Showing papers by "Trevor W. Robbins published in 2022"

Locus Coeruleus Integrity from 7 T MRI Relates to Apathy and Cognition in Parkinsonian Disorders

Abstract: Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging.

What is next for the neurobiology of temperament, personality and psychopathology?

Abstract: This paper represents the outcome of a multidisciplinary discussion on what works, what does not, and what can be improved, in ongoing work on biobehavioral taxonomies and their biomarkers. The authors of this paper, representing a wide spectrum of biobehavioral disciplines (clinical, developmental, differential psychology, neurophysiology, endocrinology, psychiatry, neurochemistry, and neurosciences), have contributed more extensive opinions to the Theme Issue 'Neurobiology of temperament, personality and psychopathology: what's next?'. The authors identified 10 directions in international and multidisciplinary cooperation, and multiple insights for ‘what is next’ for each of these directions.

A New Remote Guided Method for Supervised Web-Based Cognitive Testing to Ensure High-Quality Data: Development and Usability Study

Abstract: Background The global COVID-19 pandemic has triggered a fundamental reexamination of how human psychological research can be conducted safely and robustly in a new era of digital working and physical distancing. Online web-based testing has risen to the forefront as a promising solution for the rapid mass collection of cognitive data without requiring human contact. However, a long-standing debate exists over the data quality and validity of web-based studies. This study examines the opportunities and challenges afforded by the societal shift toward web-based testing and highlights an urgent need to establish a standard data quality assurance framework for online studies. Objective This study aims to develop and validate a new supervised online testing methodology, remote guided testing (RGT). Methods A total of 85 healthy young adults were tested on 10 cognitive tasks assessing executive functioning (flexibility, memory, and inhibition) and learning. Tasks were administered either face-to-face in the laboratory (n=41) or online using remote guided testing (n=44) and delivered using identical web-based platforms (Cambridge Neuropsychological Test Automated Battery, Inquisit, and i-ABC). Data quality was assessed using detailed trial-level measures (missed trials, outlying and excluded responses, and response times) and overall task performance measures. Results The results indicated that, across all data quality and performance measures, RGT data was statistically-equivalent to in-person data collected in the lab (P>.40 for all comparisons). Moreover, RGT participants out-performed the lab group on measured verbal intelligence (P<.001), which could reflect test environment differences, including possible effects of mask-wearing on communication. Conclusions These data suggest that the RGT methodology could help ameliorate concerns regarding online data quality—particularly for studies involving high-risk or rare cohorts—and offer an alternative for collecting high-quality human cognitive data without requiring in-person physical attendance.

Cognitive Rigidity, Habitual Tendencies, and Obsessive-Compulsive Symptoms: Individual Differences and Compensatory Interactions

Abstract: Recent theories have posited a range of cognitive risk factors for obsessive-compulsive disorder (OCD), including cognitive inflexibility and a maladaptive reliance on habits. However, empirical and methodological inconsistencies have obscured the understanding of whether inflexibility and habitual tendencies indeed shape OCD symptoms in clinical and sub-clinical populations, and whether there are notable interactions amongst these traits. The present investigation adopted an interactionist individual differences approach to examine the associations between behaviorally-assessed cognitive flexibility and subclinical OCD symptomatology in a healthy population. It also explored the nature of the interactions between cognitive flexibility and habitual tendencies, and the degree to which these cognitive traits predict subclinical OCD symptomatology. Across two studies, including a preregistration, Bayesian and regression analyses revealed that cognitive inflexibility and compulsive habitual tendencies act as unique and independent predictors of subclinical OCD symptomatology in healthy populations. Furthermore, there was a significant interaction between cognitive rigidity and habitual compulsivity, which accounted for 49.4% of the variance in subclinical OCD symptomatology in Study 1, and 37.3% in Study 2. In-depth analyses revealed a compensatory effect between cognitive inflexibility and habitual compulsivity such that both are necessary for OCD symptomatology, but neither is sufficient. These results imply that in order to generate reliable and nuanced models of the endophenotype of OCD symptomatology, it is essential to account for interactions between psychological traits. Moreover, the present findings have important implications for theories on the cognitive roots of OCD, and potentially in the development of interventions that target both cognitive inflexibility and habitual compulsivity.

Multi-omics study reveals associations among neurotransmitter, extracellular vesicle-derived microRNA and psychiatric comorbidities during heroin and methamphetamine withdrawal.

