Effects of stress-related neuromodulators on amygdala and hippocampus resting state functional connectivity.

BACKGROUND: The human stress response is characterized by increases in neuromodulators, including norepinephrine (NE) and cortisol. Both neuromodulators can enter the brain and affect neurofunctional responses. Two brain areas associated with stress are the amygdala and the hippocampus. The precise influence of NE and cortisol on the amygdala and hippocampal resting state functional connectivity (RSFC) is poorly understood. AIMS: To investigate the influence of NE and cortisol on the amygdala and hippocampal RSFC. METHODS: We recruited 165 participants who received 10 mg yohimbine and/or 10 mg hydrocortisone in a randomized, placebo-controlled design. With seed-based analyses, we compared RSFC of the hippocampus and amygdala separately between the three groups that received medication versus placebo. RESULTS: We found no differences between yohimbine and placebo condition or between hydrocortisone and placebo condition regarding amygdala or hippocampal FC. Compared with placebo, the yohimbine/hydrocortisone condition showed increased amygdala and hippocampal RSFC with the cerebellum. Also, they had increased hippocampal RSFC with the amygdala and cerebral white matter. DISCUSSION: The group with elevated NE and cortisol showed significantly increased RSFC between the amygdala, hippocampus, and cerebellum compared to placebo. These three brain areas are involved in associative learning and emotional memory, suggesting a critical role for this network in the human stress response. Our results show that NE and cortisol together may influence the strength of this association. Compared to placebo, we found no differences in the groups receiving only one medication, suggesting that increasing one neuromodulator alone may not induce differences in neurofunctional responses. The study procedure has been registered at clinicaltrials.gov (ID: NCT04359147).

The effects of yohimbine and hydrocortisone on selective attention to fearful faces: An fMRI study.

INTRODUCTION: Selective attention to salient emotional information can enable an advantage in the face of danger. The present study aims to investigate the influence of the stress neuromodulators, norepinephrine and cortisol, on selective attention processes to fearful faces and its neuronal activation. METHODS AND MATERIALS: We used a randomized, double-blind, placebo-controlled design. 167 healthy men between 18 and 35 years (mean [SD] age: 25.23 [4.24] years) participated in the study. Participants received either: (A) yohimbine (n= 41), (B) hydrocortisone (n = 41), (C) yohimbine and hydrocortisone (n = 42) or (D) placebo only (n= 43) and participated in a dot-probe task with fearful and neutral faces in an fMRI scanner. RESULTS: We found an attentional bias toward fearful faces across all groups and related neuronal activation in the left cuneus. We did not find any differences between experimental treatment groups in selective attention and its neuronal activation. DISCUSSION: Our results provide evidence that fearful faces lead to an attentional bias with related neuronal activation in the left cuneus. We did not replicate formerly reported activation in the amygdala, intraparietal sulcus, dorsal anterior cingulate cortex, and thalamus. Suitability of the dot-probe task for fMRI studies and insignificant treatment effects are discussed.

Observational reinforcement learning in children and young adults.

Observational learning is essential for the acquisition of new behavior in educational practices and daily life and serves as an important mechanism for human cognitive and social-emotional development. However, we know little about its underlying neurocomputational mechanisms from a developmental perspective. In this study we used model-based fMRI to investigate differences in observational learning and individual learning between children and younger adults. Prediction errors (PE), the difference between experienced and predicted outcomes, related positively to striatal and ventral medial prefrontal cortex activation during individual learning and showed no age-related differences. PE-related activation during observational learning was more pronounced when outcomes were worse than predicted. Particularly, negative PE-coding in the dorsal medial prefrontal cortex was stronger in adults compared to children and was associated with improved observational learning in children and adults. The current findings pave the way to better understand observational learning challenges across development and educational settings.

Fronto-striatal alterations correlate with apathy severity in behavioral variant frontotemporal dementia.

