ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Disentangling cognitive processes in externalizing psychopathology using drift diffusion modeling: Antagonism, but not disinhibition, is associated with poor cognitive control.

Although externalizing psychopathology has been linked to deficits in cognitive control, the cognitive processes underlying this association are unclear. Here, we provide a theoretical account of how research on cognitive processes can help to integrate and distinguish personality and psychopathology. We then apply this account to connect the two major subcomponents of externalizing, Antagonism and Disinhibition, with specific control processes using a battery of inhibitory control tasks and corresponding computational modeling. Participants (final N = 104) completed the flanker, go/no-go, and recent probes tasks, as well as normal and maladaptive personality inventories and measures of psychological distress. We fit participants' task behavior using a hierarchical drift diffusion model (DDM) to decompose their responses into specific cognitive processes. Using multilevel structural equation models, we found that Antagonism was associated with faster RTs on the flanker task and lower accuracy on flanker and go/no-go tasks. These results were complemented by DDM parameter associations: Antagonism was linked to decreased threshold and drift rate parameter estimates in the flanker task and a decreased drift rate on no-go trials. Altogether, our findings indicate that Antagonism is associated with specific impairments in fast (sub-second) inhibitory control processes involved in withholding prepared/prepotent responses and filtering distracting information. Disinhibition and momentary distress, however, were not associated with task performance.

Treatment outcomes of Veteran men in a comprehensive dialectical behavior therapy program: Characterizing sex differences in symptom trajectories.

Dialectical Behavior Therapy (DBT) is one of the primary psychosocial treatments for reducing suicidal behaviors and improving psychosocial outcomes among patients with borderline personality disorder (BPD) and has been shown to reduce BPD symptoms when delivered in a Veteran Affairs medical center setting. Despite evidence of similar rates of BPD in both men and women, the vast majority of treatment outcome research in BPD has focused on women. We sought to characterize sex differences in symptom trajectories among Veterans participating in a comprehensive DBT program. We found that Veteran men and women who entered the DBT program were diagnostically and demographically similar. Participants exhibited reductions in BPD symptoms and improvements in emotion regulation over the course of treatment. Moreover, Veteran men reported BPD symptom reductions that were not statistically inferior to those of Veteran women and exhibited a sharper reduction in these symptoms. This research provides support for the use of DBT as a psychosocial treatment for Veteran men with BPD symptoms.

Explanatory personality science in the neuroimaging era: The map is not the territory.

The recent rise of magnetic resonance imaging (MRI) has led to a proliferation of studies that seek to link individual differences in personality directly to their neural correlates. These studies function to describe personality at a lower level of analysis, but they do little to advance the field's understanding of the causal mechanisms that give rise to personality traits. To transition to a more explanatory personality neuroscience, researchers should strive to conduct theory-driven empirical studies that bridge multiple levels of analysis. Effectively doing so will require a continued reliance on rich description, strong theories, large samples, and careful behavioral experimentation. Integrating these components will lead to more robust and informative studies of personality neuroscience that help to move the field closer to explaining the causal sources of individual differences.

Dispositional attachment style moderates the effects of physiological coregulation on short-term changes in attachment anxiety and avoidance.

Individuals with personality disorders often experience romantic relationship dysfunction and have an insecure attachment style. Here, we examined attachment dynamics in dyadic interactions, focusing specifically on the role of physiological coregulation in state attachment processes in couples oversampled for personality pathology. A total of 121 couples completed a 10-minute discussion about an area of disagreement in their relationship and a 5-minute discussion in which they planned an event together. We used a dynamical model of heart rate changes to estimate coregulation. We found that (a) increases in state attachment avoidance were associated with contrarian coregulation (heart rate becoming misaligned with the partner's physiology) and (b) conversely, increases in state attachment anxiety were associated with dependent coregulation (heart rate becoming aligned with the partners' physiology). Dispositional attachment insecurity moderated the effects of state attachment insecurity on physiological coregulation. Whereas dispositional anxiety predicted individuals exhibiting dependent coregulation in response to state insecurity, dispositional avoidance predicted contrarian coregulation in response to state insecurity. This work provides insight into the role of physiological coregulation in attachment dynamics among couples oversampled for personality pathology, suggesting that disruptions to coregulation contribute to impaired emotion regulation during romantic conflicts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

From Description to Explanation: Integrating Across Multiple Levels of Analysis to Inform Neuroscientific Accounts of Dimensional Personality Pathology.

Dimensional approaches to psychiatric nosology are rapidly transforming the way researchers and clinicians conceptualize personality pathology, leading to a growing interest in describing how individuals differ from one another. Yet, in order to successfully prevent and treat personality pathology, it is also necessary to explain the sources of these individual differences. The emerging field of personality neuroscience is well-positioned to guide the transition from description to explanation within personality pathology research. However, establishing comprehensive, mechanistic accounts of personality pathology will require personality neuroscientists to move beyond atheoretical studies that link trait differences to neural correlates without considering the algorithmic processes that are carried out by those correlates. We highlight some of the dangers we see in overpopulating personality neuroscience with brain-trait associational studies and offer a series of recommendations for personality neuroscientists seeking to build explanatory theories of personality pathology.

Disrupted physiological coregulation during a conflict predicts short-term discord and long-term relationship dysfunction in couples with personality pathology.

Interpersonal dysfunction is a core feature of personality disorders, often affecting close relationships. Nevertheless, little is known about the moment-to-moment dynamic processes by which personality pathology contributes to dysfunctional relationships. Here, we investigated the role of physiological attunement during a conflict discussion in romantic couples oversampled for personality pathology. We hypothesized that physiological coregulation would be disrupted in individuals with personality pathology, subsequently predicting short-term discord and long-term relationship dissatisfaction. One hundred twenty-one couples completed a 10-min discussion about an area of disagreement while cardiovascular physiology and behavior were recorded. We quantified coregulation using a dynamical systems model of heart rate changes. We found that greater interpersonal problem severity was associated with more contrarian coregulation, exacerbating negative affect and interpersonal perceptions. Furthermore, the extent to which coregulation was associated with increased discord prospectively predicted relationship dissatisfaction 1 year later. Altogether, this work sheds light on a pathway by which personality pathology contributes to problems in romantic relationships. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Interpersonal dysfunction in borderline personality: a decision neuroscience perspective.

Borderline personality disorder (BPD) is characterized by disadvantageous decisions that are often expressed in close relationships and associated with intense negative emotions. Although functional neuroimaging studies of BPD have described regions associated with altered social cognition and emotion processing, these correlates do not inform an understanding of how brain activity leads to maladaptive choices. Drawing on recent research, we argue that formal models of decision-making are crucial to elaborating theories of BPD that bridge psychological constructs, behavior, and neural systems. We propose that maladaptive interactions between Pavlovian and instrumental influences play a crucial role in the expression of interpersonal problems. Finally, we articulate specific hypotheses about how clinical features of BPD may map onto neural systems that implement separable decision processes.