Abstract: Despite decades of research in the field of substance withdrawal, molecular biomarkers and related mechanistic study have generally been lacking. In addition to known neurotransmitters, circulating miRNAs are found in small vesicles known as exosomes within blood that have diagnostic potential and are known to contribute to psychiatric disorders. The aim of this work was to characterize the changes in neurotransmitter and exosomal miRNA profiles during heroin and methamphetamine withdrawal using a cross-sectional study design, and to determine their associations to psychiatric comorbidities in a large group of patients with substance use disorders (SUDs). Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal miRNAs were identified as being associated with the severity of anxiety and depression, as well as the concentrations of neurotransmitters GABA, choline, and serotonin. Bioinformatics analyses established that the differences in the miRNA profile target signaling pathways are significantly associated with developmental and intellectual abnormalities. Notably, a set of dysregulated miRNA signatures including hsa-mia-451a and hsa-mir-21a resulted in an AUC of 0.966 and 0.861, respectively, for predicting the patients with SUDs. Furthermore, hsa-miR-744a-5p was positively correlated with serotonin, and its important role in maintaining neuronal development and function was revealed using an in vitro human induced pluripotent stem cells derived neuronal model. Our results suggest that the miRNA content of circulating exosomes represent a biomolecular "fingerprint" of the progression of substance withdrawal and may uncover the putative mechanism of how these exosomal miRNAs contribute to psychiatric symptoms.

Drug Addiction

Abstract: A decade ago, we hypothesized that drug addiction can be viewed as a transition from voluntary, recreational drug use to compulsive drug-seeking habits, neurally underpinned by a transition from prefrontal cortical to striatal control over drug seeking and taking, as well as a progression from the ventral to the dorsal striatum. Here, in the light of burgeoning, supportive evidence, we reconsider and elaborate this hypothesis, in particular the refinements in our understanding of ventral and dorsal striatal mechanisms underlying goal-directed and habitual drug seeking, the influence of drug-associated Pavlovian-conditioned stimuli on drug seeking and relapse, and evidence for impairments in top-down prefrontal cortical inhibitory control over this behavior. We further review animal and human studies that have begun to define etiological factors and individual differences in the propensity to become addicted to drugs, leading to the description of addiction endophenotypes, especially for cocaine addiction. We consider the prospect of novel treatments for addiction that promote abstinence from and relapse to drug use.

A Randomized Trial Directly Comparing Ventral Capsule and Anteromedial Subthalamic Nucleus Stimulation in Obsessive-Compulsive Disorder: Clinical and Imaging Evidence for Dissociable Effects.

Abstract: (Appeared originally in Biological Psychiatry 2019; 85:726-734) Reprinted under Creative Commons CC-BY license.

Blocking D2/D3 dopamine receptors increases volatility of beliefs when we learn to trust others

Abstract: The ability to flexibly adjust beliefs about other people is crucial for human social functioning. Dopamine has been proposed to regulate the precision of beliefs, but direct behavioural evidence of this is lacking. We investigated how a relatively high dose of the selective D2/D3 dopamine receptor antagonist sulpiride impacts learning about other people’s prosocial attitudes in a repeated trust game. Using a Bayesian model of belief updating, we show that sulpiride increased the volatility of beliefs, which led to higher precision-weights on prediction errors. This effect was entirely driven by participants with genetically conferring higher dopamine availability (Taq1a polymorphism). Higher precision weights were reflected in higher reciprocal behaviour in the repeated trust game but not in single-round trust games. This finding suggests that antipsychotic medication might acutely reduce rigidity of pathological beliefs.

Dissociating reward sensitivity and negative urgency effects on impulsivity in the five-choice serial reaction time task

Abstract: Negative urgency describes the tendency for rash and impulsive behaviour during negative emotional states and has been linked to a number of psychiatric disorders. However, there has been limited research on negative urgency as an explanatory mechanism for impulsivity in experimental animals. Such research has important implications for elucidating the neurobiology of negative urgency and thereby the development of future therapeutic interventions. In this study, we investigated the effects of negative urgency using a partial reinforcement schedule to increase the frequency of non-rewarded (i.e. frustrative) trials in the five-choice serial reaction time task, a widely used task to assess visual attention and impulsivity. Using a Markov chain model to analyse trial-by-trial outcomes we found that premature (i.e. impulsive) responses in the five-choice serial reaction time task were more likely to occur after a non-rewarded trial, and mostly after a previous premature trial. However, contrary to the frustration hypothesis of negative urgency, increasing the probability of reinforcement (p(R)) from p(R) = 0.5 to p(R) = 1 increased the number of premature responses in each session. Micro and macro levels of analyses revealed that impulsivity in the five-choice serial reaction time task is governed by at least two processes, one dependent on the overall level of reinforcement hypothesised to determine the state of behavioural activation, the second dependent on trial-by-trial outcomes consistent with negative urgency effects. These processes may depend on distinct neurobiological mechanisms and have relevance for neuropsychiatric disorders that implicate impulsive behaviours dependent on positive and negative affective states.

