A Small Step Toward Generalizability: Training a Machine Learning Scoring Function for Structure-Based Virtual Screening.

Over the past few years, many machine learning-based scoring functions for predicting the binding of small molecules to proteins have been developed. Their objective is to approximate the distribution which takes two molecules as input and outputs the energy of their interaction. Only a scoring function that accounts for the interatomic interactions involved in binding can accurately predict binding affinity on unseen molecules. However, many scoring functions make predictions based on data set biases rather than an understanding of the physics of binding. These scoring functions perform well when tested on similar targets to those in the training set but fail to generalize to dissimilar targets. To test what a machine learning-based scoring function has learned, input attribution, a technique for learning which features are important to a model when making a prediction on a particular data point, can be applied. If a model successfully learns something beyond data set biases, attribution should give insight into the important binding interactions that are taking place. We built a machine learning-based scoring function that aimed to avoid the influence of bias via thorough train and test data set filtering and show that it achieves comparable performance on the Comparative Assessment of Scoring Functions, 2016 (CASF-2016) benchmark to other leading methods. We then use the CASF-2016 test set to perform attribution and find that the bonds identified as important by PointVS, unlike those extracted from other scoring functions, have a high correlation with those found by a distance-based interaction profiler. We then show that attribution can be used to extract important binding pharmacophores from a given protein target when supplied with a number of bound structures. We use this information to perform fragment elaboration and see improvements in docking scores compared to using structural information from a traditional, data-based approach. This not only provides definitive proof that the scoring function has learned to identify some important binding interactions but also constitutes the first deep learning-based method for extracting structural information from a target for molecule design.

Cognitive Performance After Facial Botulinum Toxin Treatment in a Cohort of Neurologic Patients: An Exploratory Study.

OBJECTIVE: To investigate higher cognitive functions after mimicry changes after facial botulinum toxin (BTX) injections, we tested verbal and nonverbal reasoning in patients with blepharospasm or hemifacial spasm before and after their long-term botulinum toxin treatment. DESIGN: Explorative, nonrandomized, clinical trial. SETTING: Patients receiving ambulatory care and control participants from the general community. PARTICIPANTS: Volunteer sample (N=84) of patients (n=21) with blepharospasm or hemifacial spasm who received facial BTX injections. Control participants included patients (n=30) with cervical dystonia who received cervical BTX injections and individuals without neurological disorders (n=33). INTERVENTIONS: The 2 groups receiving injections were tested before and 3 weeks after their treatment. The group without neurological disorders received no injections. MAIN OUTCOME MEASURES: Verbal and nonverbal reasoning scores. RESULTS: The key unexpected finding was that patients who received facial BTX injections perform significantly worse in nonverbal reasoning tasks, when compared with those who did not receive injections (P=.022). There was no significant difference in the baseline reasoning scores and at follow-up for verbal reasoning between the 3 groups. There was no correlation between toxin dose and reasoning scores (verbal: P=.132; nonverbal: P=.294). CONCLUSIONS: Because of potential confounders, the results do not yet allow any conclusion on causality. Further research is needed to confirm our findings.

This time it's personal: reappraisal after acquired brain injury.

Reappraisal is a widely investigated emotion regulation strategy, often impaired in those with acquired brain injury (ABI). Little is known, however, about the tools to measure this capacity in patients, who may find traditional reappraisal tasks difficult. Fifty-five participants with ABI, and thirty-five healthy controls (HCs), completed reappraisal tasks with personal and impersonal emotion elicitation components, questionnaires measuring reappraisal (the ERQ-CA), and neuropsychological assessment. The main findings demonstrated that both groups produced more reappraisals, and rated their reappraisal ideas as more effective for personal stimuli. The ABI group were significantly faster to generate reappraisals for personal, compared to impersonal, stimuli. Yet, participants with ABI performed worse than HCs on the majority of reappraisal components, across both reappraisal tasks. Results of regression analyses revealed significant relationships between certain measures of cognitive control and certain reappraisal components, which varied for the personal and impersonal reappraisal task. Notably, while inhibition predicted aspects of reappraisal in both the ABI and HC group, working memory was only related to reappraisal in participants with ABI. The study suggests that personal context plays a key role in reappraisal, and proposes a model to better understand the role of cognitive control across the reappraisal process.

