Distinct Behavioral Phenotypes Research Articles

Deconstructing the heterogeneity of alcohol use disorder: lifetime comorbid non-alcohol substance use disorder as a distinct behavioral phenotype?

Alcohol use disorder (AUD) is an etiologically and clinically heterogeneous condition. Accumulating evidence suggests that persons with lifetime histories of comorbid AUD and non-alcohol substance use disorder (DRUG) constitute an important subgroup of AUD. This study evaluated the distinctiveness of the comorbid AUD/DRUG behavioral phenotype in a community sample with respect to risk factors, AUD course features, and outcome variables assessed at age 30. Contrast groups included persons with histories of AUD only, DRUG only, and neither AUD nor DRUG. This research utilized a prospective study design with an age-based cohort (n = 732). Participants completed four comprehensive diagnostic evaluations during the high-risk periods of adolescence, emerging adulthood, and young adulthood. The comorbid AUD/DRUG group was distinguished from the AUD only group by risk factors, AUD course features, and outcomes. Group differences in outcomes were also explained by overall substance use disorder (SUD) severity. Persons with AUD/DRUG comorbidity were indistinguishable from those with DRUG only histories with respect to risk factors and outcomes but demonstrated greater overall SUD severity. Persons with AUD only were indistinguishable from those with neither AUD nor DRUG histories in risk factor endorsements and were mostly similar in outcomes. Findings collectively suggest that young adults with histories of AUD only and those with comorbid AUD/DRUG are drawn from dissimilar populations. Similarities between the AUD only group with those absent AUD or DRUG histories are likely related to the former group's developmentally limited AUD course accompanied by relatively few or short-lived alcohol-related problems.

Loss-of-Function Models of the Metabotropic Glutamate Receptor Genes Grm8a and Grm8b Display Distinct Behavioral Phenotypes in Zebrafish Larvae (Danio rerio).

Members of the family of metabotropic glutamate receptors are involved in the pathomechanism of several disorders of the nervous system. Besides the well-investigated function of dysfunctional glutamate receptor signaling in neurodegenerative diseases, neurodevelopmental disorders (NDD), like autism spectrum disorders (ASD) and attention-deficit and hyperactivity disorder (ADHD) might also be partly caused by disturbed glutamate signaling during development. However, the underlying mechanism of the type III metabotropic glutamate receptor 8 (mGluR8 or GRM8) involvement in neurodevelopment and disease mechanism is largely unknown. Here we show that the expression pattern of the two orthologs of human GRM8, grm8a and grm8b, have evolved partially distinct expression patterns in the brain of zebrafish (Danio rerio), especially at adult stages, suggesting sub-functionalization of these two genes during evolution. Using double in situ hybridization staining in the developing brain we demonstrate that grm8a is expressed in a subset of gad1a-positive cells, pointing towards glutamatergic modulation of GABAergic signaling. Building on this result we generated loss-of-function models of both genes using CRISPR/Cas9. Both mutant lines are viable and display no obvious gross morphological phenotypes making them suitable for further analysis. Initial behavioral characterization revealed distinct phenotypes in larvae. Whereas grm8a mutant animals display reduced swimming velocity, grm8b mutant animals show increased thigmotaxis behavior, suggesting an anxiety-like phenotype. We anticipate that our two novel metabotropic glutamate receptor 8 zebrafish models may contribute to a deeper understanding of its function in normal development and its role in the pathomechanism of disorders of the central nervous system.

