Bilingual Spatial Cognition: Spatial Cue Use in Bilinguals and Monolinguals.

Structural plasticity changes and functional differences in executive control tasks have been reported in bilinguals compared to monolinguals, supporting a proposed bilingual 'advantage' in executive control functions (e.g., task switching) due to continual usage of control mechanisms that inhibit one of the coexisting languages. However, it remains unknown whether these differences are also apparent in the spatial domain. The present fMRI study explores the use of spatial cues in 15 bilinguals and 14 monolinguals while navigating in an open-field virtual environment. In each trial, participants had to navigate towards a target object that was visible during encoding but hidden in retrieval. An extensive network was activated in bilinguals compared to monolinguals in the encoding and retrieval phase. During encoding, bilinguals activated the right temporal and left parietal regions (object trials) and left inferior frontal, precentral, and lingual regions more than monolinguals. During retrieval, the same contrasts activated the left caudate nucleus and the right dorsolateral prefrontal cortex (DLPFC), the left parahippocampal gyrus, as well as caudate regions. These results suggest that bilinguals may recruit neural networks known to subserve not only executive control processes but also spatial strategies.

Developmental shift in testosterone influence on prefrontal emotion control.

A paradox of testosterone effects is seen in adolescents versus adults in social emotional approach-avoidance behavior. During adolescence, high testosterone levels are associated with increased anterior prefrontal (aPFC) involvement in emotion control, whereas during adulthood this neuro-endocrine relation is reversed. Rodent work shows that, during puberty, testosterone transitions from a neuro-developmental to a social-sexual activating hormone. In this study, we explored whether this functional transition is also present in human adolescents and young adults. Using a prospective longitudinal design, we investigated the role of testosterone on neural control of social emotional behavior during the transitions from middle to late adolescence and into young adulthood. Seventy-one individuals (tested at ages 14, 17, and 20 years) performed an fMRI-adapted approach-avoidance (AA) task involving automatic and controlled actions in response to social emotional stimuli. In line with predictions from animal models, the effect of testosterone on aPFC engagement decreased between middle and late adolescence, and shifted into an activational role by young adulthood-impeding neural control of emotions. This change in testosterone function was accompanied by increased testosterone-modulated amygdala reactivity. These findings qualify the testosterone-dependent maturation of the prefrontal-amygdala circuit supporting emotion control during the transition from middle adolescence into young adulthood.

Depression recurrence is accompanied by longer periods in default mode and more frequent attentional and reward processing dynamic brain-states during resting-state activity.

Recurrence in major depressive disorder (MDD) is common, but neurobiological models capturing vulnerability for recurrences are scarce. Disturbances in multiple resting-state networks have been linked to MDD, but most approaches focus on stable (vs. dynamic) network characteristics. We investigated how the brain's dynamical repertoire changes after patients transition from remission to recurrence of a new depressive episode. Sixty two drug-free, MDD-patients with ≥2 episodes underwent a baseline resting-state fMRI scan when in remission. Over 30-months follow-up, 11 patients with a recurrence and 17 matched-remitted MDD-patients without a recurrence underwent a second fMRI scan. Recurrent patterns of functional connectivity were characterized by applying Leading Eigenvector Dynamics Analysis (LEiDA). Differences between baseline and follow-up were identified for the 11 non-remitted patients, while data from the 17 matched-remitted patients was used as a validation dataset. After the transition into a depressive state, basal ganglia-anterior cingulate cortex (ACC) and visuo-attentional networks were detected significantly more often, whereas default mode network activity was found to have a longer duration. Additionally, the fMRI signal in the basal ganglia-ACC areas underlying the reward network, were significantly less synchronized with the rest of the brain after recurrence (compared to a state of remission). No significant changes were observed in the matched-remitted patients who were scanned twice while in remission. These findings characterize changes that may be associated with the transition from remission to recurrence and provide initial evidence of altered dynamical exploration of the brain's repertoire of functional networks when a recurrent depressive episode occurs.

