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.

"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.

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.

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.

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.

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.

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.

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.

Post-Traumatic Growth in Professionals Caring for People with Intellectual Disabilities during COVID-19: A Psychological Intervention.

BACKGROUND: Health professionals present a greater vulnerability to the effects of COVID-19 on their mental health, especially those who work with vulnerable groups such as those who suffer from intellectual disability (ID). The objective of the present research was to develop and verify the effectiveness of a psychological intervention for professionals in the field of ID to improve their mental health during this health crisis. METHODS: A total of 32 professionals participated. The variables measured were: post-traumatic growth, mental health, burnout, coping strategies, resilience, life satisfaction, optimism, and cognitive and affective empathy. RESULTS: The results revealed statistically significant differences in the post-traumatic growth variable. In the rest of the variables (mental health, burnout, coping strategies, resilience, vital satisfaction, optimism, and empathy), no significant differences between groups were found. CONCLUSIONS: An increase in the levels of post-traumatic growth was observed in the intervention group after a brief online psychological intervention. However, given the small sample size, these results should be taken with caution. Institutions should foster and promote interventions aimed at reducing the high emotional impact produced by COVID-19 in professionals that care for people diagnosed with ID.

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.

Building the bond: Predictors of the alliance in neurorehabilitation.

BACKGROUND: Neurorehabilitation services are often delivered through group psycho-education programmes. However, little is known about the therapeutic process at work during such sessions. The present study is the first to gain insight into the therapeutic alliance, during a seven-session group programme. In addition, cognitive, emotional, and demographic predictors of the alliance, and participants' feelings towards their group members, were investigated, together with predictors of patient engagement. METHODS: Forty-five participants with an acquired brain injury completed a series of questionnaires, and neuropsychological assessment, following group psycho-education. The group facilitator completed a parallel therapeutic alliance questionnaire, and rated participants' engagement. RESULTS: Results demonstrated that a strong alliance can be formed in seven group sessions. Notably, no demographic or cognitive factors appear to pose a barrier to developing a therapeutic alliance, nor to group attraction. CONCLUSION: High levels of depression, however, may be a challenge, and clinicians may need to tailor their clinical skills to ensure a good therapeutic relationship with such patients. To promote engagement, clinicians may also need to provide additional support to patients with lower levels of education, working memory, and episodic memory impairment.

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.

Preserved re-experience of discrete emotions: Amnesia and executive function.

Amnesic patients can re-experience emotions elicited by forgotten events, suggesting that brain systems for episodic and emotional memory are independent. However, the range of such emotional memories remains under-investigated (most studies employing just positive-negative emotion dyads), and executive function may also play a role in the re-experience of emotions. This is the first investigation of the intensity of the emotional re-experience of a range of discrete emotions (anger, fear, sadness, and happiness) for a group of amnesic patients. Twenty Korsakoff syndrome (KS) patients and 20 neurologically normal controls listened to four novel emotional vignettes selectively eliciting the four basic emotions. Emotional experience was measured using pen-and-paper Visual Analogue Mood Scales and episodic memory using verbal recollections. After 30 min, the recollection of stories was severely impaired for the patient group, but the emotional re-experience was no different from that of controls. Notably, there was no relationship between episodic recall and the intensity of the four emotions, such that even profoundly amnesic patients reported moderate levels of the target emotion. Exploratory analyses revealed negative correlations between the intensity of basic emotions and executive functions (e.g., cognitive flexibility and response inhibition) for controls but not patients. The results suggest that discrete emotions can be re-experienced independently of episodic memory, and that the re-experience of certain discrete emotions appears to be dampened by executive control. KS patients with absent or mild cognitive symptoms should benefit from emotion-regulation interventions aimed at reducing the recognized affective burden associated with their episodic memory deficit.