The Erogenous Mirror: Intersubjective and Multisensory Maps of Sexual Arousal in Men and Women.

Erogenous zones of the body are sexually arousing when touched. Previous investigations of erogenous zones were restricted to the effects of touch on one's own body. However, sexual interactions do not just involve being touched, but also involve touching a partner and mutually looking at each other's bodies. We take a novel interpersonal approach to characterize the self-reported intensity and distribution of erogenous zones in two modalities: touch and vision. A large internet sample of 613 participants (407 women) completed a questionnaire, where they rated intensity of sexual arousal related to different body parts, both on one's own body and on an imagined partner's body in response to being touched but also being looked at. We report the presence of a multimodal erogenous mirror between sexual partners, as we observed clear correspondences in topographic distributions of self-reported arousal between individuals' own bodies and their preferences for a partner's body, as well as between those elicited by imagined touch and vision. The erogenous body is therefore organized and represented in an interpersonal and multisensory way.

Good things better? Reappraisal and discrete emotions in acquired brain injury.

There has been substantial interest in emotion after acquired brain injury (ABI), but less attention paid to emotion regulation (ER). Research has focused primarily on the ER strategy of reappraisal for regulating negative emotions, without distinguishing between classes of emotion, and there has been no attempt at exploring these differences in patients with ABI. The present study explored components of reappraisal, across classes of emotion, and their associated neuropsychological mechanisms. Thirty-five patients with ABI and twenty-two matched healthy control participants (HCs) completed two questionnaires, a battery of cognitive tasks, and an emotion regulation task (the Affective Story Recall Reappraisal task). Results suggest that those with ABI take longer, and generate fewer reappraisals than HCs across several discrete emotions. Notably, their ability to decrease emotional intensity did not differ significantly to HCs for negative emotions, but findings suggest that their reappraisals are less effective when up-regulating neutral emotions to positive. Working memory was the only significant predictor of the total number of reappraisals generated, and the time taken to produce a first reappraisal. Implications of these findings are discussed in the context of neuropsychological rehabilitation, including the role of the relatives in implementing and reinforcing micro-interventions.

Alcohol exposure during pregnancy altered childhood developmental trajectories in a rural South African community.

AIM: This study examined the effects of prenatal alcohol exposure on childhood development trajectories in a rural South African community between 2003 and 2008. METHODS: We assessed 121 children at 7-12 months (year one) and 5-6 years (year five) using the Griffiths Mental Developmental Scales - Extended Revised, which measures sensorimotor, cognitive and social development, with lower scores indicating developmental delay. We also interviewed their mothers or caregivers. Three groups were identified: 29 with foetal alcohol syndrome (FAS) or partial FAS (pFAS), 57 more who had been exposed to alcohol and 35 controls who had not. RESULTS: The scale's total score was higher in the controls than in the FAS/pFAS group at year one and year five and in the alcohol-exposed group at year five. Many groups' trajectories declined when compared with global norms, but the trajectories in the FAS/pFAS and the alcohol-exposed groups declined more than the controls for eye-hand and performance and total score. Earlier pregnancy recognition in the FAS/pFAS group correlated strongly (r = -0.77) with higher GQ in year five. CONCLUSION: FAS/pFAS and prenatal alcohol exposure affected the Griffiths scores more than the control group. Efforts are needed to detect pregnancy early and reduce alcohol exposure.

Cognitive vulnerability to bipolar disorder in offspring of parents with bipolar disorder.

