Heritability of overlapping impulsivity and compulsivity dimensional phenotypes

Funder: David Winston Turner Endowment FundAbstract: Impulsivity and compulsivity are traits relevant to a range of mental health problems and have traditionally been conceptualised as distinct constructs. Here, we reconceptualised impulsivity and compulsivity as partially overlapping phenotypes using a bifactor modelling approach and estimated heritability for their shared and unique phenotypic variance within a classical twin design. Adult twin pairs (N = 173) completed self-report questionnaires measuring psychological processes related to impulsivity and compulsivity. We fitted variance components models to three uncorrelated phenotypic dimensions: a general impulsive–compulsive dimension; and two narrower phenotypes related to impulsivity and obsessiveness.There was evidence of moderate heritability for impulsivity (A2 = 0.33), modest additive genetic or common environmental effects for obsessiveness (A2 = 0.25; C2 = 0.23), and moderate effects of common environment (C2 = 0.36) for the general dimension, This general impulsive–compulsive phenotype may reflect a quantitative liability to related mental health disorders that indexes exposure to potentially modifiable environmental risk factors

Mapping Compulsivity in the DSM-5 Obsessive Compulsive and Related Disorders: Cognitive Domains, Neural Circuitry, and Treatment.

Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in compulsive disorders such as obsessive compulsive disorder

Review: Non‐invasive brain stimulation in behavioral addictions: insights from direct comparisons with substance use disorders

Background and Objectives Treatment models developed for substance use disorders (SUDs) are often applied to behavioral addictions (BAs), even though the correspondence between these forms of addiction is unclear. This is also the case for noninvasive brain stimulation (NIBS) techniques being investigated as potential treatment interventions for SUDs and BAs. Objectives: to contribute to the development of more effective NIBS protocols for BAs. Methods Two literature searches using PubMed and Google Scholar were conducted identifying a total of 35 studies. The first search identified 25 studies examining the cognitive and neurophysiological overlap between BAs and SUDs. The second search yielded 10 studies examining the effects of NIBS in BAs. Results Impulsivity and cravings show behavioral and neurophysiologic overlaps between BAs and SUDs, however, other outcomes like working‐memory abilities or striatal connectivity, differ between BAs and SUDs. The most‐employed NIBS target in BAs was dorsolateral prefrontal cortex (DLPFC), which was associated with a decrease in cravings, and less frequently with a reduction of addiction severity. Conclusions and Scientific Significance Direct comparisons between BAs and SUDs revealed discrepancies between behavioral and neurophysiological outcomes, but overall, common and distinctive characteristics underlying each disorder. The lack of complete overlap between BAs and SUDs suggests that investigating the cognitive and neurophysiological features of BAs to create individual NIBS protocols that target risk‐factors associated specifically with BAs, might be more effective than transferring protocols from SUDs to BAs. Individualizing NIBS protocols to target specific risk‐factors associated with each BA might help to improve treatment interventions for BAs. (Am J Addict 2019;00:1–23

Brain micro-architecture and disinhibition: a latent phenotyping study across 33 impulsive and compulsive behaviours

Abstract: Impulsive and compulsive symptoms are common, tend to co-occur, and collectively account for a substantive global disease burden. Latent phenotyping offers a promising approach to elucidate common neural mechanisms conferring vulnerability to such symptoms in the general population. We utilised the Neuroscience in Psychiatry Network (NSPN), a cohort of young people (aged 18–29 years) in the United Kingdom, who provided questionnaire data and Magnetic Resonance Imaging scans. Partial Least Squares was used to identify brain regions in which intra-cortical myelination (measured using Magnetisation Transfer, MT) was significantly associated with a disinhibition phenotype, derived from bi-factor modelling of 33 impulsive and compulsive problem behaviours. The neuroimaging sample comprised 126 participants, mean 22.8 (2.7 SD) years old, being 61.1% female. Disinhibition scores were significantly and positively associated with higher MT in the bilateral frontal and parietal lobes. 1279 genes associated with disinhibition-related brain regions were identified, which were significantly enriched for functional biological interactions reflecting receptor signalling pathways. This study indicates common microstructural brain abnormalities contributing to a multitude of related, prevalent, problem behaviours characterised by disinhibition. Such a latent phenotyping approach provides insights into common neurobiological pathways, which may help to improve disease models and treatment approaches. Now that this latent phenotyping model has been validated in a general population sample, it can be extended into patient settings