No evidence for association between late pregnancy maternal cortisol and gray matter volume in a healthy community sample of young adolescents.

A compelling amount of animal and human research has shown that perceived maternal stress during pregnancy can affect the neurodevelopment of the offspring. Prenatal maternal cortisol is frequently proposed as the biological key mechanism underlying this link; however, literature that investigates the effects of prenatal cortisol on subsequent neurodevelopment in humans is scarce. By using longitudinal data from a relatively large community sample of mother-child dyads (N = 73), this pre-registered study prospectively examined the role of maternal prenatal cortisol concentrations on subsequent individual differences in gray matter volume (GMV) and hippocampal subfield volumes at the onset of puberty of the offspring (12 years of age). Two markers of cortisol, that is, evening cortisol and circadian decline over the day, were used as indicators of maternal physiological stress during the last trimester of pregnancy. The results indicate that prenatal maternal cortisol levels were not associated with GMV or hippocampal subfield volumes of the children. These findings suggest that late pregnancy maternal cortisol may not be related to the structural development of the offspring's brain, at least not in healthy community samples and at the onset of puberty. When examining the influence of prenatal stress on offspring neurodevelopment, future investigations should delineate gestational timing effects of the cortisol exposure, cortisol assessment method, and impact of additional biomarkers, as these were not investigated in this study.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Digital phenotyping and the COVID-19 pandemic: Capturing behavioral change in patients with psychiatric disorders.

The COVID-19 pandemic has led to unprecedented societal changes limiting us in our mobility and our ability to connect with others in person. These unusual but widespread changes provide a unique opportunity for studies using digital phenotyping tools. Digital phenotyping tools, such as mobile passive monitoring platforms (MPM), provide a new perspective on human behavior and hold promise to improve human behavioral research. However, there is currently little evidence that these tools can reliably detect changes in behavior. Considering the Considering the COVID-19 pandemic as a high impact common environmental factor we studied potential impact on behavior of participants using our mobile passive monitoring platform BEHAPP that was ambulatory tracking them during the COVID-19 pandemic. We pooled data from three MPM studies involving Schizophrenia (SZ), Major Depressive Disorder (MDD) and Bipolar Disorder (BD) patients (N = 12). We compared the data collected on weekdays during three weeks prior and three weeks subsequent to the start of the quarantine. We hypothesized an increase in communication and a decrease in mobility. We observed a significant increase in the total time spent on communication applications (median 179 and 243 min per week respectively, p = 0.005), and a significant decrease in the number of unique places visited (median 6 and 3 visits per week respectively, p = 0.007), while the total time spent at home did not change significantly (median 64 and 77 h per week, respectively, p = 0.594). The data provides a proof of principle that digital phenotyping tools can identify changes in human behavior incited by a common external environmental factor.

Emotional Biases and Recurrence in Major Depressive Disorder. Results of 2.5 Years Follow-Up of Drug-Free Cohort Vulnerable for Recurrence.

An interesting factor explaining recurrence risk in Major Depressive Disorder (MDD) may be neuropsychological functioning, i.e., processing of emotional stimuli/information. Negatively biased processing of emotional stimuli/information has been found in both acute and (inconclusively) remitted states of MDD, and may be causally related to recurrence of depression. We aimed to investigate self-referent, memory and interpretation biases in recurrently depressed patients in remission and relate these biases to recurrence. We included 69 remitted recurrent MDD-patients (rrMDD-patients), 35-65 years, with ≥2 episodes, voluntarily free of antidepressant maintenance therapy for at least 4 weeks. We tested self-referent biases with an emotional categorization task, bias in emotional memory by free recall of the emotion categorization task 15 min after completing it, and interpretation bias with a facial expression recognition task. We compared these participants with 43 never-depressed controls matched for age, sex and intelligence. We followed the rrMDD-patients for 2.5 years and assessed recurrent depressive episodes by structured interview. The rrMDD-patients showed biases toward emotionally negative stimuli, faster responses to negative self-relevant characteristics in the emotional categorization, better recognition of sad faces, worse recognition of neutral faces with more misclassifications as angry or disgusting faces and less misclassifications as neutral faces (0.001 < p < 0.05). Of these, the number of misclassifications as angry and the overall performance in the emotional memory task were significantly associated with the time to recurrence (p ≤ 0.04), independent of residual symptoms and number of previous episodes. In a support vector machine data-driven model, prediction of recurrence-status could best be achieved (relative to observed recurrence-rate) with demographic and childhood adversity parameters (accuracy 78.1%; 1-sided p = 0.002); neuropsychological tests could not improve this prediction. Our data suggests a persisting (mood-incongruent) emotional bias when patients with recurrent depression are in remission. Moreover, these persisting biases might be mechanistically important for recurrence and prevention thereof.