Fabry Rat Home Cage Behaviors Reveal an Ongoing Pain Phenotype

HomeCageScan (HCS) is an automated behavioral scoring system that can be used to classify and quantify rodent behaviors in the home cage. Although HCS has been used for a number of inducible models of severe pain, little has been done to validate this system in clinically relevant genetic disease models associated with chronic pain such as Fabry disease. It is also unclear if male or female rodents exhibit distinct behavioral phenotypes during ongoing pain. Therefore, we analyzed HCS data from male and female rats with Fabry disease to determine if these rats exhibited ongoing pain. Using principal component analysis, we found both sex and genotype differences in several home cage behaviors. Additionally, we used hierarchical clustering to derive behavioral clusters in an unbiased manner. Analysis of these behavioral clusters showed that Fabry animals exhibited lifestyle changes similar to that seen in patients, which includes moving less, spending less time caring for themselves, exploring less, and sleeping more. Sniffing, one of the exploratory behaviors that is depressed in Fabry animals can be partly restored with the analgesic gabapentin, indicating it may be tied to ongoing pain in our rodent model. Therefore, this approach to HCS data analysis can be used to assess analgesic drug efficacy in Fabry disease and potentially other genetic and inducible models with persistent, ongoing pain. Grant support from (NIH) R37 NS108278-02 (CLS), NIH RO1 NS070711-11 (CLS), NIH HL122358 (MRH), and NIH DK122647 (AM).

Aberrant motor contagion of emotions in psychopathy and high-functioning autism.

Psychopathy and autism are both associated with aberrant social skills and empathy, yet only psychopaths are markedly antisocial and violent. Here, we compared the functional neural alterations underlying these two groups that both have aberrant empathetic abilities but distinct behavioral phenotypes. We studied 19 incarcerated male offenders with high psychopathic traits, 20 males with high-functioning autism, and 19 age-matched healthy controls. All groups underwent functional magnetic resonance imaging while they viewed dynamic happy, angry, and disgusted faces or listened to laughter and crying sounds. Psychopathy was associated with reduced somatomotor responses to almost all expressions, while participants with autism demonstrated less marked and emotion-specific alterations in the somatomotor area. These data suggest that psychopathy and autism involve both common and distinct functional alterations in the brain networks involved in the socioemotional processing. The alterations are more profound in psychopathy, possibly reflecting the more severely disturbed socioemotional brain networks in this population.

Behavioral phenotypes of pediatric temporal lobe epilepsy.

A broad spectrum of emotional-behavioral problems have been reported in pediatric temporal lobe epilepsy (TLE), but with considerable variability in their presence and nature of expression, which hampers precise identification and treatment. The present study aimed to empirically identify latent patterns or behavioral phenotypes and their correlates. Data included parental ratings of emotional-behavioral status on the Behavior Assessment System for Children, 2nd Edition (BASC-2) of 81 children (mean age=11.79, standard deviation [SD]=3.93) with TLE. The nine clinical subscales were subjected to unsupervised machine learning to identify behavioral subgroups. To explore concurrent validity and the underlying composition of the identified clusters, we examined demographic factors, seizure characteristics, psychosocial factors, neuropsychological performance, psychiatric status, and health-related quality of life (HRQoL). Three behavioral phenotypes were identified, which included no behavioral concerns (Cluster 1, 43% of sample), externalizing problems (Cluster 2, 41% of sample), and internalizing problems (Cluster 3, 16% of sample). Behavioral phenotypes were characterized by important differences across clinical seizure variables, psychosocial/familial factors, everyday executive functioning, and HRQoL. Cluster 2 was associated with younger child age, lower maternal education, and higher rate of single-parent households. Cluster 3 was associated with older age at epilepsy onset and higher rates of hippocampal sclerosis and parental psychiatric history. Both Cluster 2 and 3 demonstrated elevated family stress. Concurrent validity was demonstrated through the association of psychiatric (i.e., rate of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) disorders and psychotropic medication) and parent-rated HRQoL variables. Youth with TLE present with three distinct behavioral phenotypes that correspond with important clinical and sociodemographic markers. The current findings demonstrate the variability of behavioral presentations in youth with TLE and provide a preliminary framework for screening and targeting intervention to enhance support for youth with TLE and their families.

Existence of Functional Connectome Fingerprint during Infancy and Its Stability over Months.

