Increased decision thresholds enhance information gathering performance in juvenile Obsessive-Compulsive Disorder (OCD).

Patients with obsessive-compulsive disorder (OCD) can be described as cautious and hesitant, manifesting an excessive indecisiveness that hinders efficient decision making. However, excess caution in decision making may also lead to better performance in specific situations where the cost of extended deliberation is small. We compared 16 juvenile OCD patients with 16 matched healthy controls whilst they performed a sequential information gathering task under different external cost conditions. We found that patients with OCD outperformed healthy controls, winning significantly more points. The groups also differed in the number of draws required prior to committing to a decision, but not in decision accuracy. A novel Bayesian computational model revealed that subjective sampling costs arose as a non-linear function of sampling, closely resembling an escalating urgency signal. Group difference in performance was best explained by a later emergence of these subjective costs in the OCD group, also evident in an increased decision threshold. Our findings present a novel computational model and suggest that enhanced information gathering in OCD can be accounted for by a higher decision threshold arising out of an altered perception of costs that, in some specific contexts, may be advantageous.

Temporally Dissociable Contributions of Human Medial Prefrontal Subregions to Reward-Guided Learning.

In decision making, dorsal and ventral medial prefrontal cortex show a sensitivity to key decision variables, such as reward prediction errors. It is unclear whether these signals reflect parallel processing of a common synchronous input to both regions, for example from mesocortical dopamine, or separate and consecutive stages in reward processing. These two perspectives make distinct predictions about the relative timing of feedback-related activity in each of these regions, a question we address here. To reconstruct the unique temporal contribution of dorsomedial (dmPFC) and ventromedial prefrontal cortex (vmPFC) to simultaneously measured EEG activity in human subjects, we developed a novel trialwise fMRI-informed EEG analysis that allows dissociating correlated and overlapping sources. We show that vmPFC uniquely contributes a sustained activation profile shortly after outcome presentation, whereas dmPFC contributes a later and more peaked activation pattern. This temporal dissociation is expressed mainly in the alpha band for a vmPFC signal, which contrasts with a theta based dmPFC signal. Thus, our data show reward-related vmPFC and dmPFC responses have distinct time courses and unique spectral profiles, findings that support distinct functional roles in a reward-processing network. SIGNIFICANCE STATEMENT: Multiple subregions of the medial prefrontal cortex are known to be involved in decision making and learning, and expose similar response patterns in fMRI. Here, we used a novel approach to analyzing simultaneous EEG-fMRI that allows to dissociate the individual time courses of brain regions. We find that vmPFC and dmPFC have distinguishable time courses and time-frequency patterns.

Conflict monitoring and error processing: new insights from simultaneous EEG-fMRI.

Error processing and conflict monitoring are essential executive functions for goal directed actions and adaptation to conflicting information. Although medial frontal regions such as the anterior cingulate cortex (ACC) and the pre-supplementary motor area (pre-SMA) are known to be involved in these functions, there is still considerable heterogeneity regarding their spatio-temporal activations. The timing of these functions has been associated with two separable event-related potentials (ERPs) usually localized to the medial frontal wall, one during error processing (ERN--error related negativity) and one during conflict monitoring (N2). In this study we aimed to spatially and temporally dissociate conflict and error processing using simultaneously recorded EEG and fMRI data from a modified Flanker task in healthy adults. We demonstrate a spatial dissociation of conflict monitoring and error processing along the medial frontal wall, with selective conflict level dependent activation of the SMA/pre-SMA. Activation to error processing was located in the ACC, rostral cingulate zone (RCZ) and pre-SMA. The EEG-informed fMRI analysis revealed that stronger ERN amplitudes are associated with increased activation in a large coherent cluster comprising the ACC, RCZ and pre-SMA, while N2 amplitudes increased with activation in the pre-SMA. Conjunction analysis of EEG-informed fMRI revealed common activation of ERN and N2 in the pre-SMA and divergent activation in the RCZ. No conjoint activation between error processing and conflict monitoring was found with standard fMRI analysis along the medial frontal wall. Our fMRI findings clearly demonstrate that conflict monitoring and error processing are spatially dissociable along the medial frontal wall. Moreover, the overlap of ERN- and N2-informed fMRI activation in the pre-SMA provides new evidence that these ERP components share conflict related processing functions and are thus not completely separable.

