The association between early regulatory problems and adult peer relationship quality is mediated by the brain's allostatic-interoceptive system.

BACKGROUND: Early regulatory problems (RPs), i.e., problems with crying, sleeping, and/or feeding during the first years, increase the risk for avoidant personality traits in adulthood, associated with social withdrawal and anxiety. Even more, RPs are linked with functional alterations in the adult default mode and salience networks, comprising the brain's allostatic-interoceptive system (AIS) and playing a role in social interactions. We investigated whether RPs assessed in infancy are associated with difficulties in adult peer relationships mediated by functional alterations of the AIS. METHODS: As part of a large case-controlled prospective study, 42 adults with previous RPs and 70 matched controls (mean age = 28.48, SD = 2.65, 51% male) underwent fMRI during rest. The analysis focused on the intrinsic functional connectivity (iFC) of key nodes of the AIS. Peer relationship quality was assessed via a semi-structured Life Course Interview and the YASR scale. In these same individuals, RPs were assessed at ages 5, 20 and 56 months. RESULTS: RPs in infancy were associated with lower-quality peer relationships and enhanced functional connectivity of the AIS nodes in adulthood, with a stronger effect for multiple and persistent RPs compared with transient-multiple or single-persistent RPs. Importantly, iFC changes of the dorsal mid insula, a primary interoceptive cortex with frontal and temporal regions, mediated the relationship between early RPs and adult peer relationship quality. CONCLUSIONS: Results indicate long-lasting social and neural changes associated with early RPs. Our findings further implicate the AIS in both interoceptive and social processes, while indicating the need for early screening of early RPs.

Social reappraisal of emotions is linked with the social presence effect in the default mode network.

Introduction: Social reappraisal, during which one person deliberately tries to regulate another's emotions, is a powerful cognitive form of social emotion regulation, crucial for both daily life and psychotherapy. The neural underpinnings of social reappraisal include activity in the default mode network (DMN), but it is unclear how social processes influence the DMN and thereby social reappraisal functioning. We tested whether the mere presence of a supportive social regulator had an effect on the DMN during rest, and whether this effect in the DMN was linked with social reappraisal-related neural activations and effectiveness during negative emotions. Methods: A two-part fMRI experiment was performed, with a psychotherapist as the social regulator, involving two resting state (social, non-social) and two task-related (social reappraisal, social no-reappraisal) conditions. Results: The psychotherapist's presence enhanced intrinsic functional connectivity of the dorsal anterior cingulate (dACC) within the anterior medial DMN, with the effect positively related to participants' trust in psychotherapists. Secondly, the social presence-induced change in the dACC was related with (a) the social reappraisal-related activation in the bilateral dorsomedial/dorsolateral prefrontal cortex and the right temporoparietal junction and (b) social reappraisal success, with the latter relationship moderated by trust in psychotherapists. Conclusion: Results demonstrate that a psychotherapist's supportive presence can change anterior medial DMN's intrinsic connectivity even in the absence of stimuli and that this DMN change during rest is linked with social reappraisal functioning during negative emotions. Data suggest that trust-dependent social presence effects on DMN states are relevant for social reappraisal-an idea important for daily-life and psychotherapy-related emotion regulation.

Common and specific large-scale brain changes in major depressive disorder, anxiety disorders, and chronic pain: a transdiagnostic multimodal meta-analysis of structural and functional MRI studies.

Major depressive disorder (MDD), anxiety disorders (ANX), and chronic pain (CP) are closely-related disorders with both high degrees of comorbidity among them and shared risk factors. Considering this multi-level overlap, but also the distinct phenotypes of the disorders, we hypothesized both common and disorder-specific changes of large-scale brain systems, which mediate neural mechanisms and impaired behavioral traits, in MDD, ANX, and CP. To identify such common and disorder-specific brain changes, we conducted a transdiagnostic, multimodal meta-analysis of structural and functional MRI-studies investigating changes of gray matter volume (GMV) and intrinsic functional connectivity (iFC) of large-scale intrinsic brain networks across MDD, ANX, and CP. The study was preregistered at PROSPERO (CRD42019119709). 320 studies comprising 10,931 patients and 11,135 healthy controls were included. Across disorders, common changes focused on GMV-decrease in insular and medial-prefrontal cortices, located mainly within the so-called default-mode and salience networks. Disorder-specific changes comprised hyperconnectivity between default-mode and frontoparietal networks and hypoconnectivity between limbic and salience networks in MDD; limbic network hyperconnectivity and GMV-decrease in insular and medial-temporal cortices in ANX; and hypoconnectivity between salience and default-mode networks and GMV-increase in medial temporal lobes in CP. Common changes suggested a neural correlate for comorbidity and possibly shared neuro-behavioral chronification mechanisms. Disorder-specific changes might underlie distinct phenotypes and possibly additional disorder-specific mechanisms.

