Cingulate dynamics track depression recovery with deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD)1. However, achieving stable recovery is unpredictable2, typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting3. We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment.

Whole brain network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression.

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment.

Obsessive-compulsive disorder, insulin signaling and diabetes - A novel form of physical health comorbidity: The sweet compulsive brain.

BACKGROUND: While a growing body of research highlights a bi-directional link between diabetes and mood disorders, little is known about the relationship between diabetes and obsessive-compulsive disorder (OCD). The aim of the present review is to investigate current evidence linking OCD, insulin-signaling and diabetes. METHODS: A PubMed search was conducted to review all the available studies assessing diabetes, glucose metabolism and insulin-signaling in OCD patients and vice versa. RESULTS: Some clinical and epidemiological studies show a higher prevalence of diabetes in OCD and vice versa compared to the general population. Animal and genetic studies suggest a possible role of insulin-signaling in the pathophysiology of OCD. Deep brain stimulation (DBS) studies suggest that abnormal dopaminergic transmission in the striatum may contribute to impaired insulin sensitivity in OCD. While DBS seems to increase insulin sensitivity, a possible protective role of serotonin reuptake-inhibitors on diabetic risk needs further studies. CONCLUSION: Despite their preliminary nature, these data highlight the importance of further investigations aimed at assessing metabolic features in OCD patients and OCD symptoms in diabetes patients to understand the impact of each condition on the pathophysiology and course of the other. Understanding the role of insulin in the obsessive-compulsive brain could open new treatment pathways for OCD.

Deep brain stimulation modulates directional limbic connectivity in obsessive-compulsive disorder.

Deep brain stimulation is effective for patients with treatment-refractory obsessive-compulsive disorder. Deep brain stimulation of the ventral anterior limb of the internal capsule rapidly improves mood and anxiety with optimal stimulation parameters. To understand these rapid effects, we studied functional interactions within the affective amygdala circuit. We compared resting state functional MRI data during chronic stimulation versus 1 week of stimulation discontinuation in patients, and obtained two resting state scans from matched healthy volunteers to account for test-retest effects. Imaging data were analysed using functional connectivity analysis and dynamic causal modelling. Improvement in mood and anxiety following deep brain stimulation was associated with reduced amygdala-insula functional connectivity. Directional connectivity analysis revealed that deep brain stimulation increased the impact of the ventromedial prefrontal cortex on the amygdala, and decreased the impact of the amygdala on the insula. These results highlight the importance of the amygdala circuit in the pathophysiology of obsessive-compulsive disorder, and suggest a neural systems model through which negative mood and anxiety are modulated by stimulation of the ventral anterior limb of the internal capsule for obsessive-compulsive disorder and possibly other psychiatric disorders.

Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression.

OBJECTIVE: Deep brain stimulation (DBS) reduces depressive symptoms in approximately 40%-60% of patients with treatment-resistant depression (TRD), but data on long-term efficacy and safety are scarce. Our objective was to assess the efficacy and safety of DBS targeted at the ventral anterior limb of the internal capsule (vALIC) in 25 patients with TRD during a 1-year, open-label, maintenance period, which followed a 1-year optimisation period. METHODS: Depression severity was measured using the 17-item Hamilton Depression Rating Scale (HAM-D-17), Montgomery-Asberg Depression Rating Scale (MADRS) and self-reported Inventory of Depressive Symptomatology (IDS-SR). Primary outcomes were response rate (≥50% HAM-D-17 score reduction) after the maintenance phase, approximately 2 years after DBS surgery, and changes in depression scores and occurrence of adverse events during the maintenance phase. RESULTS: Of 25 operated patients, 21 entered and 18 completed the maintenance phase. After the maintenance phase, eight patients were classified as responder (observed response rate: 44.4%; intention-to-treat: 32.0%). During the maintenance phase, HAM-D-17 and MADRS scores did not change, but the mean IDS-SR score decreased from 38.8 (95% CI 31.2 to 46.5) to 35.0 (95% CI 26.1 to 43.8) (p=0.008). Non-responders after optimisation did not improve during the maintenance phase. Four non-DBS-related serious adverse events occurred, including one suicide attempt. CONCLUSIONS: vALIC DBS for TRD showed continued efficacy 2 years after surgery, with symptoms remaining stable after optimisation as rated by clinicians and with patient ratings improving. This supports DBS as a viable treatment option for patients with TRD. TRIAL REGISTRATION NUMBER: NTR2118.

A transdiagnostic perspective of constructs underlying obsessive-compulsive and related disorders: An international Delphi consensus study.

BACKGROUND: The Research Domain Criteria seeks to bridge knowledge from neuroscience with clinical practice by promoting research into valid neurocognitive phenotypes and dimensions, irrespective of symptoms and diagnoses as currently conceptualized. While the Research Domain Criteria offers a vision of future research and practice, its 39 functional constructs need refinement to better target new phenotyping efforts. This study aimed to determine which Research Domain Criteria constructs are most relevant to understanding obsessive-compulsive and related disorders, based on a consensus between experts in the field of obsessive-compulsive and related disorders. METHODS: Based on a modified Delphi method, 46 experts were recruited from Australia, Africa, Asia, Europe and the Americas. Over three rounds, experts had the opportunity to review their opinion in light of feedback from the previous round, which included how their response compared to other experts and a summary of comments given. RESULTS: Thirty-four experts completed round one, of whom 28 (82%) completed round two and 24 (71%) completed round three. At the final round, four constructs were endorsed by ⩾75% of experts as 'primary constructs' and therefore central to understanding obsessive-compulsive and related disorders. Of these constructs, one came from the Positive Valence System (Habit), two from the Cognitive Control System (Response Selection/Inhibition and Performance Monitoring) and the final construct was an additional item suggested by experts (Compulsivity). CONCLUSION: This study identified four Research Domain Criteria constructs that, according to experts, cut across different obsessive-compulsive and related disorders. These constructs represent key areas for future investigation, and may have potential implications for clinical practice in terms of diagnostic processes and therapeutic management of obsessive-compulsive and related disorders.