Selective D3 receptor antagonism modulates neural response during negative emotional processing in substance dependence

Abstract: Introduction Negative affective states contribute to the chronic-relapsing nature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target. We investigated the effects of selective D3 antagonist, GSK598809, on the neural response to negative emotional processing in substance dependent individuals and healthy controls. Methodology Functional MRI BOLD response was assessed during an evocative image task, 2 h following acute administration of GSK598809 (60 mg) or placebo in a multi-site, double-blind, pseudo-randomised, cross-over design. Abstinent drug dependent individuals (DD, n = 36) comprising alcohol-only (AO, n = 19) and cocaine-alcohol polydrug (PD, n = 17) groups, and matched controls (n = 32) were presented with aversive and neutral images in a block design (contrast of interest: aversive > neutral). Whole-brain mixed-effects and a priori ROI analyses tested for group and drug effects, with identical models exploring subgroup effects. Results No group differences in task-related BOLD signal were identified between DD and controls. However, subgroup analysis revealed greater amygdala/insular BOLD signal in PD compared with AO groups. Following drug administration, GSK598809 increased BOLD response across HC and DD groups in thalamus, caudate, putamen, and pallidum, and reduced BOLD response in insular and opercular cortices relative to placebo. Multivariate analyses in a priori ROIs revealed differential effects of D3 antagonism according to subgroup in substantia nigra; GSK598809 increased BOLD response in AO and decreased response in PD groups. Conclusion Acute GSK598809 modulates the BOLD response to aversive image processing, providing evidence that D3 antagonism may impact emotional regulation. Enhanced BOLD response within D3-rich mesolimbic regions is consistent with its pharmacology and with attenuation of substance-related hypodopaminergic function. However, the lack of group differences in task-related BOLD response and the non-specific effect of GSK598809 between groups makes it difficult to ascertain whether D3 antagonism is likely to be normalising or restorative in our abstinent populations. The suggestion of differential D3 modulation between AO and PD subgroups is intriguing, raising the possibility of divergent treatment responses. Further study is needed to determine whether D3 antagonism should be recommended as a treatment target in substance dependence.

"The wrong tools for the right job": a critical meta-analysis of traditional tests to assess behavioural impacts of maternal separation.

Abstract: Abstract Rationale Unconditioned tasks in rodents have been the mainstay of behavioural assessment for decades, but their validity and sensitivity to detect the behavioural consequences of early life stress (ELS) remains contentious and highly variable. Objectives In the present study, we carried out a meta-analysis to investigate whether persistent behavioural effects, as assessed using unconditioned procedures in rats, are a reliable consequence of early repeated maternal separation, a commonly used procedure in rodents to study ELS. Methods A literature search identified 100 studies involving maternally separated rats and the following unconditioned procedures: the elevated plus maze (EPM); open field test (OFT); sucrose preference test (SPT) and forced swim task (FST). Studies were included for analysis if the separation of offspring from the dam was at least 60 min every day during the pre-weaning period prior to the start of adolescence. Results Our findings show that unconditioned tasks are generally poor at consistently demonstrating differences between control and separated groups with pooled effect sizes that were either small or non-existent (EPM: Hedge’s g = − 0.35, p = 0.01, OFT: Hedge’s g = − 0.32, p = 0.05, SPT: Hedge’s g = − 0.33, p = 0.21, FST: Hedge’s g = 0.99, p = 0.0001). Despite considerable procedural variability between studies, heterogeneity statistics were low; indicating the lack of standardization in the maternal separation protocol was the not the cause of these inconsistent effects. Conclusions Our findings indicate that in general, unconditioned tests of depression and anxiety are not sufficient to reveal the full behavioural repertoire of maternal separation stress should not be relied upon in isolation. We argue that more objective tasks that sensitively detect specific cognitive processes are better suited for translational research on stress-related disorders such as depression.

