Relationships between interoceptive sensibility and resting-state functional connectivity of the insula in obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) exhibit abnormality in their subjective perception of internal sensation, a process known as interoceptive sensibility (IS), as well as altered functioning of the insula, a key neural structure for interoception. We investigated the multivariate structure of IS in 77 OCD patients and 53 controls and examined associations of IS with resting-state functional connectivity (FC) of the insula within the OCD group. For each group, principal component analysis was performed on 8 subscales of the Multidimensional Assessment of Interoceptive Awareness assessing putatively "adaptive" and "maladaptive" aspects of IS. Associations between IS components and insula FC in the OCD group were evaluated using seed regions placed in each of 3 subdivisions of the insula (posterior, anterior dorsal, and anterior ventral). Behaviorally, controls showed a 2-component solution broadly categorized into "adaptive" and "maladaptive" IS, while OCD patients exhibited a 3-component solution. The general tendency to notice or be aware of sensation loaded onto an "adaptive" IS component in controls but loaded onto both "adaptive" and "maladaptive" IS components in OCD. Within OCD, insula FC was differentially associated with distinct aspects of IS, identifying network connections that could serve as future targets for the modulation of IS in OCD.

The buildup of an urge in obsessive-compulsive disorder: Behavioral and neuroimaging correlates.

Obsessive-compulsive disorder (OCD) is highly heterogeneous. While obsessions often involve fear of harm, many patients report uncomfortable sensations and/or urges that drive repetitive behaviors in the absence of a specific fear. Prior work suggests that urges in OCD may be similar to everyday "urges-for-action" (UFA) such as the urge to blink, swallow, or scratch, but very little work has investigated the pathophysiology underlying urges in OCD. In the current study, we used an urge-to-blink approach to model sensory-based urges that could be experimentally elicited and compared across patients and controls using the same task stimuli. OCD patients and controls suppressed eye blinking over a period of 60 s, alternating with free blinking blocks, while brain activity was measured using functional magnetic resonance imaging. OCD patients showed significantly increased activation in several regions during the early phase of eyeblink suppression (first 30 s), including mid-cingulate, insula, striatum, parietal cortex, and occipital cortex, with lingering group differences in parietal and occipital regions during late eyeblink suppression (last 30 s). There were no differences in brain activation during free blinking blocks, and no conditions where OCD patients showed reduced activation compared to controls. In an exploratory analysis of blink counts performed in a subset of subjects, OCD patients were less successful than controls in suppressing blinks. These data indicate that OCD patients exhibit altered brain function and behavior when experiencing and suppressing the urge to blink, raising the possibility that the disorder is associated with a general abnormality in the UFA system that could ultimately be targeted by future treatments.

The real-time fMRI neurofeedback based stratification of Default Network Regulation Neuroimaging data repository.

This data descriptor describes a repository of openly shared data from an experiment to assess inter-individual differences in default mode network (DMN) activity. This repository includes cross-sectional functional magnetic resonance imaging (fMRI) data from the Multi Source Interference Task, to assess DMN deactivation, the Moral Dilemma Task, to assess DMN activation, a resting state fMRI scan, and a DMN neurofeedback paradigm, to assess DMN modulation, along with accompanying behavioral and cognitive measures. We report technical validation from n=125 participants of the final targeted sample of 180 participants. Each session includes acquisition of one whole-brain anatomical scan and whole-brain echo-planar imaging (EPI) scans, acquired during the aforementioned tasks and resting state. The data includes several self-report measures related to perseverative thinking, emotion regulation, and imaginative processes, along with a behavioral measure of rapid visual information processing. Technical validation of the data confirms that the tasks deactivate and activate the DMN as expected. Group level analysis of the neurofeedback data indicates that the participants are able to modulate their DMN with considerable inter-subject variability. Preliminary analysis of behavioral responses and specifically self-reported sleep indicate that as many as 73 participants may need to be excluded from an analysis depending on the hypothesis being tested. The present data are linked to the enhanced Nathan Kline Institute, Rockland Sample and builds on the comprehensive neuroimaging and deep phenotyping available therein. As limited information is presently available about individual differences in the capacity to directly modulate the default mode network, these data provide a unique opportunity to examine DMN modulation ability in relation to numerous phenotypic characteristics.

