Intensity of repetitive negative thinking in depression is associated with greater functional connectivity between semantic processing and emotion regulation areas.

BACKGROUND: Repetitive negative thinking (RNT), a cognitive process that encompasses past (rumination) and future (worry) directed thoughts focusing on negative experiences and the self, is a transdiagnostic construct that is especially relevant for major depressive disorder (MDD). Severe RNT often occurs in individuals with severe levels of MDD, which makes it challenging to disambiguate the neural circuitry underlying RNT from depression severity. METHODS: We used a propensity score, i.e., a conditional probability of having high RNT given observed covariates to match high and low RNT individuals who are similar in the severity of depression, anxiety, and demographic characteristics. Of 148 MDD individuals, we matched high and low RNT groups (n = 50/group) and used a data-driven whole-brain voxel-to-voxel connectivity pattern analysis to investigate the resting-state functional connectivity differences between the groups. RESULTS: There was an association between RNT and connectivity in the bilateral superior temporal sulcus (STS), an important region for speech processing including inner speech. High relative to low RNT individuals showed greater connectivity between right STS and bilateral anterior insular cortex (AI), and between bilateral STS and left dorsolateral prefrontal cortex (DLPFC). Greater connectivity in those regions was specifically related to RNT but not to depression severity. CONCLUSIONS: RNT intensity is directly related to connectivity between STS and AI/DLPFC. This might be a mechanism underlying the role of RNT in perceptive, cognitive, speech, and emotional processing. Future investigations will need to determine whether modifying these connectivities could be a treatment target to reduce RNT.

Real-Time fMRI Functional Connectivity Neurofeedback Reducing Repetitive Negative Thinking in Depression: A Double-Blind, Randomized, Sham-Controlled Proof-of-Concept Trial.

INTRODUCTION: Repetitive negative thinking (RNT) is a cognitive process focusing on self-relevant and negative experiences, leading to a poor prognosis of major depressive disorder (MDD). We previously identified that connectivity between the precuneus/posterior cingulate cortex (PCC) and right temporoparietal junction (rTPJ) was positively correlated with levels of RNT. OBJECTIVE: In this double-blind, randomized, sham-controlled, proof-of-concept trial, we employed real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) to delineate the neural processes that may be causally linked to RNT and could potentially become treatment targets for MDD. METHODS: MDD-affected individuals were assigned to either active (n = 20) or sham feedback group (n = 19). RNT was measured by the Ruminative Response Scale-brooding subscale (RRS-B) before and 1 week after the intervention. RESULTS: Individuals in the active but not in the sham group showed a significant reduction in the RRS-B; however, a greater reduction in the PCC-rTPJ connectivity was unrelated to a greater reduction in the RRS-B. Exploratory analyses revealed that a greater reduction in the retrosplenial cortex (RSC)-rTPJ connectivity yielded a more pronounced reduction in the RRS-B in the active but not in the sham group. CONCLUSIONS: RtfMRI-nf was effective in reducing RNT. Considering the underlying mechanism of rtfMIR-nf, the RSC and rTPJ could be part of a network (i.e., default mode network) that might collectively affect the intensity of RNT. Understanding the relationship between the functional organization of targeted neural changes and clinical metrics, such as RNT, has the potential to guide the development of mechanism-based treatment of MDD.

Neuroethics and cultural context: The case of electroconvulsive therapy in Argentina.

As neuroethics continues to grow as an established discipline, it has been charged with not being sufficiently sensitive to the way in which the identification, conceptualization, and management of the ethical issues raised by neuroscience and its applications are shaped by local systems of knowledge and structures. Recently there have been calls for explicit recognition of the role played by local cultural contexts and for the development of cross-cultural methodologies that can facilitate meaningful cultural engagement. In this article, we attempt to fill this perceived gap by providing a culturally situated analysis of the practice of electroconvulsive therapy (ECT) in Argentina. ECT was introduced as a psychiatric treatment in Argentina in the 1930s but it is largely underutilized. While the use of ECT remains low in several countries, what makes the Argentinian case interesting is that the executive branch of government has taken a stance regarding both the scientific and moral appropriateness of ECT, recommending its prohibition. Here, we begin with a recent controversy over the use of ECT in Argentina and explain the legal recommendation to ban its application. Next, we offer an overview of some of the salient aspect of the international and local discussions on ECT. We argue that the governmental recommendation to ban the procedure should be rethought. While acknowledging the role that contexts and local conditions play in shaping the identification and assessment of the relevant ethical issues, we caution against using contextual and cultural considerations to avoid a necessary ethical debate on controversial issues.

