Modeling Avoidance in Mood and Anxiety Disorders Using Reinforcement Learning.

BACKGROUND: Serious and debilitating symptoms of anxiety are the most common mental health problem worldwide, accounting for around 5% of all adult years lived with disability in the developed world. Avoidance behavior-avoiding social situations for fear of embarrassment, for instance-is a core feature of such anxiety. However, as for many other psychiatric symptoms the biological mechanisms underlying avoidance remain unclear. METHODS: Reinforcement learning models provide formal and testable characterizations of the mechanisms of decision making; here, we examine avoidance in these terms. A total of 101 healthy participants and individuals with mood and anxiety disorders completed an approach-avoidance go/no-go task under stress induced by threat of unpredictable shock. RESULTS: We show an increased reliance in the mood and anxiety group on a parameter of our reinforcement learning model that characterizes a prepotent (Pavlovian) bias to withhold responding in the face of negative outcomes. This was particularly the case when the mood and anxiety group was under stress. CONCLUSIONS: This formal description of avoidance within the reinforcement learning framework provides a new means of linking clinical symptoms with biophysically plausible models of neural circuitry and, as such, takes us closer to a mechanistic understanding of mood and anxiety disorders

Reliability of Fronto-Amygdala Coupling during Emotional Face Processing.

One of the most exciting translational prospects for brain imaging research is the potential use of functional magnetic resonance imaging (fMRI) 'biomarkers' to predict an individual's risk of developing a neuropsychiatric disorder or the likelihood of responding to a particular intervention. This proposal depends critically on reliable measurements at the level of the individual. Several previous studies have reported relatively poor reliability of amygdala activation during emotional face processing, a key putative fMRI 'biomarker'. However, the reliability of amygdala connectivity measures is much less well understood. Here, we assessed the reliability of task-modulated coupling between three seed regions (left and right amygdala and the subgenual anterior cingulate cortex) and the dorsomedial frontal/cingulate cortex (DMFC), measured using a psychophysiological interaction analysis in 29 healthy individuals scanned approximately two weeks apart. We performed two runs on each day of three different emotional face-processing tasks: emotion identification, emotion matching, and gender classification. We tested both between-day reliability and within-day (between-run) reliability. We found good-to-excellent within-subject reliability of amygdala-DMFC coupling, both between days (in two tasks), and within day (in one task). This suggests that disorder-relevant regional coupling may be sufficiently reliable to be used as a predictor of treatment response or clinical risk in future clinical studies

Assessment of cognitive safety in clinical drug development

Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks

Cooperative Behavior in the Ultimatum Game and Prisoner's Dilemma Depends on Players' Contributions.

Economic games such as the Ultimatum Game (UG) and Prisoner's Dilemma (PD) are widely used paradigms for studying fairness and cooperation. Monetary versions of these games involve two players splitting an arbitrary sum of money. In real life, however, people's propensity to engage in cooperative behavior depends on their effort and contribution; factors that are well known to affect perceptions of fairness. We therefore sought to explore the impact of relative monetary contributions by players in the UG and PD. Adapted computerized UG and PD games, in which relative contributions from each player were manipulated, were administered to 200 participants aged 18-50 years old (50% female). We found that players' contribution had large effects on cooperative behavior. Specifically, cooperation was greater amongst participants when their opponent had contributed more to joint earnings. This was manifested as higher acceptance rates and higher offers in the UG; and fewer defects in the PD compared to when the participant contributed more. Interestingly, equal contributions elicited the greatest sensitivity to fairness in the UG, and least frequent defection in the PD. Acceptance rates correlated positively with anxiety and sex differences were found in defection behavior. This study highlights the feasibility of computerized games to assess cooperative behavior and the importance of considering cooperation within the context of effortful contribution

Do patients with schizophrenia exhibit aberrant salience?

BACKGROUND: It has been suggested that some psychotic symptoms reflect ‘aberrant salience’, related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulusreinforcement associations in the presence of distracting task-irrelevant cues. METHODS: We tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, participants made a speeded response to earn money in the presence of conditioned stimuli (CSs). Each CS comprised two visual dimensions, colour and form. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Measures of adaptive and aberrant motivational salience were calculated on the basis of latency and subjective reinforcement probability rating differences over the task-relevant and task-irrelevant dimensions respectively. RESULTS: Participants rated reinforcement significantly more likely and responded significantly faster on high-probability reinforced relative to lowprobability reinforced trials, representing adaptive motivational salience. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. In the controls, aberrant salience correlated significantly with ‘introvertive anhedonia’ schizotypy. CONCLUSIONS: These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. The relationship between aberrant salience and psychotic symptoms warrants further investigation in unmedicated patients

L\u27adaptation de l\u27organe visu el aux intermittences lumineuses et aux phosphènes électriques papillotants