Beta-adrenergic Blockade at Memory Encoding, but Not Retrieval, Decreases the Subjective Sense of Recollection.

Humans remember emotional events not only better but also exhibit a qualitatively distinct recollective experience-that is, emotion intensifies the subjective vividness of the memory, the sense of reliving the event, and confidence in the accuracy of the memory [Phelps, E. A., & Sharot, T. How (and why) emotion enhances the subjective sense of recollection. Current Directions in Psychological Science, 17, 147-152, 2008]. Although it has been demonstrated that activation of the beta-adrenergic system, linked to increases in stress hormone levels and physiological arousal, mediates enhanced emotional memory accuracy, the mechanism underlying the increased subjective sense of recollection is unknown. Behavioral evidence suggests that increased arousal associated with emotional events, either at encoding or retrieval, underlies their increased subjective sense of recollection. Using a double-blind, placebo-controlled, within-subject design, we showed that reducing arousal at encoding through oral intake of 80-mg of the beta-adrenergic receptor antagonist propranolol decreases the subjective sense of recollection for both negative and neutral stimuli 24 hr later. In contrast, administration of propranolol before memory retrieval did not alter the subjective sense of recollection. These results suggest that the neurohormonal changes underlying increased arousal at the time of memory formation, rather than the time of memory retrieval, modulate the subjective sense of recollection.

Determinants of Propranolol's Selective Effect on Loss Aversion.

Research on emotion and decision making has suggested that arousal mediates risky decisions, but several distinct and often confounded processes drive such choices. We used econometric modeling to separate and quantify the unique contributions of loss aversion, risk attitudes, and choice consistency to risky decision making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention's pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e., as a function of initial loss aversion and body mass index), and did not affect risk attitudes or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of emotion and risky decision making.

Sensory over-responsivity and orbitofrontal cortex connectivity in obsessive-compulsive disorder.

BACKGROUND: Sensory over-responsivity (SOR) in obsessive-compulsive disorder (OCD) is associated with illness severity and functional impairment. However, the neural substrates of SOR in OCD have not yet been directly probed. METHODS: We examined resting-state global functional connectivity markers of SOR in 119 adults with OCD utilizing the CONN-fMRI Functional Connectivity Toolbox for SPM (v21a). We quantified SOR with the sensory sensitivity and sensory avoiding subscales of the Adult and Adolescent Sensory Profile (AASP). We also measured: OCD severity, with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Obsessive-Compulsive Inventory-Revised (OCI-R); sensory phenomena with the Sensory Phenomena Scale (SPS); general anxiety, with the Beck Anxiety Inventory (BAI); and depressive symptomatology, with Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR). RESULTS: There was a significant positive relationship of SOR with global connectivity in anterior and medial OFC (Brodmanns area 11, k = 154, x = 14, y = 62, z = -18, whole-brain corrected at FWE p < 0.05). LIMITATIONS: Future investigations should explore neural responses to sensory stimulation tasks in OCD and compare findings with those obtained in other conditions also characterized by high SOR, such as autism spectrum disorder. CONCLUSIONS: This study implicates OFC functional connectivity as a neurobiological mechanism of SOR in OCD and suggests that the substrates of SOR in OCD may be dissociable from both that of other symptoms in OCD, and SOR in other disorders. With replication and extension, the finding may be leveraged to develop and refine treatments for OCD and investigate the pathophysiology of SOR in other conditions.

C-Reactive Protein Does Not Predict Future Depression Onset in Adolescents: Preliminary Findings from a Longitudinal Study.

