Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively-driven reverse translation framework.

A quantitatively-driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively-based reverse translation approach to clinical development. This approach was applied to characterize predictors of the trajectory of cognition in Hunter syndrome (Mucopolysaccharidosis Type II; MPS-II), a rare X-linked lysosomal storage disorder, highly heterogeneous in its course. Specifically, we considered ways to refine target populations based on age, cognitive status, and biomarkers, that is, cerebrospinal fluid glycosaminoglycans (GAG), at trial entry. Data from a total of 138 subjects (age range 2.5 to 10.1 years) from Takeda-sponsored internal studies and external natural history studies in MPS-II were included. Quantitative analyses using mixed-effects models were performed to characterize the relationships between neurocognitive outcomes and potential indicators of disease progression. Results revealed a specific trajectory in cognitive development across age with an initial progressive phase, followed by a plateau between 4 and 8 years and then a variable declining phase. Additionally, results suggest a faster decline in cognition among subjects with lower cognitive scores or with higher cerebrospinal fluid GAG at enrollment. These results support differences in the neurocognitive course of MPS-II between distinct groups of patients based on age, cognitive function, and biomarker status at enrollment. These differences should be considered when designing future clinical trials.

Chimpanzees (Pan troglodytes) with better task-based delay of gratification skills are rated as less impulsive, more agreeable, and smarter.

Delay of gratification and inhibitory control are generally considered measures of self-control. In humans, individual differences in measures of self-control are associated with a host of behavioral, neurological, cognitive, and health-related outcomes. Self-control is not unique to humans and has been demonstrated in a variety of nonhuman species using a variety of paradigms. In this study, the effect of sex and age on delay of gratification performance, as measured by the hybrid delay task, was tested in a sample of 88 chimpanzees. Additionally, whether individual differences in hybrid delay task performance were associated with different aspects of personality was examined in this study. Contrary to reports in human subjects, geriatric male chimpanzees were found to perform more efficiently than adult males, while no age differences were found between geriatric and adult females. Indeed, delay of gratification efficiency was positively associated with age in males and negatively associated with age in females. Chimpanzees that performed more efficiently on the hybrid delay task were also found to be rated as more intelligent, more extraverted, and less impulsive. These findings suggest that objective measures of efficiency in delay of gratification tasks are associated with different dimensions of personality, which have some overlapping construct validity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Principles and procedures for revising the hierarchical taxonomy of psychopathology.

Quantitative, empirical approaches to establishing the structure of psychopathology hold promise to improve on traditional psychiatric classification systems. The Hierarchical Taxonomy of Psychopathology (HiTOP) is a framework that summarizes the substantial and growing body of quantitative evidence on the structure of psychopathology. To achieve its aims, HiTOP must incorporate emerging research in a systematic, ongoing fashion. In this article, we describe the historical context and grounding of the principles and procedures for revising the HiTOP framework. Informed by strengths and shortcomings of previous classification systems, the proposed revisions protocol is a formalized system focused around three pillars: (a) prioritizing systematic evaluation of quantitative evidence by a set of transparent criteria and processes, (b) balancing stability with flexibility, and (c) promoting inclusion over gatekeeping in all aspects of the process. We detail how the revisions protocol will be applied in practice, including the scientific and administrative aspects of the process. Additionally, we describe areas of the HiTOP structure that will be a focus of early revisions and outline challenges for the revisions protocol moving forward. The proposed revisions protocol is designed to ensure that the HiTOP framework reflects the current state of scientific knowledge on the structure of psychopathology and fulfils its potential to advance clinical research and practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Characterizing the personality and gray matter volume of chimpanzees that exhibit autism-related socio-communicative phenotypes.