Effects of socioeconomic status in cognition of people with schizophrenia: results from a Latin American collaboration network with 1175 subjects.

BACKGROUND: Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. METHODS: We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. RESULTS: Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. CONCLUSIONS: Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low- and middle-income countries.

Structural brain abnormalities in schizophrenia in adverse environments: examining the effect of poverty and violence in six Latin American cities.

BACKGROUND: Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear. AIMS: We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed. METHOD: This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model. RESULTS: A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure. CONCLUSIONS: Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.

Elevated peripheral inflammation is associated with attenuated striatal reward anticipation in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide, and up to 40% of individuals with MDD do not respond to current treatments. Studies suggest that peripheral inflammation plays an important role in the striatal mesolimbic dopamine pathway and corticostriatal reward circuitry in MDD. Although MDD patients show blunted striatal responses to reward, the link between degree of inflammation and attenuation of reward processing is unclear. We investigated whether MDD patients with elevated peripheral inflammation exhibit attenuated reward responses to enhance our understanding of MDD pathophysiology and develop more effective treatments for current non-responders. METHODS: MDD subjects varying on serum C-reactive protein (CRP) concentrations (MDD-High CRP, >3 mg/L, n = 44; MDD-Low CRP, <3 mg/L, n = 44) and healthy comparisons (HC, n = 44) completed a monetary incentive delay (MID) task and provided blood samples to measure inflammation-related markers. MDD-High and MDD-Low were propensity score-matched on age, sex, body mass index (BMI), smoking status, exercise and MID task head motion. Percent change in blood oxygen level-dependent (BOLD) signal during anticipation of wins and losses was extracted from bilateral nucleus accumbens, dorsal caudate and dorsolateral putamen regions of interest (ROIs). A linear mixed-effects model was used to test group (MDD-High, MDD-Low and HC), condition (large-win, small-win and no win), and their interaction for these ROIs as well as whole-brain voxelwise data. Analyses also tested group differences in inflammatory mediators. Correlations were used to explore the relationship between inflammatory mediators and brain regions showing differences between MDD-High and MDD-Low. RESULTS: MDD-High exhibited: (a) lower BOLD signal change in dorsal caudate, thalamus, left insula and left precuneus during anticipation of small wins than MDD-Low; and (b) higher serum soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 6 (IL-6) concentrations than MDD-Low and HC. MDD as a whole, regardless of CRP-based inflammation, exhibited: (a) lower precuneus BOLD signal change to large wins than HC; and (b) higher Interleukin 1 receptor antagonist (IL-1ra), macrophage-derived chemokine (MDC) and macrophage inflammatory protein-1 alpha (MIP-1α) concentrations than HC. Higher serum sICAM-1 concentrations were associated with lower caudate BOLD signal change to small wins only within the MDD-High group. CONCLUSION: Within MDD patients, high inflammation (CRP, sICAM-1) was linked to reduced striatal activation recruited to discriminate intermediate reward magnitudes. These findings support an association between levels of peripheral inflammation and the degree of reward-related activation in individuals with MDD. REGISTRATION OF CLINICAL TRIALS: The ClinicalTrials.gov identifier for the clinical protocol associated with data published in this current paper is NCT02450240, "Latent Structure of Multi-level Assessments and Predictors of Outcomes in Psychiatric Disorders."

Brain Structural and Amyloid Correlates of Recovery From Semantic Interference in Cognitively Normal Individuals With or Without Family History of Late-Onset Alzheimer's Disease.

Failure to recover from proactive semantic interference (frPSI) has been shown to be more sensitive than traditional cognitive measures in different populations with preclinical Alzheimer's disease. The authors sought to characterize the structural and amyloid in vivo correlates of frPSI in cognitively normal offspring of patients with late-onset Alzheimer's disease (O-LOAD), compared with individuals without a family history of neurodegenerative disorders (CS). The authors evaluated the LASSI-L, a test tapping frPSI and other types of semantic interference and delayed recall on the RAVLT, along with 3-T MRI volumetry and positron emission tomography Pittsburgh compound B, in 27 O-LOAD and 18 CS with equivalent age, sex, years of education, ethnicity, premorbid intelligence, and mood symptoms. Recovery from proactive semantic interference (frPSI) and RAVLT delayed recall were lower in O-LOAD cases. Structural correlates of both cognitive dimensions were different in CS and O-LOAD, involving brain regions concerned with autonomic, motor, and motivational control in the former, and regions traditionally implicated in Alzheimer's disease in the latter. Better recovery from retroactive semantic interference was associated with less amyloid load in the left temporal lobe in O-LOAD but not CS. In middle-aged cognitively normal individuals with one parent affected with LOAD, frPSI was impaired compared with persons without a family history of LOAD. The neuroimaging correlates of such cognitive measure in those with one parent with LOAD involve Alzheimer's-relevant brain regions even at a relatively young age.