The functional connectome fingerprint is a cluster of individualized brain functional connectivity patterns that are capable of distinguishing one individual from others. Although its existence has been demonstrated in adolescents and adults, whether such individualized patterns exist during infancy is barely investigated despite its importance in identifying the origin of the intrinsic connectome patterns that potentially mirror distinct behavioral phenotypes. To fill this knowledge gap, capitalizing on a longitudinal high-resolution structural and resting-state functional MRI dataset with 104 human infants (53 females) with 806 longitudinal scans (age, 16-876 d) and infant-specific functional parcellation maps, we observe that the brain functional connectome fingerprint may exist since infancy and keeps stable over months during early brain development. Specifically, we achieve an ∼78% individual identification rate by using ∼5% selected functional connections, compared with the best identification rate of 60% without connection selection. The frontoparietal networks recognized as the most contributive networks in adult functional connectome fingerprinting retain their superiority in infants despite being widely acknowledged as rapidly developing systems during childhood. The existence and stability of the functional connectome fingerprint are further validated on adjacent age groups. Moreover, we show that the infant frontoparietal networks can reach similar accuracy in predicting individual early learning composite scores as the whole-brain connectome, again resembling the observations in adults and highlighting the relevance of functional connectome fingerprint to cognitive performance. For the first time, these results suggest that each individual may retain a unique and stable marker of functional connectome during early brain development.SIGNIFICANCE STATEMENT Functional connectome fingerprinting during infancy featuring rapid brain development remains almost uninvestigated even though it is essential for understanding the early individual-level intrinsic pattern of functional organization and its relationship with distinct behavioral phenotypes. With an infant-tailored functional connection selection and validation strategy, we strive to provide the delineation of the infant functional connectome fingerprint by examining its existence, stability, and relationship with early cognitive performance. We observe that the brain functional connectome fingerprint may exist since early infancy and remains stable over months during the first 2 years. The identified key contributive functional connections and networks for fingerprinting are also verified to be highly predictive for cognitive score prediction, which reveals the association between infant connectome fingerprint and cognitive performance.

Abstract PO-107: Fibroblast differentiation trajectories elicit regional tissue states in pancreatic cancer

Abstract Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. We recently deconvoluted regional heterogeneity in the human PDAC stroma to assess its role in disease progression and discovered two types of ‘sub-tumor microenvironments’ (subTMEs), called ‘reactive’ and ‘deserted’. These histologically definable tissue states exhibit strong regional relationships with tumor immunity, subtypes, differentiation, and treatment response. Here, we set out to define their cell biological underpinnings through a combination of subTME-specific cancer-associated fibroblast (CAF) models, integrative histopathology, quantitative image analysis, multiOMICs, scRNAseq, and controlled functional assays. Remarkably, the growth patterns of CAF cultures closely recapitulated the characteristic histomorphology of their originating subTMEs, and these distinct phenotypes were accompanied by behavioral differences. Unsupervised graph-based clustering of scRNAseq profiles showed that CAFs largely grouped by their originating subTME yet comprised up to 10 individual clusters. The subTME-specific multi-subpopulation CAF communities self-organized into distinct ‘coordinated states’, represented by cluster-overarching functional profiles and distinct morpho-histological and behavioral phenotypes. These differences originated in cellular differentiation trajectories, with an ‘intermediate’ transitory state evident both in single cell transcriptomics and in situ. Noticeably, this CAF differentiation potential was associated with distinct tumor-related functions and, similar to stem cells, was marked by RNA diversity and pluripotency markers. Therefore, regional TME programs in PDAC appear to result largely from transitions between subpopulation-overarching fibroblast differentiation states that guide multifaceted CAF and immune cell communities into recurrent tissue self-organizational units. Citation Format: Barbara T. Grünwald, Curtis McCloskey, Antoine Devisme, Foram Vyas, Geoffroy Andrieux, Kazeera Aliar, Faiyaz Notta, Grainne O’Kane, Julie Wilson, Jennifer Knox, Sandra Fischer, Thomas Kislinger, Melanie Boerries, Steven Gallinger, Rama Khokha. Fibroblast differentiation trajectories elicit regional tissue states in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-107.

