain stimulation paradigms may need to be tailored for individual patients. Importantly, this study is one of few to assess the functional consequences of brain stimulation with direct neural recordings. The approach we used for serial quantitative mood state assessment may be useful for sensitively tracking symptoms of mood disorders during clinical interventions, including DBS trials. Our identification of a novel, robust stimulation target and our observation of stimulation-induced changes in endogenous mood-related neural features together set the stage for the next generation of stimulation therapies. OFC theta power may be useful for optimization of stimulation parameters for non-invasive stimulation modalities targeting the OFC in depression, and further characterization of mood biomarkers might enable personalized closed-loop stimulation devices that ameliorate debilitating mood symptoms.

Although the OFC is currently among the least understood brain regions, it may ultimately prove important for the treatment of refractory mood disorders.

Study: Current Biology

University of California, San Francisco (UCSF)

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