Structural and functional changes in cortical and subcortical regions have been reported in behavioral variant frontotemporal dementia (bvFTD), however, a multimodal approach may provide deeper insights into the neural correlates of neuropsychiatric symptoms. In this multicenter study, we measured cortical thickness (CTh) and subcortical volumes to identify structural abnormalities in 37 bvFTD patients, and 37 age- and sex-matched healthy controls. For seed regions with significant structural changes, whole-brain functional connectivity (FC) was examined in a sub-cohort of N = 22 bvFTD and N = 22 matched control subjects to detect complementary alterations in brain network organization. To explore the functional significance of the observed structural and functional deviations, correlations with clinical and neuropsychological outcomes were tested where available. Significantly decreased CTh was observed in the bvFTD group in caudal middle frontal gyrus, left pars opercularis, bilateral superior frontal and bilateral middle temporal gyrus along with subcortical volume reductions in bilateral basal ganglia, thalamus, hippocampus, and amygdala. Resting-state functional magnetic resonance imaging showed decreased FC in bvFTD between: dorsal striatum and left caudal middle frontal gyrus; putamen and fronto-parietal regions; pallidum and cerebellum. Conversely, bvFTD showed increased FC between: left middle temporal gyrus and paracingulate gyrus; caudate nucleus and insula; amygdala and parahippocampal gyrus. Additionally, cortical thickness in caudal, lateral and superior frontal regions as well as caudate nucleus volume correlated negatively with apathy severity scores of the Neuropsychiatry Inventory Questionnaire. In conclusion, multimodal structural and functional imaging indicates that fronto-striatal regions have a considerable influence on the severity of apathy in bvFTD.

No changes in triple network engagement following (combined) noradrenergic and glucocorticoid stimulation in healthy men.

Successful recovery from stress is integral for adaptive responding to the environment. At a cellular level, this involves (slow genomic) actions of cortisol, which alter or reverse rapid effects of noradrenaline and cortisol associated with acute stress. At the network scale, stress recovery is less well understood but assumed to involve changes within salience-, executive control-, and default mode networks. To date, few studies have investigated this phase and directly tested these assumptions. Here, we present results from a double-blind, placebo-controlled, between-group paradigm (N = 165 healthy males) administering 10 mg oral yohimbine and/or 10 mg oral hydrocortisone two hours prior to resting state scanning. We found no changes in within-network connectivity of the three networks, both after single and combined drug administration. We further report the results of Bayesian parameter inference to provide evidence for the null hypothesis. Our results contrast with previous findings, which may be attributable to systematic differences between paradigms, highlighting the need to isolate paradigm-specific effects from those related to stress.

Non-instrumental information seeking is resistant to acute stress.

Previous research has shown that people intrinsically value non-instrumental information, which cannot be used to change the outcome of events, but only provides an early resolution of uncertainty. This is true even for information about rather inconsequential events, such as the outcomes of small lotteries. Here we investigated whether participants' willingness to pay for non-instrumental information about the outcome of simple coin-flip lotteries with guaranteed winnings was modulated by acute stress. Stress was induced using the Socially Evaluated Cold Pressor Test (SECPT), and information-seeking choices were compared to a warm water control group. Our results neither support the hypothesis that stress decreases information-seeking by directing cognitive resources away from the relevance of the lotteries, nor the opposite hypothesis that stress increases information-seeking by driving anxiety levels up. Instead, we found that despite successful stress induction, as evidenced by increased saliva cortisol levels in the SECPT group, information valuation was remarkably stable. This finding is in line with recent findings that experimentally increased state anxiety did not modulate non-instrumental information seeking. Together, these results suggest that the aversiveness of "not knowing" is a stable cognitive state and not easily modulated by situational context, such as acute stress.

The dorsomedial prefrontal cortex represents subjective value across effort-based and risky decision-making.

Decisions that require taking effort costs into account are ubiquitous in real life. The neural common currency theory hypothesizes that a particular neural network integrates different costs (e.g., risk) and rewards into a common scale to facilitate value comparison. Although there has been a surge of interest in the computational and neural basis of effort-related value integration, it is still under debate if effort-based decision-making relies on a domain-general valuation network as implicated in the neural common currency theory. Therefore, we comprehensively compared effort-based and risky decision-making using a combination of computational modeling, univariate and multivariate fMRI analyses, and data from two independent studies. We found that effort-based decision-making can be best described by a power discounting model that accounts for both the discounting rate and effort sensitivity. At the neural level, multivariate decoding analyses indicated that the neural patterns of the dorsomedial prefrontal cortex (dmPFC) represented subjective value across different decision-making tasks including either effort or risk costs, although univariate signals were more diverse. These findings suggest that multivariate dmPFC patterns play a critical role in computing subjective value in a task-independent manner and thus extend the scope of the neural common currency theory.