An operant ethanol self-administration paradigm that discriminates between appetitive and consummatory behaviors reveals distinct behavioral phenotypes in commonly used rat strains

Alcohol use disorder (AUD) constitutes a major burden to global health. Recently, the translational success of animal models of AUD has come under increased scrutiny. Efforts to refine models to gain a more precise understanding of the neurobiology of addiction are warranted. Appetitive responding for ethanol (seeking) and its consumption (taking) are governed by distinct neurobiological mechanisms. However, consumption is often inferred from appetitive responding in operant ethanol self-administration paradigms, preventing identification of distinct experimental effects on seeking and taking. In the present study, male Long-Evans, Wistar, and Sprague-Dawley rats were trained to lever press for ethanol using a lickometer-equipped system that precisely measures both appetitive and consummatory behavior. Three distinct operant phenotypes emerged during training: 1) Drinkers, who lever press and consume ethanol; 2) Responders, who lever press but consume little to no ethanol; and 3) Non-responders, who do not lever press. While the prevalence of each phenotype differed across strains, appetitive and consummatory behavior was similar across strains within each phenotype. Appetitive and consummatory behaviors were significantly correlated in Drinkers, but not Responders. Analysis of drinking microstructure showed that greater consumption in Drinkers relative to Responders is due to increased incentive for ethanol rather than increased palatability. Importantly, withdrawal from chronic ethanol exposure resulted in a significant increase in appetitive responding in both Drinkers and Responders, but only Drinkers exhibited a concomitant increase in ethanol consumption. Together, these data reveal important strain differences in appetitive and consummatory responding for ethanol and uncover the presence of distinct operant phenotypes.

Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test.

Humans are exposed daily to complex mixtures of chemical substances via food intake, inhalation, and dermal contact. Developmental neurotoxicity is an understudied area and entails one of the most complex areas in toxicology. Animal studies for developmental neurotoxicity (DNT) are hardly performed in the context of regular hazard studies, as they are costly and time consuming and provide only limited information as to human relevance. There is a need for a combination of in vitro and in silico tests for the assessment of chemically induced DNT in humans. The zebrafish (Danio rerio) embryo (ZFE) provides a powerful model to study DNT because it shows fast neurodevelopment with a large resemblance to the higher vertebrate, including the human system. One of the suitable readouts for DNT testing in the zebrafish is neurobehaviour (stimulus-provoked locomotion) since this provides integrated information on the functionality and status of the entire nervous system of the embryo. In the current study, environmentally relevant pharmaceuticals and their mixtures were investigated using the zebrafish light-dark transition test. Zebrafish embryos were exposed to three neuroactive compounds of concern, carbamazepine (CBZ), fluoxetine (FLX), and venlafaxine (VNX), as well as their main metabolites, carbamazepine 10,11-epoxide (CBZ 10,11E), norfluoxetine (norFLX), and desvenlafaxine (desVNX). All the studied compounds, except CBZ 10,11E, dose-dependently inhibited zebrafish locomotor activity, providing a distinct behavioural phenotype. Mixture experiments with these pharmaceuticals identified that dose addition was confirmed for all the studied binary mixtures (CBZ-FLX, CBZ-VNX, and VNX-FLX), thereby supporting the zebrafish embryo as a model for studying the cumulative effect of chemical mixtures in DNT. This study shows that pharmaceuticals and a mixture thereof affect locomotor activity in zebrafish. The test is directly applicable in environmental risk assessment; however, further studies are required to assess the relevance of these findings for developmental neurotoxicity in humans.

Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model.

Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A "Complete Deletion" (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.

Modeling heritability of temperamental differences, stress reactivity, and risk for anxiety and depression: Relevance to research domain criteria (RDoC).

Animal models provide important tools to study biological and environmental factors that shape brain function and behavior. These models can be effectively leveraged by drawing on concepts from the National Institute of Mental Health Research Domain Criteria (RDoC) Initiative, which aims to delineate molecular pathways and neural circuits that underpin behavioral anomalies that transcend psychiatric conditions. To study factors that contribute to individual differences in emotionality and stress reactivity, our laboratory utilized Sprague-Dawley rats that were selectively bred for differences in novelty exploration. Selective breeding for low versus high locomotor response to novelty produced rat lines that differ in behavioral domains relevant to anxiety and depression, particularly the RDoC Negative Valence domains, including acute threat, potential threat, and loss. Bred Low Novelty Responder (LR) rats, relative to their High Responder (HR) counterparts, display high levels of behavioral inhibition, conditioned and unconditioned fear, avoidance, passive stress coping, anhedonia, and psychomotor retardation. The HR/LR traits are heritable, emerge in the first weeks of life, and appear to be driven by alterations in the developing amygdala and hippocampus. Epigenomic and transcriptomic profiling in the developing and adult HR/LR brain suggest that DNA methylation and microRNAs, as well as differences in monoaminergic transmission (dopamine and serotonin in particular), contribute to their distinct behavioral phenotypes. This work exemplifies ways that animal models such as the HR/LR rats can be effectively used to study neural and molecular factors driving emotional behavior, which may pave the way toward improved understanding the neurobiological mechanisms involved in emotional disorders.