Cognitive flexibility: neurobehavioral correlates of changing one’s mind

Abstract: Abstract Behavioral and cognitive flexibility allow adaptation to a changing environment. Most tasks used to investigate flexibility require switching reactively in response to deterministic task-response rules. In daily life, flexibility often involves a volitional decision to change behavior. This can be instigated by environmental signals, but these are frequently unreliable. We report results from a novel “change your mind” task, which assesses volitional switching under uncertainty without the need for rule-based learning. Participants completed a two-alternative choice task, and following spurious feedback, were presented with the same stimulus again. Subjects had the opportunity to repeat or change their response. Forty healthy participants completed the task while undergoing a functional magnetic resonance imaging scan. Participants predominantly repeated their choice but changed more when their first response was incorrect or when the feedback was negative. Greater activations for changing were found in the inferior frontal junction, anterior insula (AI), anterior cingulate, and dorsolateral prefrontal cortex. Changing responses were also accompanied by reduced connectivity from the AI and orbitofrontal cortices to the occipital cortex. Using multivariate pattern analysis of brain activity, we predicted with 77% reliability whether participants would change their mind. These findings extend our understanding of cognitive flexibility in daily life by assessing volitional decision-making.

Clozapine-related obsessive–compulsive symptoms and their impact on wellbeing: a naturalistic longitudinal study

Abstract: Abstract Background Obsessive–compulsive symptoms (OCS) are commonly associated with clozapine treatment but are frequently overlooked by clinicians despite their potential impact on patients' quality of life. In this study, we explored whether OCS severity impacted subjective wellbeing and general functioning, independently of depressive and psychotic symptoms. Methods We used anonymised electronic healthcare records from a large cohort of patients who were treated with clozapine and assessed annually for OCS, wellbeing, general functioning, and psychopathology using standardised scales as part of routine clinical practice. We used statistical mixed linear model techniques to evaluate the longitudinal influence of OCS severity on wellbeing and general functioning. Results A total of 184 patients were included, with 527 face-to-face assessments and 64.7% evaluated three or more times. Different linear mixed models demonstrated that OCS in patients treated with clozapine were associated with significantly worse wellbeing scores, independently of depression and psychotic symptoms, but OCS did not impair general functioning. Obsessional thinking and hoarding behaviour, but not compulsions, were significantly associated with the impact on wellbeing, which may be attributable to the ego-syntonic nature of the compulsions. Conclusions Given the frequent occurrence of OCS and their negative impact on wellbeing, we encourage clinicians to routinely assess and treat OCS in patients who are taking clozapine.

Reward Processing as an Indicator of Vulnerability or Compensatory Resilience in Psychoses? Results From a Twin Study

Abstract: Findings of reward disturbances in unaffected relatives of patients with schizophrenia suggest reward disturbances as an endophenotype for schizophrenia. Twin studies, where 1 twin has been diagnosed with a schizophrenia spectrum disorder, can further explore this. We used Danish registries to identify twin pairs with at least 1 twin having a schizophrenia spectrum disorder diagnosis and control twin pairs matched on age, sex, and zygosity. The analyses included data from 34 unaffected co-twins (16 females), 42 probands with schizophrenia spectrum disorder (17 females), and 83 control twins (42 females). Participants performed a modified incentive delay task during functional magnetic resonance imaging. Whole-brain group differences were analyzed by performing comparisons between co-twins and control twins. Correlations with cognitive flexibility were tested. Compared with control twins, co-twins showed no differences in striatal regions, but increased signal in the dorsolateral prefrontal cortex (DLPFC) during missed target contrast was observed. In co-twins, increased DLPFC signal was associated with lower intra-extra dimensional set-shifting scores indicative of higher cognitive flexibility. Unaffected co-twins did not have decreased striatal activity during anticipation as previously reported for patients with schizophrenia. Instead, they showed increased activity in the DLPFC during evaluation of missed target contrast, which correlated with their level of cognitive flexibility. Unaffected co-twins had no diagnosis at a mean age of 40 years. This could indicate that greater cognitive flexibility and increased activity in the right DLPFC during processing of unexpected negative outcome represents a compensatory resilience mechanism in predisposed twins.

Cognitive flexibility, OCD and the brain.

Abstract: This scientific commentary refers to ‘Unbalanced fronto-pallidal neurocircuit underlying set shifting in obsessive-compulsive disorder’ by Kim et al. (https://doi.org/10.1093/brain/awab483).