Task state representations in vmPFC mediate relevant and irrelevant value signals and their behavioral influence.

The ventromedial prefrontal-cortex (vmPFC) is known to contain expected value signals that inform our choices. But expected values even for the same stimulus can differ by task. In this study, we asked how the brain flexibly switches between such value representations in a task-dependent manner. Thirty-five participants alternated between tasks in which either stimulus color or motion predicted rewards. We show that multivariate vmPFC signals contain a rich representation that includes the current task state or context (motion/color), the associated expected value, and crucially, the irrelevant value of the alternative context. We also find that irrelevant value representations in vmPFC compete with relevant value signals, interact with task-state representations and relate to behavioral signs of value competition. Our results shed light on vmPFC's role in decision making, bridging between its role in mapping observations onto the task states of a mental map, and computing expected values for multiple states.

Structural gray matter features and behavioral preliterate skills predict future literacy - A machine learning approach.

When children learn to read, their neural system undergoes major changes to become responsive to print. There seem to be nuanced interindividual differences in the neurostructural anatomy of regions that later become integral parts of the reading network. These differences might affect literacy acquisition and, in some cases, might result in developmental disorders like dyslexia. Consequently, the main objective of this longitudinal study was to investigate those interindividual differences in gray matter morphology that might facilitate or hamper future reading acquisition. We used a machine learning approach to examine to what extent gray matter macrostructural features and cognitive-linguistic skills measured before formal literacy teaching could predict literacy 2 years later. Forty-two native German-speaking children underwent T1-weighted magnetic resonance imaging and psychometric testing at the end of kindergarten. They were tested again 2 years later to assess their literacy skills. A leave-one-out cross-validated machine-learning regression approach was applied to identify the best predictors of future literacy based on cognitive-linguistic preliterate behavioral skills and cortical measures in a priori selected areas of the future reading network. With surprisingly high accuracy, future literacy was predicted, predominantly based on gray matter volume in the left occipito-temporal cortex and local gyrification in the left insular, inferior frontal, and supramarginal gyri. Furthermore, phonological awareness significantly predicted future literacy. In sum, the results indicate that the brain morphology of the large-scale reading network at a preliterate age can predict how well children learn to read.

Category-specific memory encoding in the medial temporal lobe and beyond: the role of reward.

The medial temporal lobe (MTL), including the hippocampus (HC), perirhinal cortex (PRC), and parahippocampal cortex (PHC), is central to memory formation. Reward enhances memory through interplay between the HC and substantia nigra/ventral tegmental area (SNVTA). While the SNVTA also innervates the MTL cortex and amygdala (AMY), their role in reward-enhanced memory is unclear. Prior research suggests category specificity in the MTL cortex, with the PRC and PHC processing object and scene memory, respectively. It is unknown, however, whether reward modulates category-specific memory processes. Furthermore, no study has demonstrated clear category specificity in the MTL for encoding processes contributing to subsequent recognition memory. To address these questions, we had 39 healthy volunteers (27 for all memory-based analyses) undergo functional magnetic resonance imaging while performing an incidental encoding task pairing objects or scenes with high or low reward, followed by a next-day recognition test. Behaviorally, high reward preferably enhanced object memory. Neural activity in the PRC and PHC reflected successful encoding of objects and scenes, respectively. Importantly, AMY encoding effects were selective for high-reward objects, with a similar pattern in the PRC. The SNVTA and HC showed no clear evidence of successful encoding. This behavioral and neural asymmetry may be conveyed through an anterior-temporal memory system, including the AMY and PRC, potentially in interplay with the ventromedial prefrontal cortex.

Gaze-dependent evidence accumulation predicts multi-alternative risky choice behaviour.