Cognitive flexibility in adolescence: neural and behavioral mechanisms of reward prediction error processing in adaptive decision making during development.

Adolescence is associated with quickly changing environmental demands which require excellent adaptive skills and high cognitive flexibility. Feedback-guided adaptive learning and cognitive flexibility are driven by reward prediction error (RPE) signals, which indicate the accuracy of expectations and can be estimated using computational models. Despite the importance of cognitive flexibility during adolescence, only little is known about how RPE processing in cognitive flexibility deviates between adolescence and adulthood. In this study, we investigated the developmental aspects of cognitive flexibility by means of computational models and functional magnetic resonance imaging (fMRI). We compared the neural and behavioral correlates of cognitive flexibility in healthy adolescents (12-16years) to adults performing a probabilistic reversal learning task. Using a modified risk-sensitive reinforcement learning model, we found that adolescents learned faster from negative RPEs than adults. The fMRI analysis revealed that within the RPE network, the adolescents had a significantly altered RPE-response in the anterior insula. This effect seemed to be mainly driven by increased responses to negative prediction errors. In summary, our findings indicate that decision making in adolescence goes beyond merely increased reward-seeking behavior and provides a developmental perspective to the behavioral and neural mechanisms underlying cognitive flexibility in the context of reinforcement learning.

Classifying adolescent attention-deficit/hyperactivity disorder (ADHD) based on functional and structural imaging.

Attention-deficit/hyperactivity disorder (ADHD) is a common disabling psychiatric disorder associated with consistent deficits in error processing, inhibition and regionally decreased grey matter volumes. The diagnosis is based on clinical presentation, interviews and questionnaires, which are to some degree subjective and would benefit from verification through biomarkers. Here, pattern recognition of multiple discriminative functional and structural brain patterns was applied to classify adolescents with ADHD and controls. Functional activation features in a Flanker/NoGo task probing error processing and inhibition along with structural magnetic resonance imaging data served to predict group membership using support vector machines (SVMs). The SVM pattern recognition algorithm correctly classified 77.78% of the subjects with a sensitivity and specificity of 77.78% based on error processing. Predictive regions for controls were mainly detected in core areas for error processing and attention such as the medial and dorsolateral frontal areas reflecting deficient processing in ADHD (Hart et al., in Hum Brain Mapp 35:3083-3094, 2014), and overlapped with decreased activations in patients in conventional group comparisons. Regions more predictive for ADHD patients were identified in the posterior cingulate, temporal and occipital cortex. Interestingly despite pronounced univariate group differences in inhibition-related activation and grey matter volumes the corresponding classifiers failed or only yielded a poor discrimination. The present study corroborates the potential of task-related brain activation for classification shown in previous studies. It remains to be clarified whether error processing, which performed best here, also contributes to the discrimination of useful dimensions and subtypes, different psychiatric disorders, and prediction of treatment success across studies and sites.

The feedback-related negativity (FRN) revisited: new insights into the localization, meaning and network organization.