[Endophenotypes in Psychiatry]. / Endofenotipos en Psychiatría.

We review the concept of endophenotype, and its relationship with related terms in use in the scientific literature, including "biomarker" and "intermediate phenotype". We then explain the importance of the concept in current psychiatry research. Specifically, we focus in the potential importance of endophenotypes in both disentangling the genetic causes, and improving the dimensional and pathophysiologic definition, of psychiatric nosological categories. After delineating which types of variables could constitute valid endophenotypes, we describe efforts in defining neurobiological signatures of social cognitive deficits in schizophrenia as an example with potential heuristic value.

From Semantic to Social Deficits: Dysfunction of the Nondominant Posterior Perisylvian Area in Schizophrenia.

Schizophrenia is characterized by profound deficits in social competence and functioning, independent from active psychotic symptoms at different stages of the disease. Social deficits in schizophrenia are clinically well characterized, but their neurobiological underpinnings are undetermined. This article reviews recent evidence supporting heritable deficits in a circuit necessary for appropriate naming of emotions and mental states in others, centered at the temporoparietal junction of the nondominant hemisphere. The clinical implications of this model are discussed, including the potential use of rehabilitation techniques oriented to recognition and naming of emotions and mental states as a necessary step for social rehabilitation.

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update.

The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public-private partnership, the initiative has set a new standard for data sharing without embargo and for the use of biomarkers in dementia research. The ADNI effort in North America is not the only such effort in the world. The Alzheimer's Association recognized these global efforts and formed Worldwide ADNI (WW-ADNI). By creating a platform for international collaboration and cooperation, WW-ADNI's goals are to harmonize projects and results across geographical regions and to facilitate data management and availability to investigators around the world. WW-ADNI projects include those based in North America, Europe, Japan, Australia, Korea, and Argentina.

Rumination and Overrecruitment of Cognitive Control Circuits in Depression.

BACKGROUND: Rumination is associated with greater cognitive dysfunction and treatment resistance in major depressive disorder (MDD), but its underlying neural mechanisms are not well understood. Because rumination is characterized by difficulty in controlling negative thoughts, the current study investigated whether rumination was associated with aberrant cognitive control in the absence of negative emotional information. METHODS: Individuals with MDD (n = 176) and healthy control individuals (n = 52) completed the stop signal task with varied stop signal difficulty during functional magnetic resonance imaging. In the task, a longer stop signal asynchrony made stopping difficult (hard stop), whereas a shorter stop signal asynchrony allowed more time for stopping (easy stop). RESULTS: In participants with MDD, higher rumination intensity was associated with greater neural activity in response to difficult inhibitory control in the frontoparietal regions. Greater activation for difficult inhibitory control associated with rumination was also positively related to state fear. The imaging results provide compelling evidence for the neural basis of inhibitory control difficulties in individuals with MDD with high rumination. CONCLUSIONS: The association between higher rumination intensity and greater neural activity in regions involved in difficult inhibitory control tasks may provide treatment targets for interventions aimed at improving inhibitory control and reducing rumination in this population.

Clinical Response to Neurofeedback in Major Depression Relates to Subtypes of Whole-Brain Activation Patterns During Training.

Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. Significant symptom reduction was observed in the active group (t=-4.404, d=-0.704, p<0.001) but not in the control group (t=-1.609, d=-0.430, p=0.111). However, left amygdala activation did not account for the variability in clinical efficacy. To elucidate the brain training process underlying the clinical effect, we examined whole-brain activation patterns during two critical phases of the neurofeedback procedure: activation during the self-regulation period, and transient responses to feedback signal presentations. Using a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified two subtypes of regulation activation and three subtypes of brain responses to feedback signals. These subtypes were significantly associated with the clinical effect (regulation subtype: F=8.735, p=0.005; feedback response subtype: F=5.326, p=0.008; subtypes' interaction: F=3.471, p=0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity during training is more critical for clinical efficacy than the level of activation in the neurofeedback target region itself. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.

Childhood adversity modulates structural brain changes in borderline personality but not in major depression disorder.