Efficacy of Invasive and Non-Invasive Brain Modulation Interventions for Addiction.

It is important to find new treatments for addiction due to high relapse rates despite current interventions and due to expansion of the field with non-substance related addictive behaviors. Neuromodulation may provide a new type of treatment for addiction since it can directly target abnormalities in neurocircuits. We review literature on five neuromodulation techniques investigated for efficacy in substance related and behavioral addictions: transcranial direct current stimulation (tDCS), (repetitive) transcranial magnetic stimulation (rTMS), EEG, fMRI neurofeedback and deep brain stimulation (DBS) and additionally report on effects of these interventions on addiction-related cognitive processes. While rTMS and tDCS, mostly applied at the dorsolateral prefrontal cortex, show reductions in immediate craving for various addictive substances, placebo-responses are high and long-term outcomes are understudied. The lack in well-designed EEG-neurofeedback studies despite decades of investigation impedes conclusions about its efficacy. Studies investigating fMRI neurofeedback are new and show initial promising effects on craving, but future trials are needed to investigate long-term and behavioral effects. Case studies report prolonged abstinence of opioids or alcohol with ventral striatal DBS but difficulties with patient inclusion may hinder larger, controlled trials. DBS in neuropsychiatric patients modulates brain circuits involved in reward processing, extinction and negative-reinforcement that are also relevant for addiction. To establish the potential of neuromodulation for addiction, more randomized controlled trials are needed that also investigate treatment duration required for long-term abstinence and potential synergy with other addiction interventions. Finally, future advancement may be expected from tailoring neuromodulation techniques to specific patient (neurocognitive) profiles.

Contributions of the Ventral Striatum to Conscious Perception: An Intracranial EEG Study of the Attentional Blink.

The brain is limited in its capacity to consciously process information, necessitating gating of information. While conscious perception is robustly associated with sustained, recurrent interactions between widespread cortical regions, subcortical regions, including the striatum, influence cortical activity. Here, we examined whether the ventral striatum, given its ability to modulate cortical information flow, contributes to conscious perception. Using intracranial EEG, we recorded ventral striatum activity while 7 patients performed an attentional blink task in which they had to detect two targets (T1 and T2) in a stream of distractors. Typically, when T2 follows T1 within 100-500 ms, it is often not perceived (i.e., the attentional blink). We found that conscious T2 perception was influenced and signaled by ventral striatal activity. Specifically, the failure to perceive T2 was foreshadowed by a T1-induced increase in α and low ß oscillatory activity as early as 80 ms after T1, indicating that the attentional blink to T2 may be due to very early T1-driven attentional capture. Moreover, only consciously perceived targets were associated with an increase in θ activity between 200 and 400 ms. These unique findings shed new light on the mechanisms that give rise to the attentional blink by revealing that conscious target perception may be determined by T1 processing at a much earlier processing stage than traditionally believed. More generally, they indicate that ventral striatum activity may contribute to conscious perception, presumably by gating cortical information flow. SIGNIFICANCE STATEMENT: What determines whether we become aware of a piece of information or not? Conscious access has been robustly associated with activity within a distributed network of cortical regions. Using intracranial electrophysiological recordings during an attentional blink task, we tested the idea that the ventral striatum, because of its ability to modulate cortical information flow, may contribute to conscious perception. We find that conscious perception is influenced and signaled by ventral striatal activity. Short-latency (80-140 ms) striatal responses to a first target determined conscious perception of a second target. Moreover, conscious perception of the second target was signaled by longer-latency (200-400 ms) striatal activity. These results suggest that the ventral striatum may be part of a subcortical network that influences conscious experience.

Impulsivity and decision-making in obsessive-compulsive disorder after effective deep brain stimulation or treatment as usual.

OBJECTIVE: Impulsivity and impaired decision-making have been proposed as obsessive-compulsive disorder (OCD) endophenotypes, running in OCD and their healthy relatives independently of symptom severity and medication status. Deep brain stimulation (DBS) targeting the ventral limb of the internal capsule (vALIC) and the nucleus accumbens (Nacc) is an effective treatment strategy for treatment-refractory OCD. The effectiveness of vALIC-DBS for OCD has been linked to its effects on a frontostriatal network that is also implicated in reward, impulse control, and decision-making. While vALIC-DBS has been shown to restore reward dysfunction in OCD patients, little is known about the effects of vALIC-DBS on impulsivity and decision-making. The aim of the study was to compare cognitive impulsivity and decision-making between OCD patients undergoing effective vALIC-DBS or treatment as usual (TAU), and healthy controls. METHODS: We used decision-making performances under ambiguity on the Iowa Gambling Task and reflection impulsivity on the Beads Task to compare 20 OCD patients effectively treated with vALIC-DBS, 40 matched OCD patients undergoing effective TAU (medication and/or cognitive behavioural therapy), and 40 healthy subjects. Effective treatment was defined as at least 35% improvement of OCD symptoms. RESULTS: OCD patients, irrespective of treatment modality (DBS or TAU), showed increased reflection impulsivity and impaired decision-making compared to healthy controls. No differences were observed between OCD patients treated with DBS or TAU. CONCLUSION: OCD patients effectively treated with vALIC-DBS or TAU display increased reflection impulsivity and impaired decision-making independent of the type of treatment.