Whole-brain modelling of resting state fMRI differentiates ADHD subtypes and facilitates stratified neuro-stimulation therapy

Recent advances in non-linear computational and dynamical modelling have opened up the possibility to parametrize dynamic neural mechanisms that drive complex behavior. Importantly, building models of neuronal processes is of key importance to fully understand disorders of the brain as it may provide a quantitative platform that is capable of binding multiple neurophysiological processes to phenotype profiles. In this study, we apply a newly developed adaptive frequency-based model of whole-brain oscillations to resting-state fMRI data acquired from healthy controls and a cohort of attention deficit hyperactivity disorder (ADHD) subjects. As expected, we found that healthy control subjects differed from ADHD in terms of attractor dynamics. However, we also found a marked dichotomy in neural dynamics within the ADHD cohort. Next, we classified the ADHD group according to the level of distance of each individual's empirical network from the two model-based simulated networks. Critically, the model was mirrored in the empirical behavior data with the two ADHD subgroups displaying distinct behavioral phenotypes related to emotional instability (i.e., depression and hypomanic personality traits). Finally, we investigated the applicability and feasibility of our whole-brain model in a therapeutic setting by conducting in silico excitatory stimulations to parsimoniously mimic clinical neuro-stimulation paradigms in ADHD. We tested the effect of stimulating any individual brain region on the key network measures derived from the simulated brain network and its contribution in rectifying the brain dynamics to that of the healthy brain, separately for each ADHD subgroup. This showed that this was indeed possible for both subgroups. However, the current effect sizes were small suggesting that the stimulation protocol needs to be tailored at the individual level. These findings demonstrate the potential of this new modelling framework to unveil hidden neurophysiological profiles and establish tailored clinical interventions.

Revisiting Brain Tuberous Sclerosis Complex in Rat and Human: Shared Molecular and Cellular Pathology Leads to Distinct Neurophysiological and Behavioral Phenotypes.

Tuberous sclerosis complex (TSC) is a dominant autosomal genetic disorder caused by loss-of-function mutations in TSC1 and TSC2, which lead to constitutive activation of the mammalian target of rapamycin C1 (mTORC1) with its decoupling from regulatory inputs. Because mTORC1 integrates an array of molecular signals controlling protein synthesis and energy metabolism, its unrestrained activation inflates cell growth and division, resulting in the development of benign tumors in the brain and other organs. In humans, brain malformations typically manifest through a range of neuropsychiatric symptoms, among which mental retardation, intellectual disabilities with signs of autism, and refractory seizures, which are the most prominent. TSC in the rat brain presents the first-rate approximation of cellular and molecular pathology of the human brain, showing many instructive characteristics. Nevertheless, the developmental profile and distribution of lesions in the rat brain, with neurophysiological and behavioral manifestation, deviate considerably from humans, raising numerous research and translational questions. In this study, we revisit brain TSC in human and Eker rats to relate their histopathological, electrophysiological, and neurobehavioral characteristics. We discuss shared and distinct aspects of the pathology and consider factors contributing to phenotypic discrepancies. Given the shared genetic cause and molecular pathology, phenotypic deviations suggest an incomplete understanding of the disease. Narrowing the knowledge gap in the future should not only improve the characterization of the TSC rat model but also explain considerable variability in the clinical manifestation of the disease in humans.