Human threat circuits: Threats of pain, aggressive conspecific, and predator elicit distinct BOLD activations in the amygdala and hypothalamus.

Introduction: Threat processing, enabled by threat circuits, is supported by a remarkably conserved neural architecture across mammals. Threatening stimuli relevant for most species include the threat of being attacked by a predator or an aggressive conspecific and the threat of pain. Extensive studies in rodents have associated the threats of pain, predator attack and aggressive conspecific attack with distinct neural circuits in subregions of the amygdala, the hypothalamus and the periaqueductal gray. Bearing in mind the considerable conservation of both the anatomy of these regions and defensive behaviors across mammalian species, we hypothesized that distinct brain activity corresponding to the threats of pain, predator attack and aggressive conspecific attack would also exist in human subcortical brain regions. Methods: Forty healthy female subjects underwent fMRI scanning during aversive classical conditioning. In close analogy to rodent studies, threat stimuli consisted of painful electric shocks, a short video clip of an attacking bear and a short video clip of an attacking man. Threat processing was conceptualized as the expectation of the aversive stimulus during the presentation of the conditioned stimulus. Results: Our results demonstrate differential brain activations in the left and right amygdala as well as in the left hypothalamus for the threats of pain, predator attack and aggressive conspecific attack, for the first time showing distinct threat-related brain activity within the human subcortical brain. Specifically, the threat of pain showed an increase of activity in the left and right amygdala and the left hypothalamus compared to the threat of conspecific attack (pain > conspecific), and increased activity in the left amygdala compared to the threat of predator attack (pain > predator). Threat of conspecific attack revealed heightened activity in the right amygdala, both in comparison to threat of pain (conspecific > pain) and threat of predator attack (conspecific > predator). Finally, for the condition threat of predator attack we found increased activity in the bilateral amygdala and the hypothalamus when compared to threat of conspecific attack (predator > conspecific). No significant clusters were found for the contrast predator attack > pain. Conclusion: Results suggest that threat type-specific circuits identified in rodents might be conserved in the human brain.

Your presence soothes me: a neural process model of aversive emotion regulation via social buffering.

The reduction of aversive emotions by a conspecific's presence-called social buffering-is a universal phenomenon in the mammalian world and a powerful form of human social emotion regulation. Animal and human studies on neural pathways underlying social buffering typically examined physiological reactions or regional brain activations. However, direct links between emotional and social stimuli, distinct neural processes and behavioural outcomes are still missing. Using data of 27 female participants, the current study delineated a large-scale process model of social buffering's neural underpinnings, connecting changes in neural activity to emotional behaviour by means of voxel-wise multilevel mediation analysis. Our results confirmed that three processes underlie human social buffering: (i) social support-related reduction of activity in the orbitofrontal cortex, ventromedial and dorsolateral prefrontal cortices, anterior and mid-cingulate; (ii) downregulation of aversive emotion-induced brain activity in the superficial cortex-like amygdala and mediodorsal thalamus; and (iii) downregulation of reported aversive feelings. Results of the current study provide evidence for a distinct neural process model of aversive emotion regulation in humans by social buffering.

Cognitive reward control recruits medial and lateral frontal cortices, which are also involved in cognitive emotion regulation: A coordinate-based meta-analysis of fMRI studies.