BACKGROUND: Bipolar disorder is a highly heritable illness, with a positive family history robustly predictive of its onset. It follows that studying biological children of parents with bipolar disorder may provide information about developmental pathways to the disorder. Moreover, such studies may serve as a useful test of theories that attribute a causal role in the development of mood disorders to psychological processes. METHOD: Psychological style (including self-esteem, coping style with depression, domain-specific risk-taking, sensation-seeking, sensitivity to reward and punishment, and hypomanic personality and cognition) was assessed in 30 offspring of bipolar parents and 30 children of well parents. Parents of both child groups completed identical assessments. RESULTS: Although expected differences between parents with bipolar disorder and well parents were detected (such as low self-esteem, increased rumination, high sensitivity to reward and punishment), offspring of bipolar parents were, as a group, not significantly different from well offspring, apart from a modest trend towards lower adaptive coping. When divided into affected and non-affected subgroups, both groups of index children showed lower novelty-seeking. Only affected index children showed lower self-esteem, increased rumination, sensitivity to punishment, and hypomanic cognitions. Notably, these processes were associated with symptoms of depression. CONCLUSION: Psychological abnormalities in index offspring were associated with having met diagnostic criteria for psychiatric illnesses and the presence of mood symptoms, rather than preceding them. Implications of the present findings for our understanding of the development of bipolar disorder, as well as for informing early interventions, are discussed.

"We can all relate": patient experience of an emotion-oriented group intervention after Acquired Brain Injury.

Introduction: Group interventions are carried out routinely across neuropsychological rehabilitation services, to improve understanding of brain injury and aspects of impairment. Treatment provided in a group modality can bring additional perceived benefits, such as co-operative learning. However, there are very few studies which explore patient perceptions and experiences of such interventions. In the present study we investigated the experience of attending a group-based educational intervention for the consequences of acquired brain injury (ABI), which had a strong focus on emotion and emotion regulation. Methods: Using qualitative semi-structured interviews (approximately 20 minutes), the study explores the lived experience of participating in the seven-session programme, the better to identify the perceived efficacy, salience and value of individual elements. Twenty participants with ABI took part in individual interviews, after completion of the group programme (the Brain Injury Solutions and Emotions Programme, BISEP). The study adopted a descriptive phenomenological philosophy, which focuses on lived experience to explore a phenomenon (i.e. the experience of BISEP). As regards methods, the study employed thematic analysis to cluster experiences into themes of meaning. Results: Five themes were identified: (1) 'Long term consequences and psychological needs', which related to the persistent nature of direct consequences of injury and adjustment, and how these result in a need for interventions such as BISEP. (2) 'Positive experiences of participating in the programme', referred to participants' overall experience of the programme and valued elements within it. The remaining themes referred to the programme as (3) a social milieu; (4) a place to learn; and (5) a place to promote positive emotional experiences. Discussion: Similar to previous studies, many people reported high acceptability and perceived value of the group programme, and its role in facilitating adjustment and understanding of injury. Of particular importance was the opportunity to socialise with people who "can all relate", in line with a growing emphasis on social rehabilitation. The findings especially highlight the relevance of emotion-focused group programmes for ABI, promoting emotion regulation, and practical tools that are delivered optimistically. Further implications for practice and future research include to focus on long term rehabilitation, a social milieu, and strategies to support adjustment.

Separated at birth: Rediscovering the lost emotions in Luria's Working Brain.

Aleksandr Luria repeatedly emphasised the importance of emotions and the right hemisphere in his neuropsychological writings. It is surprising, therefore, that Luria's most influential book, The Working Brain, appears to lack an explicit section on these topics. This is especially notable because of a comment in the book's English-language Introduction, by Karl Pribram, referencing Luria's thoughts about precisely this material. Remarkably, it seems that Luria did write such an explicit chapter, in the original Russian edition. However, in the English-language version, the relevant sections were separated, embedded elsewhere without chapter headings, and altered, presumably following an explicit translation decision. The present paper tracks the nature of these changes and, 50 years later, presents the material for the first time translated and reunited in English, as Luria intended. After the translation, we offer a brief commentary, on the ways in which Luria's ideas were in some respects prescient, and in other respects less well-informed about the brain basis of emotions and the right hemisphere. This reunification offers an interesting time capsule on the opinions of one of neuropsychology's greatest minds, on a topic which Luria admits had, at the time, only a modest empirical foundation.

Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling.

Antibodies with lambda light chains (λ-antibodies) are generally considered to be less developable than those with kappa light chains (κ-antibodies). Though this hypothesis has not been formally established, it has led to substantial systematic biases in drug discovery pipelines and thus contributed to kappa dominance amongst clinical-stage therapeutics. However, the identification of increasing numbers of epitopes preferentially engaged by λ-antibodies shows there is a functional cost to neglecting to consider them as potential lead candidates. Here, we update our Therapeutic Antibody Profiler (TAP) tool to use the latest data and machine learning-based structure prediction, and apply it to evaluate developability risk profiles for κ-antibodies and λ-antibodies based on their surface physicochemical properties. We find that while human λ-antibodies on average have a higher risk of developability issues than κ-antibodies, a sizeable proportion are assigned lower-risk profiles by TAP and should represent more tractable candidates for therapeutic development. Through a comparative analysis of the low- and high-risk populations, we highlight opportunities for strategic design that TAP suggests would enrich for more developable λ-antibodies. Overall, we provide context to the differing developability of κ- and λ-antibodies, enabling a rational approach to incorporate more diversity into the initial pool of immunotherapeutic candidates.

The Observed T Cell Receptor Space database enables paired-chain repertoire mining, coherence analysis, and language modeling.

T cell activation is governed through T cell receptors (TCRs), heterodimers of two sequence-variable chains (often an α and ß chain) that synergistically recognize antigen fragments presented on cell surfaces. Despite this, there only exist repositories dedicated to collecting single-chain, not paired-chain, TCR sequence data. We addressed this gap by creating the Observed TCR Space (OTS) database, a source of consistently processed and annotated, full-length, paired-chain TCR sequences. Currently, OTS contains 5.35 million redundant (1.63 million non-redundant), predominantly human sequences from across 50 studies and at least 75 individuals. Using OTS, we identify pairing biases, public TCRs, and distinct chain coherence patterns relative to antibodies. We also release a paired-chain TCR language model, providing paired embedding representations and a method for residue in-filling conditional on the partner chain. OTS will be updated as a central community resource and is freely downloadable and available as a web application.

Concrete behaviour and reappraisal deficits after a left frontal stroke: a case study.

Concrete behaviour, the inability to disengage from immediate experience in order to manipulate ideas and thoughts, has long been understood to be a common problem after frontal lobe lesions. However, there has been little consideration of the impact that concreteness may have on emotional functioning, specifically in the use of thinking to manipulate emotional responses. One widely studied emotion regulation strategy is reappraisal, which depends on several frontal lobe related cognitive control processes. While there have been numerous neuroimaging findings on reappraisal, no study has used brain injured patients to investigate this issue. The present case study is the first to describe the capacity to generate reappraisals in a patient (Mrs M), whose behaviour became concrete after a left prefrontal stroke. Using a picture-based reappraisal paradigm, her performance was compared to non-concrete brain-lesioned patients, and neurologically healthy controls. Although Mrs M showed relatively preserved overall cognitive function, she was completely unable to spontaneously generate reappraisals. In striking contrast, once external support was offered, in the form of prompts, her capacity to reappraise dramatically improved. The results are analysed in terms of three neuropsychological capacities - all compromised in Mrs M - previously proposed as reappraisal components: response inhibition, abstraction, and verbal fluency. A number of implications for rehabilitation are discussed, including how the use of prompting may facilitate reappraisal capacity.

"Talk and Chalk": An emotion regulation intervention for anger after acquired brain injury.

