Mechanisms underlying capsulotomy for refractory obsessive-compulsive disorder: neural correlates of negative affect processing overlap with deep brain stimulation targets.

Ablative procedures such as anterior capsulotomy are potentially effective in refractory obsessive-compulsive disorder (OCD). Converging evidence suggests the ventral internal capsule white matter tracts traversing the rostral cingulate and ventrolateral prefrontal cortex and thalamus is the optimal target for clinical efficacy across multiple deep brain stimulation targets for OCD. Here we ask which prefrontal regions and underlying cognitive processes might be implicated in the effects of capsulotomy by using both task fMRI and neuropsychological tests assessing OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the tracts targeted in capsulotomy. We tested OCD patients at least 6 months post-capsulotomy (n = 27), OCD controls (n = 33) and healthy controls (n = 34). We used a modified aversive monetary incentive delay paradigm with negative imagery and a within session extinction trial. Post-capsulotomy OCD subjects showed improved OCD symptoms, disability and quality of life with no differences in mood or anxiety or cognitive task performance on executive, inhibition, memory and learning tasks. Task fMRI revealed post-capsulotomy decreases in the nucleus accumbens during negative anticipation, and in the left rostral cingulate and left inferior frontal cortex during negative feedback. Post-capsulotomy patients showed attenuated accumbens-rostral cingulate functional connectivity. Rostral cingulate activity mediated capsulotomy improvement on obsessions. These regions overlap with optimal white matter tracts observed across multiple stimulation targets for OCD and might provide insights into further optimizing neuromodulation approaches. Our findings also suggest that aversive processing theoretical mechanisms may link ablative, stimulation and psychological interventions.

Frequency dependent emotion differentiation and directional coupling in amygdala, orbitofrontal and medial prefrontal cortex network with intracranial recordings.

The amygdala, orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) form a crucial part of the emotion circuit, yet their emotion induced responses and interactions have been poorly investigated with direct intracranial recordings. Such high-fidelity signals can uncover precise spectral dynamics and frequency differences in valence processing allowing novel insights on neuromodulation. Here, leveraging the unique spatio-temporal advantages of intracranial electroencephalography (iEEG) from a cohort of 35 patients with intractable epilepsy (with 71 contacts in amygdala, 31 in OFC and 43 in mPFC), we assessed the spectral dynamics and interactions between the amygdala, OFC and mPFC during an emotional picture viewing task. Task induced activity showed greater broadband gamma activity in the negative condition compared to positive condition in all the three regions. Similarly, beta activity was increased in the negative condition in the amygdala and OFC while decreased in mPFC. Furthermore, beta activity of amygdala showed significant negative association with valence ratings. Critically, model-based computational analyses revealed unidirectional connectivity from mPFC to the amygdala and bidirectional communication between OFC-amygdala and OFC-mPFC. Our findings provide direct neurophysiological evidence for a much-posited model of top-down influence of mPFC over amygdala and a bidirectional influence between OFC and the amygdala. Altogether, in a relatively large sample size with human intracranial neuronal recordings, we highlight valence-dependent spectral dynamics and dyadic coupling within the amygdala-mPFC-OFC network with implications for potential targeted neuromodulation in emotion processing.

Risk and aversion coding in human habenula high gamma activity.

Neurons in the primate lateral habenula fire in response to punishments and are inhibited by rewards. Through its modulation of midbrain monoaminergic activity, the habenula is believed to play an important role in adaptive behavioural responses to punishment and underlie depressive symptoms and their alleviation with ketamine. However, its role in value-based decision-making in humans is poorly understood due to limitations with non-invasive imaging methods which measure metabolic, not neural, activity with poor temporal resolution. Here, we overcome these limitations to more closely bridge the gap between species by recording local field potentials directly from the habenula in 12 human patients receiving deep brain stimulation treatment for bipolar disorder (n = 4), chronic pain (n = 3), depression (n = 3) and schizophrenia (n = 2). This allowed us to record neural activity during value-based decision-making tasks involving monetary rewards and losses. High-frequency gamma (60-240 Hz) activity, a proxy for population-level spiking involved in cognitive computations, increased during the receipt of loss and decreased during receipt of reward. Furthermore, habenula high gamma also encoded risk during decision-making, being larger in amplitude for high compared to low risk. For both risk and aversion, differences between conditions peaked approximately between 400 and 750 ms after stimulus onset. The findings not only demonstrate homologies with the primate habenula but also extend its role to human decision-making, showing its temporal dynamics and suggesting revisions to current models. The findings suggest that habenula high gamma could be used to optimize real-time closed-loop deep brain stimulation treatment for mood disturbances and impulsivity in psychiatric disorders.