The Role of Inner Speech in Emotion Dysregulation and Emotion Regulation Strategy Use / El Rol del Habla Interna en la Desregulación Emocional y el uso de Estrategias de Regulación Emocional

Abstract Recent studies have suggested that emotion regulation (ER) strategies, such as reappraisal and suppression, rely on the use of verbal thinking. Outside the field of ER, verbal thinking, particularly in the form of inner speech, has been largely linked to behavior and cognitive regulation. However, no article has yet directly addressed the potential role of inner speech in ER. In this study, 180 participants completed a survey that included measures of inner speech usage (Inner Speech Questionnaire), ER difficulties (Difficulties in Emotion Regulation Scale), ER strategy use (Emotion Regulation Questionnaire) and symptoms (HADS). Correlational analyses and hierarchical linear regression models were used to explore the potential relationship between inner speech and ER variables. A positive relationship was found between Inner Speech usage and the Difficulties in Emotion Regulation Scale overall score. This relationship was, however, heavily mediated by level of symptomatology. As for the ER strategies, only reappraisal presented a significant positive relationship, of medium size, with inner speech usage, which was independent of the level of symptoms. The results of this study are discussed in relation to the current conceptualization of reappraisal as well as its implications for clinical practice.

Resumen Estudios recientes han sugerido que estrategias de regulación emocional (RE) como la re-interpretación y supresión dependen del pensamiento verbal. Fuera del campo de la RE, el pensamiento verbal, como habla interna, ha sido vinculado con la regulación cognitivo/conductual. Sin embargo, a la fecha ningún estudio ha explorado el rol del habla interna en la RE. En esta investigación, 180 sujetos completaron cuestionarios de uso de habla interna (Inner Speech Questionnaire, ISQ), dificultades en la RE (Difficulties in Emotion Regulation Scale, DERS), uso de estrategias de RE (Emotion Regulation Questionnaire, ERQ) y sintomatología (HADS). Se realizaron análisis correlacionales y modelos de regresión lineal para explorar la relación entre habla interna y variables de RE. Una relación positiva fue encontrada entre frecuencia de uso de habla interna y la puntuación global de la escala de dificultades en RE -relación altamente mediada por el nivel de sintomatología. Respecto a las estrategias de RE, solo la reinterpretación presentó una relación positiva y significativa, de tamaño medio, con la frecuencia de uso de habla interna -con independencia del nivel de síntomas. Los resultados de este estudio son discutidos en relación a la conceptualización actual de la re-interpretación así como su relevancia para la práctica clínica.

Observations on Working Psychoanalytically with a Profoundly Amnesic Patient.

Individuals with profound amnesia are markedly impaired in explicitly recalling new episodic events, but appear to preserve the capacity to use information from other sources. Amongst these preserved capacities is the ability to form new memories of an emotional nature - a skill at the heart of developing and sustaining interpersonal relationships. The psychoanalytic study of individuals with profound amnesia might contribute to the understanding the importance of each memory system, including effects on key analytic processes such as transference and countertransference. However, psychoanalytic work in the presence of profound amnesia might also require important technical modifications. In the first report of its kind, we describe observations from a long term psychoanalytic process (72 sessions) with an individual (JL) who has profound amnesia after an anoxic episode. The nature of therapy was shaped by JL's impairment in connecting elements that belong to distant (and even relatively close) moments in the therapeutic process. However, we were also able to document areas of preservation, in what appears to be a functioning therapeutic alliance. As regards transference, the relationship between JL and his analyst can be viewed as the evolution of a narcissistic transference, and case material is provided that maps this into three phases: (i) rejecting; (ii) starting to take in; and (iii) full use of the analytic space - where each phase exhibits differing degrees of permeability between JL and the analyst. This investigation appears to have important theoretical implications for psychoanalytic practice, and for psychotherapy in general - and not only with regard to brain injured populations. We especially note that it raises questions concerning the mechanism of therapeutic action in psychoanalysis and psychotherapy, and the apparent unimportance of episodic memory for many elements of therapeutic change.

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.

Computational EEG modelling of decision making under ambiguity reveals spatio-temporal dynamics of outcome evaluation.

Complex human cognition, such as decision-making under ambiguity, is reflected in dynamic spatio-temporal activity in the brain. Here, we combined event-related potentials with computational modelling of the time course of decision-making and outcome evaluation during the Iowa Gambling Task. Measures of choice probability generated using the Prospect Valence Learning Delta (PVL-Delta) model, in addition to objective trial outcomes (outcome magnitude and valence), were applied as regressors in a general linear model of the EEG signal. The resulting three-dimensional spatio-temporal characterization of task-related neural dynamics demonstrated that outcome valence, outcome magnitude, and PVL-Delta choice probability were expressed in distinctly separate event related potentials. Our findings showed that the P3 component was associated with an experience-based measure of outcome expectancy.