Cognitive reward control (CRC) refers to the cognitive control of one's craving for hedonic stimuli, like food, sex, or drugs. Numerous functional magnetic resonance imaging (fMRI) studies have investigated neural sources of CRC. However, a consistent pattern of brain activation across stimulus types has not been identified so far. We addressed this question using coordinate-based meta-analysis of task-fMRI studies during CRC. To further characterize such a potential common CRC activation pattern, we extended our approach to three additional questions: (i) Do CRC meta-analytic results overlap with those during the control of emotional states, such as in cognitive regulation of aversive emotions (cognitive emotion regulation, CER)? (ii) How does the control of motivational/emotional states link to the control of action states with less motivational/emotional valence such as in response inhibition paradigms, i.e., do meta-anyltic result maps overlap? (iii) Does the control of motivational/emotional states constitute a consistent pattern of organized (i.e., coherent) ongoing or intrinsic brain activity? This question was tested by a seed-based intrinsic functional connectivity (iFC) analysis in an independent data set of resting-state fMRI. We found consistent CRC activation mainly in supplementary motor, dorsolateral prefrontal, and ventrolateral prefrontal cortices across studies. This activation pattern overlapped largely with CER-related activation, except for left-sided lateral temporal and parietal cortex activation, which was more pronounced during CER. It overlapped partly with activation during response inhibition in (pre-)supplementary motor, insular, and parietal cortices, but differed from it in dorsolateral and ventrolateral prefrontal cortices. Furthermore, it remarkably defined an iFC network covering activation patterns of both CRC and CER. Results demonstrate a consistent activation pattern of CRC across stimulus types, which overlaps largely with those of CER but only partly with those of response inhibition and constitutes an intrinsic co-activity network. These data suggest a common mechanism for the cognitive control of both motivational and emotional stimuli.

The Default Mode Network Mediates the Impact of Infant Regulatory Problems on Adult Avoidant Personality Traits.

BACKGROUND: Infant regulatory problems (RPs), i.e., problems with crying, feeding, and/or sleeping, are associated with behavioral and emotional problems in childhood. It is unclear, however, whether these behavioral and emotional problems persist into adulthood. The default mode network (DMN) and salience network (SN) support both interoceptive regulation and social and emotional abilities. We thus hypothesized that adults who had experienced RPs in infancy have more behavioral and emotional problems, which are mediated by DMN and/or SN alterations. METHODS: Within the scope of the Bavarian Longitudinal Study, adults (mean age 28 years; 50% female subjects) with (n = 79) and without (n = 254) a history of multiple and/or persistent infant RPs were assessed by the Young Adult Self Report to measure behavioral and emotional problems, and-in a subsample (n = 49 with and n = 71 without a history of infant RPs)-by resting-state functional magnetic resonance imaging to measure DMN/SN integrity via intrinsic functional connectivity (iFC). RESULTS: Compared with adults with no history of infant RPs, adults who had experienced infant RPs had more total problems (p = .002), more internalizing problems (p = .005), and more avoidant personality traits (p < .001). They showed decreased iFC of the DMN and SN. DMN iFC decreases were strongest in adults with multiple and persistent RPs, and they were linked with avoidant personality traits (r = -.42, p = .006). Remarkably, DMN iFC decrements fully mediated the association between infant RPs and adult avoidant personality traits. CONCLUSIONS: Adults who had experienced infant RPs have more avoidant personality traits that are mediated by the DMN. Persistent and/or multiple infant RPs and the DMN may be targets to attenuate behavioral and emotional problems.

Increased Global Interaction Across Functional Brain Modules During Cognitive Emotion Regulation.

Cognitive emotion regulation (CER) enables humans to flexibly modulate their emotions. While local theories of CER neurobiology suggest interactions between specialized local brain circuits underlying CER, e.g., in subparts of amygdala and medial prefrontal cortices (mPFC), global theories hypothesize global interaction increases among larger functional brain modules comprising local circuits. We tested the global CER hypothesis using graph-based whole-brain network analysis of functional MRI data during aversive emotional processing with and without CER. During CER, global between-module interaction across stable functional network modules increased. Global interaction increase was particularly driven by subregions of amygdala and cuneus-nodes of highest nodal participation-that overlapped with CER-specific local activations, and by mPFC and posterior cingulate as relevant connector hubs. Results provide evidence for the global nature of human CER, complementing functional specialization of embedded local brain circuits during successful CER.

Cognitive emotion regulation modulates the balance of competing influences on ventral striatal aversive prediction error signals.