Uncontrollable anger is a debilitating consequence of acquired brain injury (ABI). This proof-of-concept study investigated the preliminary efficacy of an emotion regulation intervention for managing post-ABI anger. A secondary objective was to determine which participant characteristics were related to intervention gains. With a pre-post intervention design and three-month follow-up, there were five individually administered meetings on Zoom, over a four-month period. 24 adults who had sustained an ABI were enrolled. Participants were mostly males, from 24 to 85 years old. A series of one-way repeated-measures ANOVAs were conducted to determine the intervention's efficacy, and Spearman's rho bivariate correlations for the association between participant characteristics and intervention gains. Significant differences were observed in external anger from baseline to post-treatment; there were no further changes from post-treatment to follow-up. Of the participant characteristics, only readiness to change and anxiety were correlated. The proposed intervention presents a brief, feasible, and preliminary efficacious alternative for regulating post-ABI anger. Intervention gains are associated with readiness to change and anxiety, which has important implications for clinical delivery.

The Bangor Gambling Task: Computerized replication and reappraisal of an emotion-based decision task.

Emotion-based decision making (EBDM) is the capacity to make decisions based on prior emotional consequences of actions. Several neuropsychological tasks, using different gambling paradigms and with different levels of complexity, have been designed to assess EBDM. The Bangor Gambling Task (BGT) was created as a brief and simple card gambling-task to assess EBDM. BGT contains a single-card deck and requires participants to decide whether to gamble or not, which can result in wins or losses. Unknown to the participant, the winning probabilities decrease throughout the task (from 0.75 in the first block to 0.25 in the fifth block), requiring participants to reduce their gambling probability to avoid long-term losses. A few studies have offered evidence regarding the BGT convergent validity. However, there are no computerized versions of BGT available, thus slowing the process of gathering information to explore the EBDM mechanisms behind the task, its validity, and clinical usefulness. In this article, we present a computerized version of the BGT using the Matlab environment and make all our code available. We explore BGT's replicability and analyze its probabilistic structure, providing trial-level and block-level analyses. Eighty-one participants performed the computerized version, which followed the same structure as the original version. It took participants 8.5 ± 3.3 minutes to complete the task, which is faster than the paper version. Replicating previous studies, participants diminished their gambling probability throughout the task, learning to inhibit the initially rewarded gambling behavior. This change in gambling probability could be considered a proxy for EBDM. Our analyses suggest that the last blocks are especially sensitive to capturing deficits in EBDM, and we propose some modifications to BGT's original version to enhance the initial exploratory and learning phase. Our results show that the BGT constitutes a quick and simple task to evaluate EBDM capacities.

Association of salivary-assessed oxytocin and cortisol levels with time of night and sleep stage.

There have been proposals for REM to have a function of emotional memory consolidation, and also for REM sleep to be involved in the promotion of attachment behaviour. The hormones cortisol and oxytocin, respectively, may be involved in these proposed REM sleep functions. However, there are conflicting reports on whether levels of cortisol differ between sleep stages when time since sleep onset (SSO) is controlled, and virtually no literature on whether levels of oxytocin differ between sleep stages. This study thus investigated the changes in levels of oxytocin (OT) and cortisol (CT) across the night, and whether these levels differ between REM and N2 sleep when time SSO is controlled. 20 participants (10 males, 10 females, mean age = 20.45, SD = 2.01) were awakened 10 min into REM and N2 sleep periods in the sleep laboratory and gave saliva samples which were assayed for OT and CT. Levels of OT were relatively constant across the night, whereas CT increased significantly. REM and N2 did not differ significantly neither for OT nor for CT. The study has implications for models of sleep-dependent memory consolidation that incorporate the late sleep increase in cortisol as a functional component of memory consolidation, and also for the medical diagnostic assaying of OT during sleep.

Cognitive decision modelling of emotion-based learning impairment in schizophrenia: the role of awareness.