Integrated Amygdala, Orbitofrontal and Hippocampal Contributions to Reward and Loss Coding Revealed with Human Intracranial EEG.

Neurophysiological work in primates and rodents have shown the amygdala plays a central role in reward processing through connectivity with the orbitofrontal cortex (OFC) and hippocampus. However, understanding the role of oscillations in each region and their connectivity in different stages of reward processing in humans has been hampered by limitations with noninvasive methods such as poor spatial and temporal resolution. To overcome these limitations, we recorded local field potentials (LFPs) directly from the amygdala, OFC and hippocampus simultaneously in human male and female epilepsy patients performing a monetary incentive delay (MID) task. This allowed us to dissociate electrophysiological activity and connectivity patterns related to the anticipation and receipt of rewards and losses in real time. Anticipation of reward increased high-frequency gamma (HFG; 60-250 Hz) activity in the hippocampus and theta band (4-8 Hz) synchronization between amygdala and OFC, suggesting roles in memory and motivation. During receipt, HFG in the amygdala was involved in outcome value coding, the OFC cue context-specific outcome value comparison and the hippocampus reward coding. Receipt of loss decreased amygdala-hippocampus theta and increased amygdala-OFC HFG amplitude coupling which coincided with subsequent adjustments in behavior. Increased HFG synchronization between the amygdala and hippocampus during reward receipt suggested encoding of reward information into memory for reinstatement during anticipation. These findings extend what is known about the primate brain to humans, showing key spectrotemporal coding and communication dynamics for reward and punishment related processes which could serve as more precise targets for neuromodulation to establish causality and potential therapeutic applications.SIGNIFICANCE STATEMENT Dysfunctional reward processing contributes to many psychiatric disorders. Neurophysiological work in primates has shown the amygdala, orbitofrontal cortex (OFC), and hippocampus play a synergistic role in reward processing. However, because of limitations with noninvasive imaging, it is unclear whether the same interactions occur in humans and what oscillatory mechanisms underpin them. We addressed this issue by recording local field potentials (LFPs) from all three regions in human epilepsy patients during monetary reward processing. There was increased amygdala-OFC high-frequency coupling when losing money which coincided with subsequent adjustments in behavior. In contrast, increased amygdala-hippocampus high-frequency phase-locking suggested a role in reward memory. The findings highlight amygdala networks for reward and punishment processes that could act as more precise neuromodulation targets to treat psychiatric disorders.

Subthalamic Oscillatory Activity of Reward and Loss Processing Using the Monetary Incentive Delay Task in Parkinson Disease.

BACKGROUND: The subthalamic nucleus (STN) is an effective deep brain stimulation target for Parkinson disease (PD) and obsessive-compulsive disorder and has been implicated in reward and motivational processing. In this study, we assessed the STN and prefrontal oscillatory dynamics in the anticipation and receipt of reward and loss using a task commonly used in imaging. MATERIALS AND METHODS: We recorded intracranial left subthalamic local field potentials from deep brain stimulation electrodes and prefrontal scalp electroencephalography in 17 patients with PD while they performed a monetary incentive delay task. RESULTS: During the expectation phase, enhanced left STN delta-theta activity was observed in both reward and loss vs neutral anticipation, with greater STN delta-theta activity associated with greater motivation specifically to reward. In the consummatory outcome phase, greater left STN delta activity was associated with a rewarding vs neutral outcome, particularly with more ventral contacts along with greater delta-theta coherence with the prefrontal cortex. We highlight a differential activity in the left STN to loss vs reward anticipation, demonstrating a distinct STN high gamma activity. Patients with addiction-like behaviors show lower left STN delta-theta activity to loss vs neutral outcomes, emphasizing impaired sensitivity to negative outcomes. CONCLUSIONS: Together, our findings highlight a role for the left STN in reward and loss processing and a potential role in addictive behaviors. These findings emphasize the cognitive-limbic function of the STN and its role as a physiologic target for neuropsychiatric disorders.