Threat reversal learning and avoidance habits in generalised anxiety disorder

Abstract: Abstract Avoidance and heightened responses to perceived threats are key features of anxiety disorders. These disorders are characterised by inflexibility in dynamically updating behavioural and physiological responses to aversively conditioned cues or environmental contexts which are no longer objectively threatening, often manifesting in perseverative avoidance. However, less is known about how anxiety disorders might differ in adjusting to threat and safety shifts in the environment or how idiosyncratic avoidance responses are learned and persist. Twenty-eight patients with generalised anxiety disorder (GAD), without DSM co-morbidities, and 27 matched healthy controls were administered two previously established paradigms: Pavlovian threat reversal and shock avoidance habits through overtraining (assessed following devaluation with measures of perseverative responding). For both tasks we used subjective report scales and skin conductance responses (SCR). In the Pavlovian threat reversal task, patients with GAD showed a significantly overall higher SCR as well as a reduced differential SCR response compared to controls in the early but not late reversal phase. During the test of habitual avoidance responding, GAD patients did not differ from controls in task performance, habitual active avoidance responses during devaluation, or corresponding SCR during trials, but showed a trend toward more abstract confirmatory subjective justifications for continued avoidance following the task. GAD patients exhibited significantly greater skin conductance responses to signals of threat than controls, but did not exhibit the major deficits in reversal and safety signal learning shown previously by patients with OCD. Moreover, this patient group, again unlike OCD patients, did not show evidence of altered active avoidance learning or enhanced instrumental avoidance habits. Overall, these findings indicate no deficits in instrumental active avoidance or persistent avoidance habits, despite enhanced responses to Pavlovian threat cues in GAD. They suggest that GAD is characterised by passive, and not excessively rigid, avoidance styles.

Alterations in white matter microstructure in alcohol and alcohol‐polydrug dependence: Associations with lifetime alcohol and nicotine exposure

Abstract: Evidence suggests that alcohol dependence (AD) is associated with microstructural deficits in white matter, but the relationship with lifetime alcohol exposure and the impact of polydrug dependence is not well understood. Using diffusion tensor magnetic resonance (MR) imaging, we examined white matter microstructure in relation to alcohol and polydrug dependence using data from the Imperial College Cambridge Manchester (ICCAM) platform study. Tract‐based spatial statistics were used to examine fractional anisotropy (FA) in a cohort of abstinent AD participants, most of whom had a lifetime history of dependence to nicotine. A further subgroup also had a lifetime history of dependence to cocaine and/or opiates. Individuals with AD had lower FA throughout the corpus callosum, and negative associations with alcohol and nicotine exposure were found. A group‐by‐age interaction effect was found showing greater reductions with age in the alcohol‐dependent group within corpus callosum, overlapping with the group difference. We found no evidence of recovery with abstinence. A comparison of alcohol‐only‐ and alcohol‐polydrug‐dependent groups found no differences in FA. Overall, our findings show that AD is associated with lower FA and suggest that these alterations are primarily driven by lifetime alcohol consumption and cigarette smoking, showing no relationship with exposure to other substances such as cocaine, opiates or cannabis. Reductions in FA across the adult lifespan are more pronounced in AD and offer further support for the notion of accelerated ageing in relation to alcohol dependence. These findings highlight there may be lasting structural differences in white matter in alcohol dependence, despite continued abstinence.

E01 The HD young adult study 2: longitudinal follow up

Abstract:

Background

The HD Young Adult Study provided deep phenotyping of the earliest cohort of adult HD mutation carriers to date. We previously reported elevated levels of neurofilament light protein, suggestive of early neurodegenerative change. Putaminal volumes were also significantly reduced in HD mutation carriers. However, there was no evidence of any motor, cognitive or neuropsychiatric impairment approximately 24 years before expected disease onset.

Aims

We aim to follow up this valuable cohort to quantify longitudinal changes in imaging and biofluid markers and document premanifest emergence of motor, cognitive and neuropsychiatric changes.

Methods

We will undertake two follow up visits on our cohort of 64 young adult premanifest HD mutation carriers (preHD) and 67 matched controls at 5 and 6.5 years post baseline. In addition to the clinical, cognitive, neuropsychiatric, imaging and biofluid assessments acquired at baseline, we will perform novel 7T-MRI and magnetoencephalography assessments in a subset of 20 controls and 20 preHD. This will test for early layer-specific cortical degeneration and functional connectivity. We have also implemented a new cognitive task designed to probe goal-directed behaviour. Finally, we will examine the effect of somatic expansion on brain structure and function.