Changes in response contingencies require adjusting ones assumptions about outcomes of behaviors. Such adaptation processes are driven by reward prediction error (RPE) signals which reflect the inadequacy of expectations. Signals resembling RPEs are known to be encoded by mesencephalic dopamine neurons projecting to the striatum and frontal regions. Although regions that process RPEs, such as the dorsal anterior cingulate cortex (dACC), have been identified, only indirect evidence links timing and network organization of RPE processing in humans. In electroencephalography (EEG), which is well known for its high temporal resolution, the feedback-related negativity (FRN) has been suggested to reflect RPE processing. Recent studies, however, suggested that the FRN might reflect surprise, which would correspond to the absolute, rather than the signed RPE signals. Furthermore, the localization of the FRN remains a matter of debate. In this simultaneous EEG-functional magnetic resonance imaging (fMRI) study, we localized the FRN directly using the superior spatial resolution of fMRI without relying on any spatial constraint or other assumption. Using two different single-trial approaches, we consistently found a cluster within the dACC. One analysis revealed additional activations of the salience network. Furthermore, we evaluated the effect of signed RPEs and surprise signals on the FRN amplitude. We considered that both signals are usually correlated and found that only surprise signals modulate the FRN amplitude. Last, we explored the pathway of RPE signals using dynamic causal modeling (DCM). We found that the surprise signals are directly projected to the source region of the FRN. This finding contradicts earlier theories about the network organization of the FRN, but is in line with a recent theory stating that dopamine neurons also encode surprise-like saliency signals. Our findings crucially advance the understanding of the FRN. We found compelling evidence that the FRN originates from the dACC. Furthermore, we clarified the functional role of the FRN, and determined the role of the dACC within the RPE network. These findings should enable us to study the processing of surprise and adjustment signals in the dACC in healthy and also in psychiatric patients.

A randomized, double-blind, placebo-controlled study to test the efficacy of topical 2-hydroxypropyl-Beta-cyclodextrin in the prophylaxis of recurrent herpes labialis.

Herpes labialis affects one third of the population. We evaluated the topical application of an antiviral compound, hydroxypropyl-ß-cyclodextrin (2-HPßCD), in reducing herpes labialis relapses. In this double-blind, randomized, placebo-controlled trial, 40 patients were randomized to a polyethylene glycol (PEG) formulation containing 20% 2-HPßCD or to a vehicle control arm. The gel was applied to the lips twice daily for 6 months. The primary objective was reducing herpes relapses. Surprisingly, the drug group had significantly more relapses than the vehicle group (p = 0.003). While the median numbers of relapses in the preceding year were 12 in the vehicle group and 10 in the drug group, both groups experienced very few relapses during the 6-month treatment period, with a median of 0 in the vehicle group and a median of 2 in the drug group. The impressive reduction of relapses in both groups may be due to a placebo effect or due to the topical treatment with PEG.

Neuroimaging of cognitive brain function in paediatric obsessive compulsive disorder: a review of literature and preliminary meta-analysis.

Obsessive compulsive disorder (OCD) is a frequent psychiatric disorder with a prevalence of 1-3 %, and it places an enormous burden on patients and their relatives. Up to 50 % of all cases suffer from onset in childhood or adolescence, and the disorder often takes a chronic course with a poor long-term prognosis. Paediatric OCD, with its high familiality, is often referred to as a distinct OCD subtype that coincides with a developmental period in which the prefrontal cortex exhibits extensive structural and functional maturation. In the present review, we included all studies examining cognitive brain activation in children and/or adolescents with OCD. We conducted extensive literature searches for relevant articles (Pubmed, ScienceDirect) and summarize, tabulate, and discuss their results. For the eight activation studies using functional magnetic resonance imaging, we also performed preliminary meta-analyses to assess the most consistent hypo- and hyperactivation in paediatric OCD patients during cognitive task performance. The review of literature as well as our preliminary meta-analyses of paediatric studies indicated altered functional activation in the same brain regions of affective and cognitive cortico-striatal-thalamic (CST) circuits as for adult OCD patients despite some variations in the direction of activation difference. The still small number of studies that examined brain activation in paediatric OCD patients thereby largely converged with previous findings in adult patients and with the established neurobiological models of CST circuit dysfunction in OCD.

From spontaneous to strategic natural window ventilation: Improving indoor air quality in Swiss schools.