Choices are influenced by gaze allocation during deliberation, so that fixating an alternative longer leads to increased probability of choosing it. Gaze-dependent evidence accumulation provides a parsimonious account of choices, response times and gaze-behaviour in many simple decision scenarios. Here, we test whether this framework can also predict more complex context-dependent patterns of choice in a three-alternative risky choice task, where choices and eye movements were subject to attraction and compromise effects. Choices were best described by a gaze-dependent evidence accumulation model, where subjective values of alternatives are discounted while not fixated. Finally, we performed a systematic search over a large model space, allowing us to evaluate the relative contribution of different forms of gaze-dependence and additional mechanisms previously not considered by gaze-dependent accumulation models. Gaze-dependence remained the most important mechanism, but participants with strong attraction effects employed an additional similarity-dependent inhibition mechanism found in other models of multi-alternative multi-attribute choice.

Neural correlates of successful costly punishment in the Ultimatum game on a trial-by-trial basis.

Costly punishment describes decisions of an interaction partner to punish an opponent for violating rules of fairness at the expense of personal costs. Here, we extend the interaction process by investigating the impact of a socio-emotional reaction of the opponent in response to the punishment that indicates whether punishment was successful or not. In a modified Ultimatum game, emotional facial expressions of the proposer in response to the decision of the responder served as feedback stimuli. We found that both honored reward following acceptance of an offer (smiling compared to neutral facial expression) and successful punishment (sad compared to neutral facial expression) elicited a reward positivity, indicating that punishment was the intended outcome. By comparing the pattern of results with a probabilistic learning task, we show that the reward positivity on sad facial expressions was specific for the context of costly punishment. Additionally, acceptance rates on a trial-by-trial basis were altered according to P3 amplitudes in response to the emotional facial reaction of the proposer. Our results are in line with the concept of costly punishment as an intentional act following norm-violating behavior. Socio-emotional stimuli have an important influence on the perception and behavior in economic bargaining.

Dynamic computation of value signals via a common neural network in multi-attribute decision-making.

Studies in decision neuroscience have identified robust neural representations for the value of choice options. However, overall values often depend on multiple attributes, and it is not well understood how the brain evaluates different attributes and integrates them to combined values. In particular, it is not clear whether attribute values are computed in distinct attribute-specific regions or within the general valuation network known to process overall values. Here, we used a functional magnetic resonance imaging choice task in which abstract stimuli had to be evaluated based on variations of the attributes color and motion. The behavioral data showed that participants responded faster when overall values were high and attribute value differences were low. On the neural level, we did not find that attribute values were systematically represented in areas V4 and V5, even though these regions are associated with attribute-specific processing of color and motion, respectively. Instead, attribute values were associated with activity in the posterior cingulate cortex, ventral striatum and posterior inferior temporal gyrus. Furthermore, overall values were represented in dorsolateral and ventromedial prefrontal cortex, and attribute value differences in dorsomedial prefrontal cortex, which suggests that these regions play a key role for the neural integration of attribute values.

The neural basis of effort valuation: A meta-analysis of functional magnetic resonance imaging studies.

Choosing how much effort to expend is critical for everyday decisions. While several neuroimaging studies have examined effort-based decision-making, results have been highly heterogeneous, leaving unclear which brain regions process effort-related costs and integrate them with rewards. We conducted two meta-analyses of functional magnetic resonance imaging data to examine consistent neural correlates of effort demands (23 studies, 15 maps, 549 participants) and net value (15 studies, 11 maps, 428 participants). The pre-supplementary motor area (pre-SMA) scaled positively with pure effort demand, whereas the ventromedial prefrontal cortex (vmPFC) showed the opposite effect. Moreover, regions that have been previously implicated in value integration in other cost domains, such as the vmPFC and ventral striatum, were consistently involved in signaling net value. The opposite response patterns of the pre-SMA and vmPFC imply that they are differentially involved in the representation of effort costs and value integration. These findings provide conclusive evidence that the vmPFC is a central node for net value computation and reveal potential brain targets to treat motivation-related disorders.

Effects of non-invasive brain stimulation on visual perspective taking: A meta-analytic study.