Results

We will report on early data collection and participant retention. We will present our pilot data on the novel cognitive task and 7T-MRI and magnetoencephalography.

Conclusions

Longitudinal follow up will allow us to identify early neurodegenerative changes in this novel far-from-onset cohort, which has implications for future disease prevention trials.

Theory of visual attention (TVA) applied to rats performing the 5-choice serial reaction time task: differential effects of dopaminergic and noradrenergic manipulations

Abstract: Attention is compromised in many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). While dopamine and noradrenaline systems have been implicated in ADHD, their exact role in attentional processing is yet unknown.We applied the theory of visual attention (TVA) model, adapted from human research, to the rat 5-choice serial reaction time task (5CSRTT) to investigate catecholaminergic modulation of visual attentional processing in healthy subjects of high- and low-attention phenotypes.Rats trained on the standard 5CSRTT and tested with variable stimulus durations were treated systemically with noradrenergic and/or dopaminergic agents (atomoxetine, methylphenidate, amphetamine, phenylephrine and atipamezole). TVA modelling was applied to estimate visual processing speed for correct and incorrect visual perceptual categorisations, independent of motor reaction times, as measures of attentional capacity.Atomoxetine and phenylephrine decreased response frequencies, including premature responses, increased omissions and slowed responding. In contrast, methylphenidate, amphetamine and atipamezole sped up responding and increased premature responses. Visual processing speed was also affected differentially. Atomoxetine and phenylephrine slowed, whereas methylphenidate and atipamezole sped up, visual processing, both for correct and incorrect categorisations. Amphetamine selectively improved visual processing for correct, though not incorrect, responses in high-attention rats only, possibly reflecting improved attention.These data indicate that the application of TVA to the 5CSRTT provides an enhanced sensitivity to capturing attentional effects. Unexpectedly, we found overall slowing effects, including impaired visual processing, following drugs either increasing extracellular noradrenaline (atomoxetine) or activating the α1-adrenoceptor (phenylephrine), while also ameliorating premature responses (impulsivity). In contrast, amphetamine had potential pro-attentional effects by enhancing visual processing, probably due to central dopamine upregulation.

Bobby Fischer and the delusions of a king of logic.

Abstract: This Essay relates the intriguing story of Bobby Fischer and his severe mental illness. It does so through the lens of what appears to be a paradox: how could someone whose mind was so exquisitely tuned to the logic and strategy of chess at the elite level, develop a system of firmly held beliefs that seemed clearly to defy logic and rationality? In fact, we suggest, the case of Bobby Fischer highlights something that is often overlooked: that delusional thinking may be underpinned not by a failure of logic but rather by a train of logic that, though internally consistent, is insufficiently constrained by past experiences and by the capacity to consider prevailing assessments of environmental uncertainty and volatility. Commemorating the 50th anniversary of his unforgettable world championship victory, we examine how his persisting brilliance on the chessboard could co-exist with his profoundly anomalous conception of reality and speculate on how informative this might prove in thinking about the mechanisms of delusion formation.

Specificity of cortical area and thickness as biomarkers for comorbid internalizing and externalizing mental disorders in pre-adolescence

Abstract: Abstract Background: Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical changes represent a simple aggregate of the effects on each disorder, and if comorbidity-related cortical surface changes relate to a distinct genetic underpinning. Methods: We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9-10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (Dysthymia, Major Depressive Disorder, Disruptive Mood Dysregulation Disorder, Agoraphobia, Panic Disorder, Specific Phobia, Separation Anxiety Disorder, Social Anxiety Disorder, Generalized Anxiety Disorder, Post-Traumatic Stress Disorder), externalizing diagnostic groups (Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct disorder) a group with comorbidity of the two and a healthy control group. Genome-wide association analysis and cell type specificity analysis were performed on 4,716 unrelated European participants from this cohort. Results: Reduced cortical surface area but increased thickness occurs across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT changes, while those patient groups without comorbidity had significant thickness increases. Distinct biological pathways were implicated for regional SA and CT changes. Specifically, CT changes were associated with immune-related processes implicating microglia, while SA-related changes related mainly to excitatory neurons. Conclusions: The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be a simple additive neurobiological effect. Distinct risk-adaptation processes, with unique genetic and cell-specific factors may underlie SA and CT changes. Children with highest risk but lowest resilience, both captured in their developmental morphometry, develop a comorbid illness pattern.