Introduction: Neuroinflammatory processes have been extensively implicated in the underlying neurobiology of numerous neuropsychiatric disorders. Elevated C-reactive protein (CRP), an indicator of nonspecific inflammation commonly utilized in clinical practice, has been associated with depression in adults. In adolescents, our group previously found CRP to be associated with altered neural reward function but not with mood and anxiety symptoms assessed cross-sectionally. We hypothesized that the distinct CRP findings in adolescent versus adult depression may be due to chronicity, with neuroinflammatory effects on psychiatric disorders gradually accumulating over time. Here, we conducted a longitudinal study to evaluate if CRP levels predicted future onset or progression of depression in adolescents. Methods: Participants were 53 adolescents (age = 14.74 ± 1.92 years, 35 female), 40 with psychiatric symptoms and 13 healthy controls. At baseline, participants completed semistructured diagnostic evaluations; dimensional assessments for anxiety, depression, anhedonia, and suicidality severity; and bloodwork to quantify CRP levels. Clinical assessments were repeated at longitudinal follow-up after ∼1.5 years. Spearman's correlation between CRP levels and follow-up symptom severity were controlled for body mass index, age, sex, and follow-up interval and considered significant at the two-tailed, Bonferroni-adjusted p < 0.05 level. Results: After correction for multiple comparisons, no relationships were identified between baseline CRP levels and follow-up symptom severity. Conclusion: CRP levels were not significantly associated with future psychiatric symptoms in adolescents in this preliminary analysis. This may suggest that CRP is not a useful biomarker for adolescent depression and anxiety. However, future longitudinal studies with larger sample sizes and incorporating additional indicators of neuroinflammation are needed.

Identifying subgroups of urge suppression in Obsessive-Compulsive Disorder using machine learning.

Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous. While predominant models suggest fear and harm prevention drive compulsions, many patients also experience uncomfortable sensory-based urges ("sensory phenomena") that may be associated with heightened interoceptive sensitivity. Using an urge-to-blink eyeblink suppression paradigm to model sensory-based urges, we previously found that OCD patients as a group had more eyeblink suppression failures and greater activation of sensorimotor-interoceptive regions than controls. However, conventional approaches assuming OCD homogeneity may obscure important within-group variability, impeding precision treatment development. This study investigated the heterogeneity of urge suppression failure in OCD and examined relationships with clinical characteristics and neural activation. Eighty-two patients with OCD and 38 controls underwent an fMRI task presenting 60-s blocks of eyeblink suppression alternating with free-blinking blocks. Latent profile analysis identified OCD subgroups based on number of erroneous blinks during suppression. Subgroups were compared on behavior, clinical characteristics, and brain activation during task. Three patient subgroups were identified. Despite similar overall OCD severity, the subgroup with the most erroneous eyeblinks had the highest sensory phenomena severity, interoceptive sensitivity, and subjective urge intensity. Compared to other subgroups, this subgroup exhibited more neural activity in somatosensory and interoceptive regions during the early phase (first 30 s) of blink suppression and reduced activity in the middle frontal gyrus during the late phase (second 30 s) as the suppression period elapsed. Heterogeneity of urge suppression in OCD was associated with clinical characteristics and brain function. Our results reveal potential treatment targets that could inform personalized medicine.

Age, Motion, Medical, and Psychiatric Associations With Incidental Findings in Brain MRI.