The relation between infant freezing and the development of internalizing symptoms in adolescence: A prospective longitudinal study.

Given the long-lasting detrimental effects of internalizing symptoms, there is great need for detecting early risk markers. One promising marker is freezing behavior. Whereas initial freezing reactions are essential for coping with threat, prolonged freezing has been associated with internalizing psychopathology. However, it remains unknown whether early life alterations in freezing reactions predict changes in internalizing symptoms during adolescent development. In a longitudinal study (N = 116), we tested prospectively whether observed freezing in infancy predicted the development of internalizing symptoms from childhood through late adolescence (until age 17). Both longer and absent infant freezing behavior during a standard challenge (robot-confrontation task) were associated with internalizing symptoms in adolescence. Specifically, absent infant freezing predicted a relative increase in internalizing symptoms consistently across development from relatively low symptom levels in childhood to relatively high levels in late adolescence. Longer infant freezing also predicted a relative increase in internalizing symptoms, but only up until early adolescence. This latter effect was moderated by peer stress and was followed by a later decrease in internalizing symptoms. The findings suggest that early deviations in defensive freezing responses signal risk for internalizing symptoms and may constitute important markers in future stress vulnerability and resilience studies.

Investigation of the Stability of Human Freezing-Like Responses to Social Threat From Mid to Late Adolescence.

Freezing behavior, a commonly observed defensive stress response, shows relatively high stability over time in animals. Given the relevance of freezing for stress-coping and human psychopathology, it is relevant to know whether freezing behavior is also stable in humans, particularly during adolescence, when most affective symptoms develop. In a prospective longitudinal study, we investigated freezing-like behavior in response to social threat in 75 adolescents at age 14, repeated 3 years later at age 17. We used a well-established method combining electrocardiography (ECG; heart rate) and posturography (body sway) in response to emotional picture-viewing of angry, happy, and neutral faces. We hypothesized that individual differences in freezing-like behavior in response to social threat-operationalized by contrasting angry vs. neutral faces-would be relatively stable over time. Our results indeed showed relative stability between ages 14 and 17 in individual differences in freezing-like behavior in heart rate (r = 0.82), as well as in combined heart rate and body sway measures (r = 0.65). These effects were not specific for the angry vs. neutral contrast; they were also visible in other emotion contrasts. Exploratory analysis in males and females separately showed stability in body sway specifically for angry vs. neutral faces only in females. Together, these results suggest moderate to strong stability in human freezing-like behavior in response to social threat from mid to late adolescence (with exception for the body sway measure in males). This relative stability was not specific for threat-induction and may reflect a general stability that is particularly strong for heart rate. The fact that this relative stability was found over a relatively long time range of 3 years is promising for studies aiming to use freezing-like behavior as a marker for internalizing symptoms in adolescent development.

Early-life and pubertal stress differentially modulate grey matter development in human adolescents.