Adverse childhood experiences (ACEs) negatively affect the function and structure of emotion brain circuits, increasing the risk of various psychiatric disorders. It is unclear if ACEs show disorder specificity with respect to their effects on brain structure. We aimed to investigate whether the structural brain effects of ACEs differ between patients with major depression (MDD) and borderline personality disorder (BPD). These disorders share many symptoms but likely have different etiologies. To achieve our goal, we obtained structural 3T-MRI images from 20 healthy controls (HC), 19 MDD patients, and 18 BPD patients, and measured cortical thickness and subcortical gray matter volumes. We utilized the Adverse Childhood Experiences (ACE) questionnaire to quantify self-reported exposure to childhood trauma. Our findings suggest that individuals with MDD exhibit a smaller cortical thickness when compared to those with BPD. However, ACEs showed a significantly affected relationship with cortical thickness in BPD but not in MDD. ACEs were found to be associated with thinning in cortical regions involved in emotional behavior in BPD, whereas HC showed an opposite association. Our results suggest a potential mechanism of ACE effects on psychopathology involving changes in brain structure. These findings highlight the importance of early detection and intervention strategies.

[DSM-5: a young Kraepelin and the "schizoaffective disorder" oxymoron]. / El nuevo DSM-V o Kraepelin antes de su madurez: el oxímoron del "Trastorno esquizoafectivo"

The last several years have witnessed the accumulation of evidence suggesting that the Kraepelinian binary system of classification of the psychoses does not capture their true nature, as Kraepelin himself had cautioned in his late years. The long-awaited new edition of the APA's Diagnostic and Statistical Manual will in all probability incorporate symptom dimensions and suppress schizophrenia subtypes. However, the initial Kraepelinian conceptualization of the psychoses is maintained, along with the diagnostic category that epitomizes its obsolescence: schizoaffective disorder. We hereby make a brief critical appraisal of this fact, pointing out how the current classification system might be an obstacle to much-needed advances in this knowledge field.

Personalized Definition of Surgical Targets in Major Depression and Obsessive-Compulsive Disorder: A Potential Role for Low-Intensity Focused Ultrasound?

Major Depressive Disorder (MDD) and Obsessive-Compulsive Disorder (OCD) are common and potentially incapacitating conditions. Even when recognized and adequately treated, in over a third of patients with these conditions the response to first-line pharmacological and psychotherapeutic measures is not satisfactory. After more assertive measures including pharmacological augmentation (and in the case of depression, transcranial magnetic stimulation, electroconvulsive therapy, or treatment with ketamine or esketamine), a significant number of individuals remain severely symptomatic. In these persons, different ablation and deep-brain stimulation (DBS) psychosurgical techniques have been employed. However, apart from the cost and potential morbidity associated with surgery, on average only about half of patients show adequate response, which limits the widespread application of these potentially life-saving interventions. Possible reasons are considered for the wide variation in outcomes across different series of patients with MDD or OCD exposed to ablative or DBS psychosurgery, including interindividual anatomical and etiological variability. Low-intensity focused ultrasound (LIFU) is an emerging technique that holds promise in its ability to achieve anatomically circumscribed, noninvasive, and reversible neuromodulation of deep brain structures. A possible role for LIFU in the personalized presurgical definition of neuromodulation targets in the individual patient is discussed, including a proposed roadmap for clinical trials addressed at testing whether this technique can help to improve psychosurgical outcomes.

Trait repetitive negative thinking in depression is associated with functional connectivity in negative thinking state rather than resting state.

Resting-state functional connectivity (RSFC) has been proposed as a potential indicator of repetitive negative thinking (RNT) in depression. However, identifying the specific functional process associated with RSFC alterations is challenging, and it remains unclear whether alterations in RSFC for depressed individuals are directly related to the RNT process or to individual characteristics distinct from the negative thinking process per se. To investigate the relationship between RSFC alterations and the RNT process in individuals with major depressive disorder (MDD), we compared RSFC with functional connectivity during an induced negative-thinking state (NTFC) in terms of their predictability of RNT traits and associated whole-brain connectivity patterns using connectome-based predictive modeling (CPM) and connectome-wide association (CWA) analyses. Thirty-six MDD participants and twenty-six healthy control participants underwent both resting state and induced negative thinking state fMRI scans. Both RSFC and NTFC distinguished between healthy and depressed individuals with CPM. However, trait RNT in depressed individuals, as measured by the Ruminative Responses Scale-Brooding subscale, was only predictable from NTFC, not from RSFC. CWA analysis revealed that negative thinking in depression was associated with higher functional connectivity between the default mode and executive control regions, which was not observed in RSFC. These findings suggest that RNT in depression involves an active mental process encompassing multiple brain regions across functional networks, which is not represented in the resting state. Although RSFC indicates brain functional alterations in MDD, they may not directly reflect the negative thinking process.

Trait repetitive negative thinking in depression is associated with functional connectivity in negative thinking state rather than resting state.