Importance: Few investigations have evaluated rates of brain-based magnetic resonance imaging (MRI) incidental findings (IFs) in large lifespan samples, their stability over time, or their associations with health outcomes. Objectives: To examine rates of brain-based IFs across the lifespan, their persistence, and their associations with phenotypic indicators of behavior, cognition, and health; to compare quantified motion with radiologist-reported motion and evaluate its associations with IF rates; and to explore IF consistency across multiple visits. Design, Setting, and Participants: This cross-sectional study included participants from the Nathan Kline Institute-Rockland Sample (NKI-RS), a lifespan community-ascertained sample, and the Healthy Brain Network (HBN), a cross-sectional community self-referred pediatric sample focused on mental health and learning disorders. The NKI-RS enrolled participants (ages 6-85 years) between March 2012 and March 2020 and had longitudinal participants followed up for as long as 4 years. The HBN enrolled participants (ages 5-21 years) between August 2015 and October 2021. Clinical neuroradiology MRI reports were coded for radiologist-reported motion as well as presence, type, and clinical urgency (category 1, no abnormal findings; 2, no referral recommended; 3, consider referral; and 4, immediate referral) of IFs. MRI reports were coded from June to October 2021. Data were analyzed from November 2021 to February 2023. Main Outcomes and Measures: Rates and type of IFs by demographic characteristics, health phenotyping, and motion artifacts; longitudinal stability of IFs; and Euler number in projecting radiologist-reported motion. Results: A total of 1300 NKI-RS participants (781 [60.1%] female; mean [SD] age, 38.9 [21.8] years) and 2772 HBN participants (976 [35.2%] female; mean [SD] age, 10.0 [3.5] years) had health phenotyping and neuroradiology-reviewed MRI scans. IFs were common, with 284 of 2956 children (9.6%) and 608 of 1107 adults (54.9%) having IFs, but rarely of clinical concern (category 1: NKI-RS, 619 [47.6%]; HBN, 2561 [92.4%]; category 2: NKI-RS, 647 [49.8%]; HBN, 178 [6.4%]; category 3: NKI-RS, 79 [6.1%]; HBN, 30 [1.1%]; category 4: NKI-RS: 12 [0.9%]; HBN, 6 [0.2%]). Overall, 46 children (1.6%) and 79 adults (7.1%) required referral for their IFs. IF frequency increased with age. Elevated blood pressure and BMI were associated with increased T2 hyperintensities and age-related cortical atrophy. Radiologist-reported motion aligned with Euler-quantified motion, but neither were associated with IF rates. Conclusions and Relevance: In this cross-sectional study, IFs were common, particularly with increasing age, although rarely clinically significant. While T2 hyperintensity and age-related cortical atrophy were associated with BMI and blood pressure, IFs were not associated with other behavioral, cognitive, and health phenotyping. Motion may not limit clinical IF detection.

Immunological correlates of suicidality among adolescents with internalizing symptoms.

Background: Suicide is a leading cause of death in adolescents and young adults globally. Well-established risk factors for suicide are depression and past suicide attempts. People experiencing suicidality may represent a distinct neurobiological group of people with depression. Because converging evidence has implicated inflammation in depression, we sought to investigate relationships between suicidality and immune markers in youth experiencing diverse mood and anxiety symptoms. We hypothesized that adolescents with suicidality would exhibit a unique immune signature. Methods: Adolescents underwent semi-structured interviews and completed self-reported measures to assess psychopathology, including suicidality (suicidal ideation, plans, or attempts). Fasting blood samples were collected, cultured with and without lipopolysaccharide (LPS) to stimulate an inflammatory response, and analyzed for 41 immune analytes. To assess how immune function related to suicidality categorically and dimensionally, we conducted group comparisons and correlations while controlling for multiple comparisons using false discovery rate (FDR). To further uncover subtle immune-suicidality relationships, we employed a data-driven approach using factor analysis to extract major immune factors, each of which was subsequently correlated with suicidality measures. Results: Among 126 participants, 29 were healthy controls and 97 participants had internalizing symptoms; within the clinical group, 57 experienced suicidality. Three immune analytes differed between healthy controls, suicidal, and non-suicidal adolescents with internalizing symptoms in the LPS condition: Flt-3L (p FDR = 0.0246), GM-CSF (p FDR = 0.0246), and IFN-γ (p FDR = 0.0246). These analytes were negatively correlated with the Beck Scale for Suicide Ideation (BSSI): Flt-3L (ρ = -0.19, p = 0.04); GM-CSF (ρ = -0.26, p = 0.004); IFN-γ (ρ =-0.33, p = 0.0003). GM-CSF also negatively correlated with number of suicide attempts (ρ = -0.39, p = 0.003). Factor analysis reduced 41 analytes to several common immune factors across experimental conditions, with Flt-3L, GM-CSF, and IFN-γ all loading heavily onto immune factors that were hypoactive in suicidality. Through this data-driven approach, we detected further associations between suicidality and immune factors across all conditions. Conclusions: Peripheral immune function may be distinctly altered in adolescent suicidality. Future work should examine immune-suicidality relationships longitudinally.