Individuals with schizophrenia often lack insight or awareness. Resulting impairment has been observed in various cognitive domains and, recently, linked to problems in emotion-based learning. The Iowa Gambling Task (IGT) has been used to assess emotion-based decision-making in patients with schizophrenia, but results have been inconclusive. The current study further investigates emotion-based decision-making in schizophrenia by elucidating the unique contribution of awareness. Twenty-five patients with schizophrenia and 24 healthy controls were assessed with a modified version of the IGT recording awareness at regular intervals. Symptom assessment, medication and medical history were recorded for the clinical group. Patients with schizophrenia underperformed on the IGT compared to controls. Subjective awareness levels were significantly lower in the schizophrenia group and were associated with hallucination severity. Cognitive decision modelling further indicated that patients with schizophrenia had impaired attention to losses, compared to controls. This parameter was positively correlated with awareness. We also found that positive symptoms altered awareness levels and suggest that this disruption may contribute to sub-optimal decision-making. Overall, a lack of awareness may be an important aspect in understanding impaired social cognitive functioning and emotion-based learning observed in schizophrenia.

Shades of Rage: Applying the Process Model of Emotion Regulation to Managing Anger After Brain Injury.

Uncontrollable anger is common following an acquired brain injury (ABI), with impaired emotion regulation (ER) being one of the main contributors. Existing psychological interventions appear moderately effective, though studies typically include limitations such as small sample sizes, issues of long-term efficacy, and standardization of content. While ER has been a popular research field, the study of ER for anger management after ABI is less well investigated, and contains few interventions based on the widely used Process Model of ER. This review surveys the efficacy of ER strategies in individuals with ABI, and proposes a novel research design for future interventions. Recommendations are made about: strategy number and type, shared decision-making, approaches to data analysis, and mode of delivery.

Like a rolling stone: Psychotherapy without (episodic) memory.

People with profound amnesia still retain the capacity to learn about the emotional value of experiences, which is crucial in developing and sustaining interpersonal relationships. In a 2017 paper, we demonstrated for the first time (with patient JL) that transferential feelings develop across the therapeutic process, despite profound episodic memory impairment after medial temporal lesions. This paper reports a second case (GA) of a profoundly amnesic patient in psychotherapy, this time after lesions to the anterior fornix. The work with GA opens issues such as the differences and similarities to the previous case, counter-transference phenomena, and the effects of hyperphagia. The findings make it clear that many phenomena are common to both GA and JL, such as forgetfulness, various types of repetition, the importance of the therapeutic alliance, and the ability to make therapeutic gain. However, there were differences between the cases, for example as regards confabulation, which may relate to either pre-morbid personality or lesion site. The paper also discusses the way in which patients of this type bear the very status of psychotherapeutic work with profoundly amnesic patients. Where others have seen barriers and in principle problems in working with such patients, we see many opportunities.

Remembering relationships: preserved emotion-based learning in Alzheimer's disease.

Research into Alzheimer's disease has long focused on cognitive impairments. Advocates of the person-centered approach argue that emotions and interpersonal responses may remain intact. The answer to this paradox may derive from the neuropsychology of emotion, demonstrating preserved ability on simple emotion learning tasks, though this may not capture the complex interpersonal interactions that some patients appear able to manage in everyday life. This study demonstrates, for the first time, preserved complex emotion-based learning capacity, despite profound episodic memory impairment in Alzheimer's disease. These findings offer a starting point for the development of a solid neuropsychological and neuroanatomical account for the person-centered approach.

The Neuropsychology of Emotion and Emotion Regulation: The Role of Laterality and Hierarchy.

Over the last few decades, work in affective neuroscience has increasingly investigated the neural basis of emotion. A central debate in the field, when studying individuals with brain damage, has been whether emotional processes are lateralized or not. This review aims to expand this debate, by considering the need to include a hierarchical dimension to the problem. The historical journey of the diverse literature is presented, particularly focusing on the need to develop a research program that explores the neural basis of a wide range of emotional processes (perception, expression, experience, regulation, decision making, etc.), and also its relation to lateralized cortical and deep-subcortical brain structures. Of especial interest is the study of the interaction between emotional components; for example, between emotion generation and emotion regulation. Finally, emerging evidence from lesion studies is presented regarding the neural basis of emotion-regulation strategies, for which the issue of laterality seems most relevant. It is proposed that, because emotion-regulation strategies are complex higher-order cognitive processes, the question appears to be not the lateralization of the entire emotional process, but the lateralization of the specific cognitive tools we use to manage our feelings, in a range of different ways.