Functional differences in the hypothalamic-pituitary-gonadal axis are associated with alternative reproductive tactics based on an inversion polymorphism

The evolution of social behavior depends on genetic changes, yet, how genomic variation manifests itself in behavioral diversity is still largely unresolved. Chromosomal inversions can play a pivotal role in producing distinct behavioral phenotypes, in particular, when inversion genes are functionally associated with hormone synthesis and signaling. Male ruffs exhibit alternative reproductive tactics (ARTs) with an autosomal inversion determining two alternative morphs with clear behavioral and hormonal differences from the ancestral morph. We investigated hormonal and transcriptomic differences in the pituitary and gonads. Using a GnRH challenge, we found that the ability to synthesize testosterone in inversion carriers is severely constrained, whereas the synthesis of androstenedione, a testosterone precursor, is not. Inversion morphs were able to produce a transient increase in androstenedione following the GnRH injection, supporting the view that pituitary sensitivity to GnRH is comparable to that of the ancestral morph. We then performed gene expression analyses in a second set of untreated birds and found no evidence of alterations to pituitary sensitivity, gonadotropin production or gonad sensitivity to luteinizing hormone or follicle-stimulating hormone across morphs. Inversion morphs also showed reduced progesterone receptor expression in the pituitary. Strikingly, in the gonads, inversion morphs over-expressed STAR, a gene that is located outside of the inversion and responsible for providing the cholesterol substrate required for the synthesis of sex hormones. In conclusion, our results suggest that the gonads determine morph-specific differences in hormonal regulation.

Association between behavioral phenotypes and response to a physical activity intervention using gamification and social incentives: Secondary analysis of the STEP UP randomized clinical trial.

Participants often vary in their response to behavioral interventions, but methods to identify groups of participants that are more likely to respond are lacking. In this secondary analysis of a randomized clinical trial, we used baseline characteristics to group participants into distinct behavioral phenotypes and evaluated differential responses to a physical activity intervention. Latent class analysis was used to segment participants based on baseline participant data including demographics, validated measures of psychosocial variables, and physical activity behavior. The trial included 602 adults from 40 U.S. states with body mass index ≥25 who were randomized to control or one of three gamification interventions (supportive, collaborative, or competitive) to increase physical activity. Daily step counts were monitored using a wearable device for a 24-week intervention with 12 weeks of follow-up. The model segmented participants into three classes named for key defining traits: Class 1, extroverted and motivated; Class 2, less active and less social; Class 3, less motivated and at-risk. Adjusted regression models were used to test for differences in intervention response relative to control within each behavioral phenotype. In Class 1, only participants in the competitive arm increased their mean daily steps during the intervention (adjusted difference, 945; 95% CI, 352-1537; P = .002), but it was not sustained during follow-up. In Class 2, participants in all three gamification arms significantly increased their mean daily steps compared to control during the intervention (supportive arm adjusted difference 1172; 95% CI, 363-1980; P = .005; collaborative arm adjusted difference 1119; 95% CI, 319-1919; P = .006; competitive arm adjusted difference 1179; 95% CI, 400-1957; P = .003) and all three had sustained impact during follow-up. In Class 3, none of the interventions had a significant effect on physical activity. Three behavioral phenotypes were identified, each with a different response to the interventions. This approach could be used to better target behavioral interventions to participants that are more likely to respond to them.

A-092 Behavioral Phenotypes of Childhood Idiopathic Epilepsies

Abstract Objective To characterize the presence and nature of discrete behavioral phenotypes and their correlates in a cohort of youth with new and recent onset focal and generalized epilepsies (YWE). Methods The parents of 297 YWE (age 8–18; n = 183) and typically developing participants (n = 107), completed the Child Behavior Checklist. The 8 behavior problem scales were subjected to hierarchical clustering analytics to identify behavioral subgroups. Factors examined included: demographics, neuropsychological data, history of academic problems, epilepsy characteristics, parental IQ and education, cortical thickness, daily executive functioning, and number of lifetime-to-date DSM-IV diagnoses. Results Hierarchical clustering identified three behavioral phenotypes which included: no behavioral complications (Cluster 1, 67% of YWE), internalizing problems (Cluster 2, 11% of YWE), and combined internalizing and externalizing problems (Cluster 3, 22% of YWE). These behavioral phenotypes were characterized by orderly differences in the factors analyzed. Cluster 1 was most similar to controls across most metrics while Cluster 3 was the most abnormal. Epilepsy syndrome was not a predictor of cluster membership. Conclusion YWE fall into 3 distinct behavioral phenotypes associated with a variety of co-occurring features and comorbidities. This approach identifies important phenotypes of behavior problem presentations and their accompanying factors that serve to advance clinical and theoretical understanding of the behavioral complications of children with epilepsy and the complex conditions with which they co-occur.