Autism spectrum disorder (ASD) is a developmental disorder characterized by stereotypies or repetitive behaviors and impairments in social behavior and socio-communicative skills. One hallmark phenotype of ASD is poor joint attention skills compared to neurotypical controls. In addition, individuals with ASD have lower scores on several of the Big 5 personality dimensions, including Extraversion. Here, we examine these traits in a nonhuman primate model (chimpanzees; Pan troglodytes) to further understand the relationship between personality and joint attention skills, as well as the genetic and neural systems that contribute to these phenotypes. We used archival data including receptive joint attention (RJA) performance, personality based on caretaker ratings, and magnetic resonance images from 189 chimpanzees. We found that, like humans, chimpanzees who performed worse on the RJA task had lower Extraversion scores. We also found that joint attention skills and several personality dimensions, including Extraversion, were significantly heritable. There was also a borderline significant genetic correlation between RJA and Extraversion. A conjunction analysis examining gray matter volume showed that there were five main brain regions associated with both higher levels of Extraversion and social cognition. These regions included the right posterior middle and superior temporal gyrus, bilateral inferior frontal gyrus, left inferior frontal sulcus, and left superior frontal sulcus, all regions within the social brain network. Altogether, these findings provide further evidence that chimpanzees serve as an excellent model for understanding the mechanisms underlying social impairment related to ASD. Future research should further examine the relationship between social cognition, personality, genetics, and neuroanatomy and function in nonhuman primate models.

Assessing the measurement invariance of the Personality Inventory for DSM-5 across Black and White americans.

The Personality Inventory for DSM-5 (PID-5) is the primary tool for assessing maladaptive personality traits within the DSM-5 alternative model for personality disorders. Evidence has begun to accumulate on the replicability and measurement invariance of its five-domain factor structure across countries, clinical and community populations, and sex, but its equivalency across racial groups within a given country is largely unstudied. Attempting to replicate the evidence of noninvariance demonstrated by Bagby et al. (2022), we examined the factor structure of the PID-5 across White Americans (n = 612) and Black Americans (n = 613) within the United States. The five-domain structure emerged across both samples with reasonably congruent factor loadings. Therefore, we tested for measurement invariance using the 13-step framework advocated by Marsh et al. (2009) for personality data. We found support for the PID-5's comparability across racial groups, offering some preliminary backing for its use with Black Americans, though additional evidence is needed to clarify the conflicting results and further validate the instrument. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Using a smartwatch and smartphone to assess early Parkinson's disease in the WATCH-PD study.

Digital health technologies can provide continuous monitoring and objective, real-world measures of Parkinson's disease (PD), but have primarily been evaluated in small, single-site studies. In this 12-month, multicenter observational study, we evaluated whether a smartwatch and smartphone application could measure features of early PD. 82 individuals with early, untreated PD and 50 age-matched controls wore research-grade sensors, a smartwatch, and a smartphone while performing standardized assessments in the clinic. At home, participants wore the smartwatch for seven days after each clinic visit and completed motor, speech and cognitive tasks on the smartphone every other week. Features derived from the devices, particularly arm swing, the proportion of time with tremor, and finger tapping, differed significantly between individuals with early PD and age-matched controls and had variable correlation with traditional assessments. Longitudinal assessments will inform the value of these digital measures for use in future clinical trials.

Hippocampal anterior- posterior shift in childhood and adolescence.

Hippocampal-cortical networks play an important role in neurocognitive development. Applying the method of Connectivity-Based Parcellation (CBP) on hippocampal-cortical structural covariance (SC) networks computed from T1-weighted magnetic resonance images, we examined how the hippocampus differentiates into subregions during childhood and adolescence (N = 1105, 6-18 years). In late childhood, the hippocampus mainly differentiated along the anterior-posterior axis similar to previous reported functional differentiation patterns of the hippocampus. In contrast, in adolescence a differentiation along the medial-lateral axis was evident, reminiscent of the cytoarchitectonic division into cornu ammonis and subiculum. Further meta-analytical characterization of hippocampal subregions in terms of related structural co-maturation networks, behavioural and gene profiling suggested that the hippocampal head is related to higher order functions (e.g. language, theory of mind, autobiographical memory) in late childhood morphologically co-varying with almost the whole brain. In early adolescence but not in childhood, posterior subicular SC networks were associated with action-oriented and reward systems. The findings point to late childhood as an important developmental period for hippocampal head morphology and to early adolescence as a crucial period for hippocampal integration into action- and reward-oriented cognition. The latter may constitute a developmental feature that conveys increased propensity for addictive disorders.