How obsessive-compulsive and bipolar disorders meet each other? An integrative gene-based enrichment approach

Background: The novel approaches to psychiatric classification assume that disorders, contrary to what was previously thought, are not completely separate phenomena. In this regard, in addition to symptom-based criteria, disturbances are also considered on the basis of lower level components. With this viewpoint, identifying common biochemical markers would be beneficial in adopting a comprehensive strategy for prevention, diagnosis and treatment. Main body: One of the problematic areas in clinical settings is the coexistence of both obsessive-compulsive disorder (OCD) and bipolar disorder (BD) that is challenging and difficult to manage. In this study, using a system biologic approach we aimed to assess the interconnectedness of OCD and BD at different levels. Gene Set Enrichment Analysis (GSEA) method was used to identify the shared biological network between the two disorders. The results of the analysis revealed 34 common genes between the two disorders, the most important of which were CACNA1C, GRIA1, DRD2, NOS1, SLC18A1, HTR2A and DRD1. Dopaminergic synapse and cAMP signaling pathway as the pathways, dopamine binding and dopamine neurotransmitter receptor activity as the molecular functions, dendrite and axon part as the cellular component and cortex and striatum as the brain regions were the most significant commonalities. Short conclusion: The results of this study highlight the role of multiple systems, especially the dopaminergic system in linking OCD and BD. The results can be used to estimate the disease course, prognosis, and treatment choice, particularly in the cases of comorbidity. Such perspectives, going beyond symptomatic level, help to identify common endophenotypes between the disorders and provide diagnostic and therapeutic approaches based on biological in addition to the symptomatic level. © 2020 The Author(s)

Children at high-familial risk for Eating Disorders: study of psychopathology, neuropsychology and neuroimaging

Evidence suggest that a diagnosis of an eating disorder (ED) is associated with differential neurocognitive functioning and neural mechanisms. However, whether differences are present prior to the onset of the disorder (‘trait’), possibly affecting risk status for development of an ED; or whether differences are a consequence of secondary features of the disorder such as low nutritional intake (‘state’), is not clear. Family studies have established that first-degree relatives of individuals with ED are at higher risk of developing an ED than the general population, therefore, children of mothers with an ED (current or history) are the perfect group to study risk pathways to developing ED. This is the first study to explore neural alterations as well as neurocognitive functioning in girls at high-familial risk of developing an ED, in comparison to children who are not. High risk status of girls were defined using a maternal clinical interview to confirm lifetime ED diagnosis. Intelligence, social cognition, reward responsiveness, neuropsychological function and brain imaging were investigated in girls at high-familial risk. Girls at high familial risk demonstrated difficulties in set-shifting (cognitive flexibility) and increased reward responsiveness when compared to girls at low risk. Girls at risk also had overall increased Gray matter (GM) volume, and specifically increased GM in amygdala, caudate, hippocampus and orbitofrontal cortex when compared to girls at low risk. There were no differences in white matter (WM) connectivity from amygdala to areas of the cortex in girls at risk compared to girls at low risk. Results suggest that differences observed may constitute putative intermediate phenotypes for ED, although this requires further study with larger samples. Findings are important as they support hypothesis of altered set-shifting as an endophenotype for ED. They also provide evidence of alterations in ventral (limbic) neurcircuit that includes the amygdala and caudate, both of which are of importance for identifying emotional stimuli and generation of affective response to these as well as playing a role in reward processes and behaviour regulation