Evidence Accumulation and Neural Correlates of Uncertainty in Obsessive-Compulsive Disorder.

BACKGROUND: Decision making is frequently associated with risk taking under uncertainty. Elevated intolerance of uncertainty is suggested to be a critical feature of obsessive-compulsive disorder (OCD). However, impairments of latent constructs of uncertainty processing and its neural correlates remain unclear in OCD. METHODS: In 83 participants (24 OCD patients treated with capsulotomy, 28 OCD control participants, and 31 healthy control participants), we performed magnetic resonance imaging using a card gambling task in which participants made decisions whether to bet or not that the next card would be larger than the current one. A hierarchical drift diffusion model was used to dissociate speed and amount of evidence accumulated before a decisional threshold (i.e., betting or no betting) was reached. RESULTS: High uncertainty was characterized by a smaller amount of evidence accumulation (lower thresholds), thus dissociating uncertainty from conflict tasks and highlighting the specificity of this task to test value-based uncertainty. OCD patients exhibited greater caution with poor performance and greater evidence accumulation overall along with slower speed of accumulation, particularly under low uncertainty. Bilateral dorsal anterior cingulate and anterior insula distinguished high- and low-uncertainty decision processes in healthy control participants but not in the OCD groups, indicating impairments in anticipation of differences in outcome variance and salience network activity. There were no behavioral or imaging differences relating to capsulotomy despite improvements in OCD symptoms. CONCLUSIONS: Our findings highlight greater impairments particularly in more certain trials in the OCD groups along with impaired neural differentiation of high and low uncertainty and suggest uncertainty processing as a trait cognitive endophenotype rather than a state-specific factor.

Power signatures of habenular neuronal signals in patients with bipolar or unipolar depressive disorders correlate with their disease severity.

The habenula is an epithalamic structure implicated in negative reward mechanisms and plays a downstream modulatory role in regulation of dopaminergic and serotonergic functions. Human and animal studies show its hyperactivity in depression which is curtailed by the antidepressant response of ketamine. Deep brain stimulation of habenula (DBS) for major depression have also shown promising results. However, direct neuronal activity of habenula in human studies have rarely been reported. Here, in a cross-sectional design, we acquired both spontaneous resting state and emotional task-induced neuronal recordings from habenula from treatment resistant depressed patients undergoing DBS surgery. We first characterise the aperiodic component (1/f slope) of the power spectrum, interpreted to signify excitation-inhibition balance, in resting and task state. This aperiodicity for left habenula correlated between rest and task and which was significantly positively correlated with depression severity. Time-frequency responses to the emotional picture viewing task show condition differences in beta and gamma frequencies for left habenula and alpha for right habenula. Notably, alpha activity for right habenula was negatively correlated with depression severity. Overall, from direct habenular recordings, we thus show findings convergent with depression models of aberrant excitatory glutamatergic output of the habenula driving inhibition of monoaminergic systems.

Acute Time-Locked Alpha Frequency Subthalamic Stimulation Reduces Negative Emotional Bias in Parkinson's Disease.

BACKGROUND: Emotional processing is a core cognitive process cutting across neuropsychiatric disorders. Understanding the neurophysiological features underlying depressive symptoms and their sensitivity to modulation is critical to modifying emotional bias. The subthalamic nucleus (STN), targeted in Parkinson's disease, shows a late alpha desynchronization to affective stimuli. We targeted this alpha desynchronization using a novel stimulation protocol asking if brief alpha (10 Hz) frequency stimulation time-locked to unpleasant imagery might influence subjective emotion. METHODS: A total of 27 patients with Parkinson's disease were recruited. The first study tested patients (n = 16) on affective stimuli with STN local field potential recordings assessed bilaterally without stimulation. In the second study, patients (n = 24) were tested on two affective tasks comparing negative and neutral stimuli paired with acute right-STN stimulation, with one of the negative conditions stimulated briefly for 1 second at either 130 Hz or 10 Hz. The subjects rated valence and arousal of negative and neutral stimuli. RESULTS: We confirmed greater alpha desynchronization in both negative and positive affect relative to neutral in the right STN. Using acute stimulation of the right STN, we show a critical interaction effect between ratings, stimulation, and frequency; alpha frequency stimulation increased the subjective pleasantness of negative imagery, particularly with ventromedial contacts. Higher depression scores were associated with a positive bias to 10-Hz but not 130-Hz stimulation. CONCLUSIONS: We highlight the potential of brief alpha frequency subthalamic stimulation to reduce negative emotional bias. This finding provides mechanistic insights underlying subjective emotional valence and has implications for the management of depression using neuromodulation.