Behavioral phenotypes of childhood idiopathic epilepsies.

To characterize the presence and nature of discrete behavioral phenotypes and their correlates in a cohort of youth with new and recent onset focal and generalized epilepsies. The parents of 290 youth (age = 8-18 years) with epilepsy (n=183) and typically developing participants (n=107) completed the Child Behavior Checklist for children aged 6-18 from the Achenbach System of Empirically Based Assessment. The eight behavior problem scales were subjected to hierarchical clustering analytics to identify behavioral subgroups. To characterize the external validity and co-occurring comorbidities of the identified subgroups, we examined demographic features (age, gender, handedness), cognition (language, perception, attention, executive function, speed), academic problems (present/absent), clinical epilepsy characteristics (epilepsy syndrome, medications), familial factors (parental intelligence quotient, education, employment), neuroimaging features (cortical thickness), parent-observed day-to-day executive function, and number of lifetime-to-date Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnoses. Hierarchical clustering identified three behavioral phenotypes, which included no behavioral complications (Cluster 1, 67% of epilepsy cohort [n=122]), nonexternalizing problems (Cluster 2, 11% of cohort [n=21]), and combined internalizing and externalizing problems (Cluster 3, 22% of cohort [n=40]). These behavioral phenotypes were characterized by orderly differences in personal characteristics, neuropsychological status, history of academic problems, parental status, cortical thickness, daily executive function, and number of lifetime-to-date DSM-IV diagnoses. Cluster 1 was most similar to controls across most metrics, whereas Cluster 3 was the most abnormal compared to controls. Epilepsy syndrome was not a predictor of cluster membership. Youth with new and recent onset epilepsy fall into three distinct behavioral phenotypes associated with a variety of co-occurring features and comorbidities. This approach identifies important phenotypes of behavior problem presentations and their accompanying factors that serve to advance clinical and theoretical understanding of the behavioral complications of children with epilepsy and the complex conditions with which they co-occur.

O1.5. CLUSTERING-BASED BEHAVIOURAL PHENOTYPES OF INTRINSIC MOTIVATION IN SCHIZOPHRENIA DETERMINED USING OBJECTIVELY QUANTIFIED REAL-WORLD PERFORMANCE

BackgroundIntrinsic motivation (IM) deficits are a prominent feature of schizophrenia that substantially impacts functional outcome. Previous investigations have primarily assessed IM as a general construct or towards specific activities, but multifaceted examination of IM using objective and ecologically valid means has been lacking. The current study aimed to determine whether IM-driven real-world behaviours of individuals with and without schizophrenia reveal distinct behavioural phenotypes that predict differential clinical and functional profiles.MethodsForty-five stable adult outpatients with schizophrenia or schizoaffective disorder (SZ) and 47 healthy controls (HC), group-matched for age and sex, completed the study. Wireless motion capture was used to quantify participants’ behaviour (during two previously validated 15-minute open-field tasks) aligning with distinct aspects of IM: exploratory behaviour (in an unfamiliar setting that contained common and uncommon objects) and unincentivized activity engagement (under provision of explicit choice between active versus passive engagement options). Sparse k-means clustering was applied to task-derived indices of locomotion and object exploration, and activity duration, intensity, and persistence to identify behaviourally differentiable subgroups. Clusters were compared across standard clinical measures of general amotivation, cognition, and community functioning. Diagnostic group by cluster assignment interaction effects were evaluated to identify potential discrepancies in within-cluster SZ versus HC differences across clusters.ResultsThree clusters emerged: medium activity and low exploration (20 SZ and 19 HC), low activity and medium exploration (15 SZ and 8 HC), and high activity and exploration (10 SZ and 20 HC). Cluster assignment did not significantly predict diagnostic group (Fisher’s exact p=0.067) but indicated increased odds of diminished exploration or activity in SZ (odds ratio=2.57, p=0.047). General amotivation differed across clusters (F(2,89)=6.31, p=0.003) due to significantly elevated scores in the low exploration and low activity clusters versus the high performance cluster. Evaluation of the diagnostic group by cluster assignment interaction effect for amotivation (F(2,86)=3.12, p=0.062) revealed significantly higher scores in SZ versus HC within the low exploration and high performance clusters, but not the low activity cluster. Evaluation of the interaction effect for community functioning (F(2,86)=4.86, p=0.007) revealed significantly lower scores in SZ versus HC within all clusters, with the discrepancy increasing from high performance to low activity to low exploration.DiscussionMultidimensional characterization of IM stands to provide valuable insights into motivation and functioning deficits in schizophrenia that behaviourally manifest differently across individuals. Impairment in IM-driven behaviour may be substantially detrimental particularly for individuals with schizophrenia, as SZ participants demonstrated clinically observable deficits even compared to within-cluster HC counterparts. The current lack of objective standards to measure IM underscores the benefit of behaviour-based characterization. Further, as IM has been deemed a valuable psychosocial intervention target in schizophrenia, multidimensional behavioural phenotyping may help guide personalized therapy by differentiating between IM impairments demanding amelioration versus unimpaired tendencies that may be leveraged to facilitate remediation.