U vezi s problemom mehanizma vidnih osjeta i s pitanjem, kako djeluje svijetlo na vidnu funkciju. izvršene su tri serije eksperimenata, i to: 1. ispitano je, kojom brzinom i u kojim granicama dolazi do adaptacije na treperenje izazvano isprekidanim svijetlom odnosno isprekidanim električnim podražajima oka; 2. ispitano je, kako utječe na kritičnu frekvenciju prethodno podraživanje oka treptavim svijetlom različite frekvencije a stalnog trajanja; i 3. ispitan je utjecaj intermitentnih električnih fosfena na frekvenciju fuzije svijetla. Rezultati tih pokusa bili su: a) pri podraživanju oka isprekidanom električnom strujom dolazi mnogo brže do adaptacije na treperenje i opseg adaptacije znatno je veći, nego kad se oko podražuje isprekidanim svijetlom; b) prethodno podraži van je vidnog organa različitim subfuzionalnim frekvencijama svijetla smanjuje kritičnu frekvenciju za svijetlo. Maksimalno smanjenje nađene je nakon ekspozicije na treptave svijetlo od oko 20/sek. sa simetričnim opadanjem smanjenja za brže i sporije frekvencije; c) prethodno podraživanje oka isprekidanom strujom različite frekvencije ne utječe na kritičnu frekvenciju za svijetlo. Na osnovi tih rezultata autor se priklanja hipotezi, da je brza adaptacija na intermitentne električne fosfene uvjetovana u prvom redu inhibicijom, koja nastaje u živčanim elementima retine, dok bi relativno uska adaptacija na treperenje svijetla bila rezultat prvenstveno pogoršanja u funkcionalnom stanju vidnog korteksa. Kod normalnog kontinuiranog podraživanja svijetlom dolazi do zaštitne inhibicije u· centrima, koja sprečava da kortikalne strukture dođu u takvo stanje uzbuđenja, koje ih iscrpljuje. Naprotiv diskontinuirano uzbuđivanje sprečava, da se ta zaštitna inhibicija razvije u dovoljnoj mjeri, a to tada dovodi do smanjenja funkcionalne sposobnosti centara, što se očituje u subjektivnoj fuziji isprekidanih podražaja, odnosno u sniženju kritične frekvencije. Maksimalno sniženje kritične frekvencije nakon ekspozicije na treperenje svijetla od oko 20/sek odgovara pristizanju grupiranih živčanih impulsa u momentima, kad se vidni korteks nalazi u svojoj supranormalnoj fazi podražljivosti.Dans le cadre des problèmes concernant le mécanisme de la vision et l\u27influence de la lumière intermittente nous avons étudié: 1) l\u27adaptation au papillotement produit soit par la lumière intermittente soit par la stimulation électrique interrompue à des fréquences préfusionnelles: 2) les changements de la fréquence critique sous J\u27influence des stimulations lumineuses intermittentes de diverses cadences et d\u27une durée de 30 sec.; et 3) l\u27influence des stimulations intermittentes électriques sur la fréquence de fusion de la lumière. Les résultats ont montré; a) l\u27adaptation au papillotement provoqué par une stimulation intermittente électrique (courant continu interrompu) se produit beaucoup plus vite et dans une marge des fréquences beaucoup plus grande que l\u27adaptation aux intermittences lumineuses. En général, l\u27adaptation au papillotement est d\u27autant plus rapide que la fréquence d\u27intermittences est plus grande. Le nombre total d\u27intermittences nécessaires à la disparition du papillotement augmente proportionnellement à la diminution de la fréquence; b) la stimulation préalable de l\u27oeil par la lumière à des fréquences préfusionnelles diminue la fréquence de fusion. La diminution maximum de la fréquence de fusion était obtenue après une stimulation à la cadence d\u27environ 20 cycles par sec. L\u27influence de la stimulation intermittente préalable sur la fréquence de fusion décroît presque symétriquement pour les fréquences de stimulation supérieures ou inférieures à 20/sec. L\u27exposition préalable de l\u27oeil aux fréquences suprafusionnelles ne change pas la fréquence de fusion; c) la stimulation électrique interrompue ne modifie pas la fréquence critique de la lumière. L\u27auteur émet l\u27hypothèse que l\u27adaptation rapide aux phosphènes électriques intermittents, qui se manifeste par la disparation des phosphènes, pourrait être attribuée à. l\u27inhibition des éléments rétiniens. Au contraire, l\u27adaptation lente au papillotement lumineux (homogénéisation apparente de stimulus) - l\u27adaptation que l\u27on peut obtenir seulement avec des fréquences assez voisines à la fréquence de fusion - serait plutôt l\u27effet d\u27une détérioration des éléments corticaux. Des modifications centrales semblables pourraient être aussi responsables de la diminution de la fréquence de fusion après l\u27exposition aux intermittences lumineuses

Affective resonance in response to others' emotional faces varies with affective ratings and psychopathic traits in amygdala and anterior insula

Despite extensive research on the neural basis of empathic responses for pain and disgust, there is limited data about the brain regions that underpin affective response to other people's emotional facial expressions. Here, we addressed this question using event-related functional magnetic resonance imaging to assess neural responses to emotional faces, combined with online ratings of subjective state. When instructed to rate their own affective response to others' faces, participants recruited anterior insula, dorsal anterior cingulate, inferior frontal gyrus, and amygdala, regions consistently implicated in studies investigating empathy for disgust and pain, as well as emotional saliency. Importantly, responses in anterior insula and amygdala were modulated by trial-by-trial variations in subjective affective responses to the emotional facial stimuli. Furthermore, overall task-elicited activations in these regions were negatively associated with psychopathic personality traits, which are characterized by low affective empathy. Our findings suggest that anterior insula and amygdala play important roles in the generation of affective internal states in response to others' emotional cues and that attenuated function in these regions may underlie reduced empathy in individuals with high levels of psychopathic traits.This work was supported by the Portuguese Foundation for Science and Technology (Fundação para a Ciencia e Tecnologia) under grant number [SFRH/BD/60279/2009] awarded to A.S.C.; the Economic and Social Research Council under grant number [RES-062-23-2202] award to E.V; E.V. is a Royal Society Wolfson Research Merit Award holder; C.L.S. was partially supported during the writing of this article by an Economic and Social Research Council award [ES/K008951/1]; J.P.R. is funded by the Wellcome Trust