The role of emotion in learning trustworthiness from eye-gaze: Evidence from facial electromyography.

Gaze direction can be used to rapidly and reflexively lead or mislead others' attention as to the location of important stimuli. When perception of gaze direction is congruent with the location of a target, responses are faster compared to when incongruent. Faces that consistently gaze congruently are also judged more trustworthy than faces that consistently gaze incongruently. However, it's unclear how gaze-cues elicit changes in trust. We measured facial electromyography (EMG) during an identity-contingent gaze-cueing task to examine whether embodied emotional reactions to gaze-cues mediate trust learning. Gaze-cueing effects were found to be equivalent regardless of whether participants showed learning of trust in the expected direction or did not. In contrast, we found distinctly different patterns of EMG activity in these two populations. In a further experiment we showed the learning effects were specific to viewing faces, as no changes in liking were detected when viewing arrows that evoked similar attentional orienting responses. These findings implicate embodied emotion in learning trust from identity-contingent gaze-cueing, possibly due to the social value of shared attention or deception rather than domain-general attentional orienting.

Incidental learning of trust: Examining the role of emotion and visuomotor fluency.

Eye gaze is a powerful directional cue that automatically evokes joint attention states. Even when faces are ignored, there is incidental learning of the reliability of the gaze cueing of another person, such that people who look away from targets are judged less trustworthy. In a series of experiments, we demonstrated further properties of the incidental learning of trust from gaze direction. First, the emotion of the face, whether neutral or smiling, influenced the pattern of trust learning. Second, the effect was specific to judgments of trust; reliability of gaze direction did not influence other emotional judgments of a person, such as liking. And third, visuomotor fluency was not sufficient for learning of trust, whether or not the face served as a target or as a distractor. Taken together, incidental learning of trust is influenced by facial emotion, it is a specific effect that does not generalize to other emotional assessments, and it is not determined solely by processing fluency. (PsycINFO Database Record

The late positive potential indexes a role for emotion during learning of trust from eye-gaze cues.

Gaze direction perception triggers rapid visuospatial orienting to the location observed by others. When this is congruent with the location of a target, reaction times are faster than when incongruent. Functional magnetic resonance imaging studies suggest that the non-joint attention induced by incongruent cues are experienced as more emotionally negative and this could relate to less favorable trust judgments of the faces when gaze-cues are contingent with identity. Here, we provide further support for these findings using time-resolved event-related potentials. In addition to replicating the effects of identity-contingent gaze-cues on reaction times and trust judgments, we discovered that the emotion-related late positive potential increased across blocks to incongruent compared to congruent faces before, during and after the gaze-cue, suggesting both learning and retrieval of emotion states associated with the face. We also discovered that the face-recognition-related N250 component appeared to localize to sources in anterior temporal areas. Our findings provide unique electrophysiological evidence for the role of emotion in learning trust from gaze-cues, suggesting that the retrieval of face evaluations during interaction may take around 1000 ms and that the N250 originates from anterior temporal face patches.

Neural responses to facial expressions support the role of the amygdala in processing threat.

The amygdala is known to play an important role in the response to facial expressions that convey fear. However, it remains unclear whether the amygdala's response to fear reflects its role in the interpretation of danger and threat, or whether it is to some extent activated by all facial expressions of emotion. Previous attempts to address this issue using neuroimaging have been confounded by differences in the use of control stimuli across studies. Here, we address this issue using a block design functional magnetic resonance imaging paradigm, in which we compared the response to face images posing expressions of fear, anger, happiness, disgust and sadness with a range of control conditions. The responses in the amygdala to different facial expressions were compared with the responses to a non-face condition (buildings), to mildly happy faces and to neutral faces. Results showed that only fear and anger elicited significantly greater responses compared with the control conditions involving faces. Overall, these findings are consistent with the role of the amygdala in processing threat, rather than in the processing of all facial expressions of emotion, and demonstrate the critical importance of the choice of comparison condition to the pattern of results.