Arid1b haploinsufficiency in parvalbumin- or somatostatin-expressing interneurons leads to distinct ASD-like and ID-like behavior

Inhibitory interneurons are essential for proper brain development and function. Dysfunction of interneurons is implicated in several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID). We have previously shown that Arid1b haploinsufficiency interferes with interneuron development and leads to social, cognitive, and emotional impairments consistent with ASD and ID. It is unclear, however, whether interneurons play a major role for the behavioral deficits in Arid1b haploinsufficiency. Furthermore, it is critical to determine which interneuron subtypes contribute to distinct behavioral phenotypes. In the present study, we generated Arid1b haploinsufficient mice in which a copy of the Arid1b gene is deleted in either parvalbumin (PV) or somatostatin (SST) interneurons, and examined their ASD- and ID-like behaviors. We found that Arid1b haploinsufficiency in PV or SST interneurons resulted in distinct features that do not overlap with one another. Arid1b haploinsufficiency in PV neurons contributed to social and emotional impairments, while the gene deletion in the SST population caused stereotypies as well as learning and memory dysfunction. These findings demonstrate a critical role of interneurons in Arid1b haploinsufficient pathology and suggest that PV and SST interneurons may have distinct roles in modulating neurological phenotypes in Arid1b haploinsufficiency-induced ASD and ID.

Monoaminergic balances predict non-depression-like phenotype in Learned Helplessness Paradigm

Monoamine neuronal system abnormality is hypothesized to be the neurochemical pathology in depression, as it is supported by the efficacy of conventional antidepressants. The learned helplessness paradigm generates depression-like (LH) and non-depression-like (non-LH) behavioral models. Examination of the neurochemical states accompanying such distinct behavioral phenotypes can facilitate investigations of the mechanisms underlying resilience and the search for new strategies for depression prevention and therapy. Here, we measured the levels of monoamines, including noradrenaline (NA), serotonin (5-HT), and dopamine (DA), and their metabolites in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), hippocampus, nucleus accumbens (NAc), amygdala, and striatum in LH, non-LH, and non-manipulated (naïve) rats. Compared with LH rats, non-LH rats showed lower 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and NA turnovers in the amygdala and higher 5-HT levels in the NAc. Compared with naïve rats, non-LH rats showed increased DA and homovanillic acid (HVA) levels in the amygdala and increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus and NAc, whereas LH rats exhibited increased HVA levels and DA turnovers in the hippocampus, decreased 5-HIAA levels in the mPFC, increased DA turnovers in the OFC, and decreased DA turnovers in the amygdala. Comparison between LH and non-LH suggest that suppressed amygdaloid NA activity and elevated 5-HT activity in the NAc are related to stress resilience. Changes that occurred in LH or non-LH rats when compared with those in naïve rats suggest that suppressed DA activity in the hippocampus and OFC; elevated DA activity in the amygdala; and facilitated 5-HT activity in the hippocampus, mPFC, and NAc are phenomena related to the expression of a non-depression-like phenotype.