Resting-state functional connectivity (RSFC) has been proposed as a potential indicator of repetitive negative thinking (RNT) in depression. However, identifying the specific functional process associated with RSFC alterations is challenging, and it remains unclear whether alterations in RSFC for depressed individuals are directly related to the RNT process or to individual characteristics distinct from the negative thinking process per se. To investigate the relationship between RSFC alterations and the RNT process in individuals with major depressive disorder (MDD), we compared RSFC with functional connectivity during an induced negative-thinking state (NTFC) in terms of their predictability of RNT traits and associated whole-brain connectivity patterns using connectome-based predictive modeling (CPM) and connectome-wide association (CWA) analyses. Thirty-six MDD participants and twenty-six healthy control participants underwent both resting state and induced negative thinking state fMRI scans. Both RSFC and NTFC distinguished between healthy and depressed individuals with CPM. However, trait RNT in depressed individuals, as measured by the Ruminative Responses Scale-Brooding subscale, was only predictable from NTFC, not from RSFC. CWA analysis revealed that negative thinking in depression was associated with higher functional connectivity between the default mode and executive control regions, which was not observed in RSFC. These findings suggest that RNT in depression involves an active mental process encompassing multiple brain regions across functional networks, which is not represented in the resting state. Although RSFC indicates brain functional alterations in MDD, they may not directly reflect the negative thinking process.

Thalamo-cortical circuits associated with trait- and state-repetitive negative thinking in major depressive disorder.

BACKGROUND: Repetitive negative thinking (RNT), often referred to as rumination in the mood disorders literature, is a symptom dimension associated with poor prognosis and suicide in major depressive disorder (MDD). Given the transdiagnostic nature of RNT, this study aimed to evaluate the hypothesis that neurobiological substrates of RNT in MDD may share the brain mechanisms underlying obsessions, particularly those involving cortico-striatal-thalamic-cortical (CSTC) circuits. METHODS: Thirty-nine individuals with MDD underwent RNT induction during fMRI. Trait-RNT was measured by the Ruminative Response Scale (RRS) and state-RNT was measured by a visual analogue scale. We employed a connectome-wide association analysis examining the association between RNT intensity with striatal and thalamic connectivity. RESULTS: A greater RRS score was associated with hyperconnectivity of the right mediodorsal thalamus with prefrontal cortex, including lateral orbitofrontal cortex, along with Wernicke's area and posterior default mode network nodes (t = 4.66-6.70). A greater state-RNT score was associated with hyperconnectivity of the right laterodorsal thalamus with bilateral primary sensory and motor cortices, supplementary motor area, and Broca's area (t = 4.51-6.57). Unexpectedly, there were no significant findings related to the striatum. CONCLUSIONS: The present results suggest RNT in MDD is subserved by abnormal connectivity between right thalamic nuclei and cortical regions involved in both visceral and higher order cognitive processing. Emerging deep-brain neuromodulation methods may be useful to establish causal relationships between dysfunction of right thalamic-cortical circuits and RNT in MDD.

Transdiagnostic behavioral and genetic contributors to repetitive negative thinking: A machine learning approach.

BACKGROUND: Repetitive negative thinking (RNT) is a symptom that can negatively impact the treatment and course of common psychiatric disorders such as depression and anxiety. We aimed to characterize behavioral and genetic correlates of RNT to infer potential contributors to its genesis and maintenance. METHODS: We applied a machine learning (ML) ensemble method to define the contribution of fear, interoceptive, reward, and cognitive variables to RNT, along with polygenic risk scores (PRS) for neuroticism, obsessive compulsive disorder (OCD), worry, insomnia, and headaches. We used the PRS and 20 principal components of the behavioral and cognitive variables to predict intensity of RNT. We employed the Tulsa-1000 study, a large database of deeply phenotyped individuals recruited between 2015 and 2018. RESULTS: PRS for neuroticism was the main predictor of RNT intensity (R2=0.027,p<0.001). Behavioral variables indicative of faulty fear learning and processing, as well as aberrant interoceptive aversiveness, were significant contributors to RNT severity. Unexpectedly, we observed no contribution of reward behavior and diverse cognitive function variables. LIMITATIONS: This study is an exploratory approach that must be validated with a second, independent cohort. Furthermore, this is an association study, limiting causal inference. CONCLUSIONS: RNT is highly determined by genetic risk for neuroticism, a behavioral construct that confers risk to a variety of internalizing disorders, and by emotional processing and learning features, including interoceptive aversiveness. These results suggest that targeting emotional and interoceptive processing areas, which involve central autonomic network structures, could be useful in the modulation of RNT intensity.