Animal and human studies have shown that both early-life traumatic events and ongoing stress episodes affect neurodevelopment, however, it remains unclear whether and how they modulate normative adolescent neuro-maturational trajectories. We characterized effects of early-life (age 0-5) and ongoing stressors (age 14-17) on longitudinal changes (age 14 to17) in grey matter volume (GMV) of healthy adolescents (n = 37). Timing and stressor type were related to differential GMV changes. More personal early-life stressful events were associated with larger developmental reductions in GMV over anterior prefrontal cortex, amygdala and other subcortical regions; whereas ongoing stress from the adolescents' social environment was related to smaller reductions over the orbitofrontal and anterior cingulate cortex. These findings suggest that early-life stress accelerates pubertal development, whereas an adverse adolescent social environment disturbs brain maturation with potential mental health implications: delayed anterior cingulate maturation was associated with more antisocial traits - a juvenile precursor of psychopathy.

Defensive freezing links Hypothalamic-Pituitary-Adrenal-axis activity and internalizing symptoms in humans.

The Hypothalamic-Pituitary-Adrenal (HPA)-axis plays an important role in the expression of defensive freezing. Adaptive freezing reactivity, characterized by an immediate increase in acute stress and timely termination upon threat offset or need to act, is essential for adequate stress coping. Blunted HPA-axis activity in animals is associated with blunted freezing reactivity and internalizing symptoms. Despite their potential relevance, it remains unknown whether these mechanisms apply to humans and human psychopathology. Using a well-established method combining electrocardiography and posturography, we assessed freezing before, immediately after, and one hour after a stress induction in 92 human adolescents. In line with animal models, human adolescents showed stress-induced freezing, as quantified by relative reductions in heart rate and body sway after, as compared to before, stress. Moreover, relatively lower basal cortisol was associated with reduced stress-induced freezing reactivity (i.e., less immediate freezing and less recovery). Path analyses showed that decreased freezing recovery in individuals with reduced cortisol levels was associated with increased levels of internalizing symptoms. These findings suggest that reduced freezing recovery may be a promising marker for the etiology of internalizing symptoms.

The brain-derived neurotrophic factor Val66Met polymorphism affects encoding of object locations during active navigation.

The brain-derived neurotrophic factor (BDNF) was shown to be involved in spatial memory and spatial strategy preference. A naturally occurring single nucleotide polymorphism of the BDNF gene (Val66Met) affects activity-dependent secretion of BDNF. The current event-related fMRI study on preselected groups of 'Met' carriers and homozygotes of the 'Val' allele investigated the role of this polymorphism on encoding and retrieval in a virtual navigation task in 37 healthy volunteers. In each trial, participants navigated toward a target object. During encoding, three positional cues (columns) with directional cues (shadows) were available. During retrieval, the invisible target had to be replaced while either two objects without shadows (objects trial) or one object with a shadow (shadow trial) were available. The experiment consisted of blocks, informing participants of which trial type would be most likely to occur during retrieval. We observed no differences between genetic groups in task performance or time to complete the navigation tasks. The imaging results show that Met carriers compared to Val homozygotes activate the left hippocampus more during successful object location memory encoding. The observed effects were independent of non-significant performance differences or volumetric differences in the hippocampus. These results indicate that variations of the BDNF gene affect memory encoding during spatial navigation, suggesting that lower levels of BDNF in the hippocampus results in less efficient spatial memory processing.

Testosterone during Puberty Shifts Emotional Control from Pulvinar to Anterior Prefrontal Cortex.