Situating Psychopathy Within the DSM-5 Alternative Model of Personality Disorders (AMPD) Among Italian Community-Dwelling Adults.

Given growing evidence for a joint hierarchical framework of clinical and personality symptomatology, situating triarchic traits within this model would acknowledge transdiagnostic trait-related variance and provide a basis for linking the DSM-5 Alternative Model of Personality Disorders (AMPD) domains to established indicators of these neurobehavioral traits. The current study (N = 2,041 Italian adults) sought to replicate and extend recent evidence regarding the locations of triarchic traits within the AMPD and to examine relations with criterion measures at different levels of the hierarchy. "Bass-ackwards" analyses revealed a hierarchical structure of personality pathology in which triarchic traits aligned with broad dispositional domains of the AMPD. Boldness, meanness, and disinhibition were clearly situated within the Externalizing branch of the hierarchy and helped to differentiate the Negative Affect, Antagonism, Detachment, and Disinhibition domains at lower levels. The current findings support the view of psychopathy as multidimensional and encompassing developmentally meaningful and neurobehaviorally relevant traits.

Pathological personality in relation to multiple domains of quality of life and impairment: Evidence for the specific relevance of the maladaptive poles of major trait domains.

The current study examined whether personality domains have nonmonotonic relationships with functional outcomes, specifically in relation to quality of life and impairment. Four samples were utilized, which were drawn from the United States and Germany. Personality trait domains were measured via the IPIP-NEO and PID-5; quality of life (QoL) was measured with the WHOQOL-BREF, and impairment was measured using the WHODAS-2.0. The PID-5 was analyzed in all four samples. Two-line testing, which fits two spline regression lines separated at a break point, was conducted to evaluate potential nonmonotonicity of the relationship between personality traits and quality of life. Overall, results demonstrated little support for nonmonotonic relationships in the PID-5 and IPIP-NEO dimensions. Rather, our results indicate that there is one clear pathological pole of major domains of personality that is associated with lower quality of life and increased impairment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychopathology in children: The transdiagnostic contribution of affiliative capacity and inhibitory control.

Recent initiatives have focused on integrating transdiagnostic biobehavioral processes or dispositions with dimensional models of psychopathology. Toward this goal, biobehavioral traits of affiliative capacity (AFF) and inhibitory control (INH) hold particular promise as they demonstrate transdiagnostic stability and predictive validity across developmental stages and differing measurement modalities. The current study employed data from different modes of measurement in a sample of 1830 children aged 5-10 years to test for associations of AFF and INH, individually and interactively, with broad dimensions of psychopathology. Low AFF, assessed via parent-report, evidenced predictive relations with distress- and externalizing-related problems. INH as assessed by cognitive-task performance did not relate itself to either psychopathology dimension, but it moderated the effects observed for low AFF, such that high INH protected against distress symptoms in low-AFF participants, whereas low INH amplified distress and externalizing symptoms in low-AFF participants. Results are discussed in the context of the interface of general trait transdiagnostic risk factors with quantitatively derived dimensional models of psychopathology.

New approaches to deep phenotyping in addictions.

OBJECTIVE: The causes of substance use disorders (SUDs) are largely unknown and the effectiveness of their treatments is limited. One crucial impediment to research and treatment progress surrounds how SUDs are classified and diagnosed. Given the substantial heterogeneity among individuals diagnosed with a given SUD (e.g., alcohol use disorder [AUD]), identifying novel research and treatment targets and developing new study designs is daunting. METHOD: In this article, we review and integrate two recently developed frameworks, the National Institute on Drug Abuse's Phenotyping Assessment Battery (NIDA PhAB) and the Hierarchical Taxonomy of Psychopathology (HiTOP), that hope to accelerate progress in understanding the causes and consequences of psychopathology by means of deep phenotyping, or finer-grained analysis of phenotypes. RESULTS AND CONCLUSIONS: NIDA PhAB focuses on addiction-related processes across multiple units of analysis, whereas HiTOP focuses on clinical phenotypes and covers a broader range of psychopathology. We highlight that NIDA PhAB and HiTOP together provide deep and broad characterizations of people diagnosed with SUDs and complement each other in their efforts to address widely known limitations of traditional classification systems and their diagnostic categories. Next, we show how NIDA PhAB and HiTOP can be integrated to facilitate optimal rich phenotyping of addiction-related phenomena. Finally, we argue that such deep phenotyping promises to advance our understanding of the neurobiology of SUD and addiction, which will guide the development of personalized medicine and interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Personality Neuroscience: An Emerging Field with Bright Prospects.