Apathy and Impulsivity in Frontotemporal Lobar Degeneration Syndromes

There has been considerable progress in the clinical, pathological and genetic fractionation of frontotemporal lobar degeneration syndromes in recent years, driving the development of novel diagnostic criteria. However, phenotypic boundaries are not always distinct and syndromes converge with disease progression, limiting the insights available from traditional diagnostic classification. Alternative transdiagnostic approaches may provide novel insights into the neurobiological underpinnings of symptom commonalities across the frontotemporal lobar degeneration spectrum. In this thesis, I illustrate the use of transdiagnostic methods to investigate apathy and impulsivity. These two multifaceted constructs are observed across all frontotemporal lobar degeneration syndromes, including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. They cause substantial patient morbidity and carer distress, often coexist and are undertreated. Using data from the Pick’s disease and Progressive supranuclear palsy Prevalence and INcidence (PiPPIN) Study, I examine the frequency, characteristics and components of apathy and impulsivity across the frontotemporal lobar degeneration spectrum. A principal component analysis of the neuropsychological data identified eight distinct components of apathy and impulsivity, separating patient ratings, carer ratings and behavioural tasks. Apathy and impulsivity measures were positively correlated, frequently loading onto the same components and providing evidence of their overlap. The data confirmed that apathy and impulsivity are common across the spectrum of frontotemporal lobar degeneration syndromes. Voxel based morphometry revealed distinct neural correlates for the components of apathy and impulsivity. Patient ratings correlated with white matter changes in the corticospinal tracts, which may reflect retained insight into their physical impairments. Carer ratings correlated with grey and white matter changes in frontostriatal, frontotemporal and brainstem systems, which have previously been implicated in motivation, arousal and goal directed behaviour. Response inhibition deficits on behavioural tasks correlated with focal frontal cortical atrophy in areas implicated in goal-directed behaviour and cognitive control. Diffusion tensor imaging was highly sensitive to the white matter changes underlying apathy and impulsivity in frontotemporal lobar degeneration syndromes. Diffusion tensor imaging findings were largely consistent with voxel-based morphometry, with carer ratings reflecting widespread changes while objective measures showed changes in focal, task-specific brain regions. White matter abnormalities often extended beyond observed grey matter changes, providing supportive evidence that white matter dysfunction represents a core pathophysiology in frontotemporal lobar degeneration. Apathy was a significant predictor of death within two and a half years from assessment, consistent with studies linking apathy to poor outcomes. The prognostic importance of apathy warrants more accurate measurement tools to facilitate clinical trials. Although causality remains unclear, the influence of apathy on survival suggests effective symptomatic treatments may also prove disease-modifying. These findings have several implications. First, clinical studies for apathy/impulsivity in frontotemporal lobar degeneration syndromes should target patients who present with these symptoms, irrespective of their diagnostic category. Second, data-driven approaches can inform the choice of assessment tools for clinical trials, and their link to neural drivers of apathy and impulsivity. Third, the components and their neural correlates provide a principled means to measure (and interpret) the effects of novel treatments in the context of frontotemporal lobar degeneration.NIHR Cambridge Biomedical Research Centre, the Cambridge Home and EU Scholarship Scheme, the James F McDonnell Foundation (21st Century Science Initiative for Understanding Human Cognition), Wellcome Trust (103838); Medical Research Council (MC US A060 30PQ, and RG62761), the Cambridge Brain Bank, PSP association and the Evelyn Trust

Regional, circuit and network heterogeneity of brain abnormalities in psychiatric disorders

The substantial individual heterogeneity that characterizes people with mental illness is often ignored by classical case-control research, which relies on group mean comparisons. Here we present a comprehensive, multiscale characterization of the heterogeneity of gray matter volume (GMV) differences in 1,294 cases diagnosed with one of six conditions (attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive-compulsive disorder and schizophrenia) and 1,465 matched controls. Normative models indicated that person-specific deviations from population expectations for regional GMV were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience-ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia and attention-deficit/hyperactivity disorder. Phenotypic differences between cases assigned the same diagnosis may thus arise from the heterogeneous localization of specific regional deviations, whereas phenotypic similarities may be attributable to the dysfunction of common functional circuits and networks