Natural window ventilation is frequently employed in schools in Europe and often leads to inadequate levels of human bioeffluents. However, intervention studies that verify whether recommended ventilation targets can be achieved in practice with reasonable ventilation regimes and that are also suitable for countries with cold winters are practically non-existent. To explore the initial situation in Switzerland we carried out carbon dioxide (CO2) measurements during the winter in 100 classrooms, most of which (94%) had natural window ventilation. In more than two thirds of those, the hygienic limit value of 2000 ppm specified for CO2 in the Swiss Standard SN 520180 (2014) was exceeded. To improve ventilation behavior, an intervention was implemented in 23 classrooms during the heating season. Ventilation was performed exclusively during breaks (to avoid discomfort from cold and drafts), efficiently, and only for as long as was necessary to achieve the ventilation objective of compliance with the hygienic limit value (strategic ventilation). The intervention included verbal and written instructions, awareness-raising via a school lesson and an interactive tool for students, which was also used to estimate the required duration of ventilation. CO2 exposure was significantly reduced in pilot classes (Wilcoxon signed-rank test, p = 3.815e-06). Median CO2 levels decreased from 1600 ppm (control group) to 1097 ppm (intervention group), and the average proportion of teaching time at 400-1400 ppm CO2 increased from 40% to 70%. The duration of ventilation was similar to spontaneous natural window ventilation (+5.8%). Stricter ventilation targets are possible. The concept of the intervention is suitable for immediate adoption in schools with natural window ventilation for a limited period, pending the installation of a mechanical ventilation system. The easy integration of this intervention into everyday school life promotes compliance, which is particularly important during the COVID-19 pandemic.

Role of the medial prefrontal cortex in impaired decision making in juvenile attention-deficit/hyperactivity disorder.

IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) has been associated with deficient decision making and learning. Models of ADHD have suggested that these deficits could be caused by impaired reward prediction errors (RPEs). Reward prediction errors are signals that indicate violations of expectations and are known to be encoded by the dopaminergic system. However, the precise learning and decision-making deficits and their neurobiological correlates in ADHD are not well known. OBJECTIVE: To determine the impaired decision-making and learning mechanisms in juvenile ADHD using advanced computational models, as well as the related neural RPE processes using multimodal neuroimaging. DESIGN, SETTING, AND PARTICIPANTS: Twenty adolescents with ADHD and 20 healthy adolescents serving as controls (aged 12-16 years) were examined using a probabilistic reversal learning task while simultaneous functional magnetic resonance imaging and electroencephalogram were recorded. MAIN OUTCOMES AND MEASURES: Learning and decision making were investigated by contrasting a hierarchical Bayesian model with an advanced reinforcement learning model and by comparing the model parameters. The neural correlates of RPEs were studied in functional magnetic resonance imaging and electroencephalogram. RESULTS: Adolescents with ADHD showed more simplistic learning as reflected by the reinforcement learning model (exceedance probability, Px = .92) and had increased exploratory behavior compared with healthy controls (mean [SD] decision steepness parameter ß: ADHD, 4.83 [2.97]; controls, 6.04 [2.53]; P = .02). The functional magnetic resonance imaging analysis revealed impaired RPE processing in the medial prefrontal cortex during cue as well as during outcome presentation (P < .05, family-wise error correction). The outcome-related impairment in the medial prefrontal cortex could be attributed to deficient processing at 200 to 400 milliseconds after feedback presentation as reflected by reduced feedback-related negativity (ADHD, 0.61 [3.90] µV; controls, -1.68 [2.52] µV; P = .04). CONCLUSIONS AND RELEVANCE: The combination of computational modeling of behavior and multimodal neuroimaging revealed that impaired decision making and learning mechanisms in adolescents with ADHD are driven by impaired RPE processing in the medial prefrontal cortex. This novel, combined approach furthers the understanding of the pathomechanisms in ADHD and may advance treatment strategies.