Personality neuroscience is the study of persistent psychological individual differences, typically in the general population, using neuroscientific methods. It has the potential to shed light on the neurobiological mechanisms underlying individual differences and their manifestation in ongoing behavior and experience. The field was inaugurated many decades ago, yet has only really gained momentum in the last two, as suitable technologies have become widely available. Personality neuroscience employs a broad range of methods, including molecular genetics, pharmacological assays or manipulations, electroencephalography, and various neuroimaging modalities, such as magnetic resonance imaging and positron emission tomography. Although exciting progress is being made in this young field, much remains unknown. In this brief review, we discuss discoveries that have been made, methodological challenges and advances, and important questions that remain to be answered. We also discuss best practices for personality neuroscience research and promising future directions for the field.

How Robust Is the p Factor? Using Multitrait-Multimethod Modeling to Inform the Meaning of General Factors of Youth Psychopathology.

We used multitrait-multimethod (MTMM) modeling to examine general factors of psychopathology in three samples of youth (Ns = 2119, 303, 592) for whom three informants reported on the youth's psychopathology (e.g., child, parent, teacher). Empirical support for the p-factor diminished in multi-informant models compared with mono-informant models: the correlation between externalizing and internalizing factors decreased and the general factor in bifactor models essentially reflected externalizing. Widely used MTMM-informed approaches for modeling multi-informant data cannot distinguish between competing interpretations of the patterns of effects we observed, including that the p-factor reflects, in part, evaluative consistency bias or that psychopathology manifests differently across contexts (e.g., home vs. school). Ultimately, support for the p-factor may be stronger in mono-informant designs, although it is does not entirely vanish in multi-informant models. Instead, the general factor of psychopathology in any given mono-informant model likely reflects a complex mix of variances, some substantive and some methodological.

The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

Answering questions about the Hierarchical Taxonomy of Psychopathology (HiTOP): Analogies to whales and sharks miss the boat.

This commentary discusses questions and misconceptions about HiTOP raised by Haeffel et al. (2021). We explain what the system classifies and why it is descriptive and atheoretical, highlighting benefits and limitations of this approach. We clarify why the system is organized according to patterns of covariation or comorbidity among signs and symptoms of psychopathology, and we discuss how it is designed to be falsifiable and revised in a manner that is responsive to data. We refer to the body of evidence for HiTOP's external validity and for its scientific and clinical utility. We further describe how the system is currently used in clinics. In sum, many of Haeffel et al.'s concerns about HiTOP are unwarranted, and for those concerns that reflect real current limitations of HiTOP, our consortium is working to address them, with the aim of creating a nosology that is comprehensive and useful to both scientists and clinicians.

The COVID-19-Related Lockdown in Qatar: Associations Among Demographics, Social Distancing, Mood Changes, and Quality of Life.

