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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.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.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.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.

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.

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.

ObjectivesConverging evidence supports the effectiveness of anterior capsulotomy in the management of selected patients with refractory obsessive-compulsive disorder (OCD). Less is understood about the post-operative neural changes that contribute to clinical improvements or impairments that might occur which potentially could be avoided. The objective of this study is to identify the neuropsychological changes underlying the symptomatic relief in capsulotomy using an affective task-based fMRI study, and to discern potential post-operative cognitive changes associated with the surgery itself.MethodsA task-based fMRI study using a modified aversive monetary incentive delay paradigm with negative imagery (separated into two phases: anticipation and feedback) and subsequent expectancy violation was applied to study emotional regulation, with specific focus on the functional changes along the fronto-striatal pathway. Selected tests from the Cambridge Neuropsychological Automated Test Battery (CANTAB) covering attention, memory and executive function known to be impaired in OCD were administered to assess the cognitive function in three groups of age, gender matched participants: OCD patients (OCD), OCD capsulotomy patients (at least six months after surgery, CAP), and healthy controls (HC). Voxel-based morphometry (VBM) was applied to detect whole-brain grey matter volume differences between HC, OCD and CAP, and its association with cognitive deficits.ResultsCAP showed lower OCD severity (Yale Brown Obsessive Compulsive Score), and better activities of daily living and quality of life scores compared to OCD controls with no differences in depression or anxiety scores.Task-based fMRI revealed decreased nucleus accumbens (NAc) activity during aversive anticipation in CAP, which correlated with the symptomatic ratings after surgery. Whole-brain analyses during the feedback phase found interaction effects in the left pregenual anterior cingulate cortex (pgACC) and the left inferior frontal cortex (IFG), where CAP showed lower activity towards the aversive outcome and towards the expected but missing aversive image during the expectancy violation phase, with both positively correlated with symptomatic ratings. Attenuated functional connectivity between seed NAc and pgACC was found in CAP as expected during aversive versus neutral anticipation (aversive>neutral), suggesting a surgical impact of capsulotomy through downregulating the functional communication along the fronto-striatal pathway.Cognitive testing focusing on the differences between OCD and CAP or the potential effect of capsulotomy showed greater impairments in CAP in paired associative learning (PAL). All other cognitive measures were no different from OCD controls. CAP exhibited overall reduction of grey matter volume (GMV) in the ventral striatum, thalamus and left inferior frontal gyrus (IFG) relative to OCD controls. The total PAL error in CAP was associated with lower GMV in the left inferior frontal gyrus.ConclusionsWe show improvements in OCD severity, quality of life and disability post-capsulotomy. Potential impairments in cognitive status were limited to associative learning correlating with lower left inferior frontal cortex volumes which may reflect underlying severity or be related to capsulotomy effects. Our findings suggest targeting connectivity between NAc and pgACC, similar to the optimal target for deep brain stimulation in OCD, with post-operative effects modifying aversive processing. In contrast, potentially preserving tracts to the left inferior frontal cortex might be indicated. Our study contributes to the literature of anterior capsulotomy as an effective and well-tolerated treatment option for selected patients with refractory OCD and highlights overlaps between deep brain stimulation and capsulotomy in optimal targeting.

Objectives/AimsThe amygdala, orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) form a crucial part of the emotion circuit and their dysfunction is implicated in affective disorders attested by numerous functional magnetic resonance (fMRI) studies. However, the precise nature of emotion induced spectral responses and interactions amongst this circuitry have not been investigated with direct human intracranial recordings which may enable new knowledge for neuromodulation and translational benefits.MethodsWe acquired intracranial electroencephalography (iEEG) data from a cohort of 35 patients with intractable epilepsy, who underwent an emotional picture viewing task localising 71 contacts in the amygdala, 31 in OFC and 43 in mPFC. We first quantified high frequency activity (30–140 Hz) responses and subsequently assessed the lower frequency spectral dynamics. Finally, we investigated connectivity between these regions, with a hierarchical approach using functional undirected connectivity (coherence), functional direct connectivity (spectral granger causality) and model based-effective connectivity (dynamic causal modelling – DCM).ResultsEmotional stimuli induced high frequency responses in the amygdala, but which were remarkably absent in the OFC and mPFC. All three regions showed valence dependent differences in lower frequencies in theta (amygdala), alpha (OFC) and beta. In particular, beta activity was increased to negative relative to positive stimuli in both the amygdala and OFC with the opposite direction of effect was observed in the mPFC. Functional connectivity analyses showed predominant bi-directional coupling in low frequency (ConclusionsOur findings demonstrate a complex orchestration of emotion induced spectral responses, in the amygdala, OFC and mPFC differentiating valence conditions. We demonstrate for the first time using direct intracranial recordings evidence for a top-down influence of mPFC over the amygdala and bidirectional connectivity between the OFC and the amygdala coupling during emotional processing, thus extending the current account of prefrontal-amygdala interaction. Future work could build on this and explore dynamic modulations and the effects of stimulation between these nodes and circuit with implications for neuromodulation targets for affective pathologies.

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.

Objectives/AimsTo examine the causal role of the subthalamic nucleus (STN) in externally cued or internally generated decisions to execute or withhold an action by recording and stimulating neural activity in this region using deep brain stimulation (DBS) electrodes implanted for the treatment of Parkinson’s disease (PD).Methods20 PD patients completed an intentional inhibition task in which they were instructed by visual cues to go, stop or choose to go or stop. Each cue was on the screen until the patient pressed a button with their left thumb or for a maximum of 1500 ms and was preceded by a fixation cross for 1000–1500 ms. Local field potentials (LFP) were simultaneously recorded from the left STN and stimulated in the right STN at the clinical frequency of 130Hz or theta frequency 7Hz for 500 ms prior to the onset of the cue on half of the choice trials.ResultsOn non-stimulation choice trials, analysis of the LFP’s showed a significant decrease in theta activity when patients chose to stop compared to go. This difference began prior to the onset of the response. Behaviourally, patients chose to respond less when the STN was stimulated at a frequency of 7 hz for 500 ms prior to the onset of the cue but not at 130 Hz.On non-stimulation choice trials, analysis of the LFP’s also showed that there was a significant decrease in theta activity when patients chose to stop compared to go. This difference began prior to the onset of the response.ConclusionsThe findings suggest that pre-existing theta activity in the STN may bias one’s pre-disposition to choose to initiate an action and that stimulation of this activity may interfere with this process.

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.