UNLABELLED: Increased limbic and striatal activation in adolescence has been attributed to a relative delay in the maturation of prefrontal areas, resulting in the increase of impulsive reward-seeking behaviors that are often observed during puberty. However, it remains unclear whether and how this general developmental pattern applies to the control of social emotional actions, a fundamental adult skill refined during adolescence. This domain of control pertains to decisions involving emotional responses. When faced with a social emotional challenge (e.g., an angry face), we can follow automatic response tendencies and avoid the challenge or exert control over those tendencies by selecting an alternative action. Using an fMRI-adapted social approach-avoidance task, this study identifies how the neural regulation of emotional action control changes as a function of human pubertal development in 14-year-old adolescents (n = 47). Pubertal maturation, indexed by testosterone levels, shifted neural regulation of emotional actions from the pulvinar nucleus of the thalamus and the amygdala to the anterior prefrontal cortex (aPFC). Adolescents with more advanced pubertal maturation showed greater aPFC activity when controlling their emotional action tendencies, reproducing the same pattern consistently observed in adults. In contrast, adolescents of the same age, but with less advanced pubertal maturation, showed greater pulvinar and amygdala activity when exerting similarly effective emotional control. These findings qualify how, in the domain of social emotional actions, executive control shifts from subcortical to prefrontal structures during pubertal development. The pulvinar and the amygdala are suggested as the ontogenetic precursors of the mature control system centered on the anterior prefrontal cortex. SIGNIFICANCE STATEMENT: Adolescents can show distinct behavioral problems when emotionally aroused. This could be related to later development of frontal regions compared with deeper brain structures. This study found that when the control of emotional actions needs to be exerted, more mature adolescents, similar to adults, recruit the anterior prefrontal cortex (aPFC). Less mature adolescents recruit specific subcortical regions, namely the pulvinar and amygdala. These findings identify the subcortical pulvino-amygdalar pathway as a relevant precursor of a mature aPFC emotional control system, opening the way for a neurobiological understanding of how emotion control-related disorders emerge during puberty.

Encoding and retrieval of landmark-related spatial cues during navigation: an fMRI study.

To successfully navigate, humans can use different cues from their surroundings. Learning locations in an environment can be supported by parallel subsystems in the hippocampus and the striatum. We used fMRI to look at differences in the use of object-related spatial cues while 47 participants actively navigated in an open-field virtual environment. In each trial, participants navigated toward a target object. During encoding, three positional cues (columns) with directional cues (shadows) were available. During retrieval, the removed target had to be replaced while either two objects without shadows (objects trial) or one object with a shadow (shadow trial) were available. Participants were informed in blocks about which type of retrieval trial was most likely to occur, thereby modulating expectations of having to rely on a single landmark or on a configuration of landmarks. How the spatial learning systems in the hippocampus and caudate nucleus were involved in these landmark-based encoding and retrieval processes were investigated. Landmark configurations can create a geometry similar to boundaries in an environment. It was found that the hippocampus was involved in encoding when relying on configurations of landmarks, whereas the caudate nucleus was involved in encoding when relying on single landmarks. This might suggest that the observed hippocampal activation for configurations of objects is linked to a spatial representation observed with environmental boundaries. Retrieval based on configurations of landmarks activated regions associated with the spatial updation of object locations for reorientation. When only a single landmark was available during retrieval, regions associated with updating the location of oneself were activated. There was also evidence that good between-participant performance was predicted by right hippocampal activation. This study therefore sheds light on how the brain deals with changing demands on spatial processing related purely to landmarks.

Gray and white matter correlates of navigational ability in humans.

Humans differ widely in their navigational abilities. Studies have shown that self-reports on navigational abilities are good predictors of performance on navigation tasks in real and virtual environments. The caudate nucleus and medial temporal lobe regions have been suggested to subserve different navigational strategies. The ability to use different strategies might underlie navigational ability differences. This study examines the anatomical correlates of self-reported navigational ability in both gray and white matter. Local gray matter volume was compared between a group (N = 134) of good and bad navigators using voxel-based morphometry (VBM), as well as regional volumes. To compare between good and bad navigators, we also measured white matter anatomy using diffusion tensor imaging (DTI) and looked at fractional anisotropy (FA) values. We observed a trend toward higher local GM volume in right anterior parahippocampal/rhinal cortex for good versus bad navigators. Good male navigators showed significantly higher local GM volume in right hippocampus than bad male navigators. Conversely, bad navigators showed increased FA values in the internal capsule, the white matter bundle closest to the caudate nucleus and a trend toward higher local GM volume in the caudate nucleus. Furthermore, caudate nucleus regional volume correlated negatively with navigational ability. These convergent findings across imaging modalities are in line with findings showing that the caudate nucleus and the medial temporal lobes are involved in different wayfinding strategies. Our study is the first to show a link between self-reported large-scale navigational abilities and different measures of brain anatomy.