The worldwide spread of the coronavirus disease (COVID-19), the absence of medical treatment and vaccination, the delayed onset of symptoms, and the rapid human-to-human transmission have led the vast majority of countries to impose strict social distancing procedures. Whereas it appears that social distancing is an effective strategy for mitigating spread, it may also result in a variety of unintended negative consequences to individuals' psychological well-being and mental health. During the peak of the COVID-19 pandemic, the present study examined associations among some demographic variables (gender, age, marital and working statuses, and having a family member or a friend infected with COVID-19), acceptance of social distancing, mood changes, and quality of life (QoL) in Qatar, a high-income Middle Eastern Arabic-speaking country. Older, married, and working participants were more accepting of social distancing than younger, unmarried, and non-working participants, respectively. Participants indicated that, during this time, they became more distressed, upset, scared, irritable, nervous, and afraid, and less inspired and determined. In a stark contrast, more individuals indicated that they became more interested, alert, and attentive, whereas higher percentages of participants reported feeling less guilty, hostile, and ashamed. Social distancing correlated positively with negative affect, whereas social avoidances correlated positively with positive affect and with physical, psychological, social, and environmental QoL. Finally, positive affect correlated positively, and negative affect correlated negatively, with these four domains of QoL. These results highlight the need for public health and clinical providers to consider peoples' psychological well-being and mental health during the COVID-19 pandemic.

Exploring the Effects of Parental Involvement on Broad and Specific Dimensions of Behavioral Problems in Adolescence.

Few studies have differentiated the specificity from the generality of the associations between parental involvement and adolescent behavioral problems across levels of the psychopathology hierarchy. Among 537 adolescents aged 11-17 years, the current study considered the extent to which associations between mother- and father- involvement and behavioral problems (assessed via the parent-reported Child Behavior Checklist) were unique to a specific dimension or reflective of associations with higher-order factors. The hierarchical structure of behavioral problems fit well, with total problems at the top, internalizing and externalizing at the second level, and eight specific symptom dimensions at the third level. Mother and father involvement were protective factors for withdrawn/depressed symptoms and risk factors for anxious/depressed symptoms that were not accounted for by internalizing or total problems. Mother involvement was also a protective factor for rule-breaking behavior and a risk factor for social problems symptoms and aggressive behavior symptoms that were not accounted for by externalizing or total problems.

Pursuing the developmental aims of the triarchic model of psychopathy: Creation and validation of triarchic scales for use in the USC: RFAB longitudinal twin project.

The triarchic model was advanced as an integrative, trait-based framework for investigating psychopathy using different assessment methods and across developmental periods. Recent research has shown that the triarchic traits of boldness, meanness, and disinhibition can be operationalized effectively in youth, but longitudinal research is needed to realize the model's potential to advance developmental understanding of psychopathy. We report on the creation and validation of scale measures of the triarchic traits using questionnaire items available in the University of Southern California Risk Factors for Antisocial Behavior (RFAB) project, a large-scale longitudinal study of the development of antisocial behavior that includes measures from multiple modalities (self-report, informant rating, clinical-diagnostic, task-behavioral, physiological). Using a construct-rating and psychometric refinement approach, we developed triarchic scales that showed acceptable reliability, expected intercorrelations, and good temporal stability. The scales showed theory-consistent relations with external criteria including measures of psychopathy, internalizing/externalizing psychopathology, antisocial behavior, and substance use. Findings demonstrate the viability of measuring triarchic traits in the RFAB sample, extend the known nomological network of these traits into the developmental realm, and provide a foundation for follow-up studies examining the etiology of psychopathic traits and their relations with multimodal measures of cognitive-affective function and proneness to clinical problems.

Connecting quantitatively derived personality-psychopathology models and neuroscience.

Traditionally, personality has been conceptualized in terms of dimensions of human experience - habitual ways of thinking, feeling, and behaving. By contrast, psychopathology has traditionally been conceptualized in terms of categories of disorder - disordered thinking, feeling, and behaving. The empirical literature, however, routinely shows that psychopathology does not coalesce into readily distinguishable categories. Indeed, psychopathology tends to delineate dimensions that are relatively similar to dimensions of personality. In this special issue of Personality Neuroscience, authors took up the challenge of reconceptualizing personality and psychopathology in terms of connected and interrelated dimensions, and they considered the utility of pursuing neuroscientific inquiry from this more integrative perspective. In this editorial article, we provide the relevant background to the interface between personality, psychopathology, and neuroscience; summarize contributions to the special issue; and point toward directions for continued research and refinement. All told, it is evident that quantitatively derived, integrative models of personality-psychopathology represent a particularly promising conduit for advancing our understanding of the neurobiological foundation of human experience, both functional and dysfunctional.