Visual perspective taking (VPT) is a critical ability required by complex social interaction. Non-invasive brain stimulation (NIBS) has been increasingly used to examine the causal relationship between brain activity and VPT, yet with heterogeneous results. In the current study, we conducted two meta-analyses to examine the effects of NIBS of the right temporoparietal junction (rTPJ) or dorsomedial prefrontal cortex (dmPFC) on VPT, respectively. We performed a comprehensive literature search to identify qualified studies and computed the standardized effect size (ES) for each combination of VPT level (Level-1: visibility judgment; Level-2: mental rotation) and perspective (self and other). Thirteen studies (rTPJ: 12 studies, 23 ESs; dmPFC: 4 studies, 14 ESs) were included in the meta-analyses. Random-effects models were used to generate the overall effects. Subgroup analyses for distinct VPT conditions were also performed. We found that rTPJ stimulation significantly improved participants' visibility judgment from the allocentric perspective, whereas its effects on other VPT conditions are negligible. Stimulation of dmPFC appeared to influence Level-1 performance from the egocentric perspective, although this finding was only based on a small number of studies. Notably, contrary to some theoretical models, we did not find strong evidence that these regions are involved in Level-2 VPT with a higher requirement of mental rotation. These findings not only advance our understanding of the causal roles of the rTPJ and dmPFC in VPT, but also reveal that the efficacy of NIBS on VPT is relatively small. Additionally, researchers should also be cautious about the potential publication bias and selective reporting.

Neural processing of vision and language in kindergarten is associated with prereading skills and predicts future literacy.

The main objective of this longitudinal study was to investigate the neural predictors of reading acquisition. For this purpose, we followed a sample of 54 children from the end of kindergarten to the end of second grade. Preliterate children were tested for visual symbol (checkerboards, houses, faces, written words) and auditory language processing (spoken words) using a passive functional magnetic resonance imaging paradigm. To examine brain-behavior relationships, we also tested cognitive-linguistic prereading skills at kindergarten age and reading performance of 48 of the same children 2 years later. Face-selective response in the bilateral fusiform gyrus was positively associated with rapid automatized naming (RAN). Response to both spoken and written words at preliterate age was negatively associated with RAN in the dorsal temporo-parietal language system. Longitudinally, neural response to faces in the ventral stream predicted future reading fluency. Here, stronger neural activity in inferior and middle temporal gyri at kindergarten age was associated with higher reading performance. Our results suggest that interindividual differences in the neural system of language and reading affect literacy acquisition and thus might serve as a marker for successful reading acquisition in preliterate children.

No Words for Feelings? Not Only for My Own: Diminished Emotional Empathic Ability in Alexithymia.

The present study has been designed to disentangle cognitive and emotional dimensions of empathy in a group of mentally healthy and highly alexithymic individuals (ALEX, n = 24) and well-matched controls (n = 26) through questionnaire Interpersonal Reactivity Index (IRI) and Multifaceted Empathy Task (MET) used during the fMRI and after the fMRI. Simultaneously, Skin Conductance Response (SCR) has been acquired as an implicit measure of emotional reaction. Results show an impaired emotional empathic ability in alexithymic individuals, with lower levels of SCR and higher activation in prefrontal brain regions such as the ventrolateral prefrontal cortex (VLPFC) and inferior frontal gyrus (IFG). Cognitive empathy was not impaired in the alexithymic group and the results were accompanied by a higher activation left IFG. The study leads to the conclusion that alexithymia does not only involve a diminished ability to identify and describe one's own emotions. Furthermore, it is related to a deeper disability of emotion regulation, which becomes visible through impaired emotional concern for others and higher levels of personal distress.

Fear-induced increases in loss aversion are linked to increased neural negative-value coding.

Human decisions are often influenced by emotions. An economically relevant example is the role of fear in generating loss aversion. Previous research implicates the amygdala as a key brain structure in the experience of fear and loss aversion. The neural mechanism behind emotional influences on loss aversion is, however, unclear. To address this, we measured brain activation with functional magnetic resonance imaging (fMRI) while participants made decisions about monetary gambles after viewing fearful or neutral faces. We observed that loss aversion following the presentation of neutral faces was mainly predicted by greater deactivations for prospective losses (relative to activations for prospective gains) in several brain regions, including the amygdala. By contrast, increases in loss aversion following the presentation of fearful faces were mainly predicted by greater activations for prospective losses. These findings suggest a fear-induced shift from positive to negative value coding that reflects a context-dependent involvement of distinct valuation processes.