Cognitive emotion regulation (CER) is a critical human ability to face aversive emotional stimuli in a flexible way, via recruitment of specific prefrontal brain circuits. Animal research reveals a central role of ventral striatum in emotional behavior, for both aversive conditioning, with striatum signaling aversive prediction errors (aPE), and for integrating competing influences of distinct striatal inputs from regions such as the prefrontal cortex (PFC), amygdala, hippocampus and ventral tegmental area (VTA). Translating these ventral striatal findings from animal research to human CER, we hypothesized that successful CER would affect the balance of competing influences of striatal afferents on striatal aPE signals, in a way favoring PFC as opposed to 'subcortical' (i.e., non-isocortical) striatal inputs. Using aversive Pavlovian conditioning with and without CER during fMRI, we found that during CER, superior regulators indeed reduced the modulatory impact of 'subcortical' striatal afferents (hippocampus, amygdala and VTA) on ventral striatal aPE signals, while keeping the PFC impact intact. In contrast, inferior regulators showed an opposite pattern. Our results demonstrate that ventral striatal aPE signals and associated competing modulatory inputs are critical mechanisms underlying successful cognitive regulation of aversive emotions in humans.

How do you make me feel better? Social cognitive emotion regulation and the default mode network.

Socially-induced cognitive emotion regulation (Social-Reg) is crucial for emotional well-being and social functioning; however, its brain mechanisms remain poorly understood. Given that both social cognition and cognitive emotion regulation engage key regions of the default-mode network (DMN), we hypothesized that Social-Reg would rely on the DMN, and that its effectiveness would be associated with social functioning. During functional MRI, negative emotions were elicited by pictures, and - via short instructions - a psychotherapist either down-regulated participants' emotions by employing reappraisal (Reg), or asked them to simply look at the pictures (Look). Adult Attachment Scale was used to measure social functioning. Contrasting Reg versus Look, aversive emotions were successfully reduced during Social-Reg, with increased activations in the prefrontal and parietal cortices, precuneus and the left temporo-parietal junction. These activations covered key nodes of the DMN and were associated with Social-Reg success. Furthermore, participants' attachment security was positively correlated with both Social-Reg success and orbitofrontal cortex involvement during Social-Reg. In addition, specificity of the neural correlates of Social-Reg was confirmed by comparisons with participants' DMN activity at rest and their brain activations during a typical emotional self-regulation task based on the same experimental paradigm without a psychotherapist. Our results provide first evidence for the specific involvement of the DMN in Social-Reg, and the association of Social-Reg with individual differences in attachment security. The findings suggest that DMN dysfunction, found in many neuropsychiatric disorders, may impair the ability to benefit from Social-Reg.

Mindful attention to breath regulates emotions via increased amygdala-prefrontal cortex connectivity.

Mindfulness practice is beneficial for emotion regulation; however, the neural mechanisms underlying this effect are poorly understood. The current study focuses on effects of attention-to-breath (ATB) as a basic mindfulness practice on aversive emotions at behavioral and brain levels. A key finding across different emotion regulation strategies is the modulation of amygdala and prefrontal activity. It is unclear how ATB relevant brain areas in the prefrontal cortex integrate with amygdala activation during emotional stimulation. We proposed that, during emotional stimulation, ATB down-regulates activation in the amygdala and increases its integration with prefrontal regions. To address this hypothesis, 26 healthy controls were trained in mindfulness-based attention-to-breath meditation for two weeks and then stimulated with aversive pictures during both attention-to-breath and passive viewing while undergoing fMRI. Data were controlled for breathing frequency. Results indicate that (1) ATB was effective in regulating aversive emotions. (2) Left dorso-medial prefrontal cortex was associated with ATB in general. (3) A fronto-parietal network was additionally recruited during emotional stimulation. (4) ATB down regulated amygdala activation and increased amygdala-prefrontal integration, with such increased integration being associated with mindfulness ability. Results suggest amygdala-dorsal prefrontal cortex integration as a potential neural pathway of emotion regulation by mindfulness practice.

Cognitive emotion regulation enhances aversive prediction error activity while reducing emotional responses.

Cognitive emotion regulation is a powerful way of modulating emotional responses. However, despite the vital role of emotions in learning, it is unknown whether the effect of cognitive emotion regulation also extends to the modulation of learning. Computational models indicate prediction error activity, typically observed in the striatum and ventral tegmental area, as a critical neural mechanism involved in associative learning. We used model-based fMRI during aversive conditioning with and without cognitive emotion regulation to test the hypothesis that emotion regulation would affect prediction error-related neural activity in the striatum and ventral tegmental area, reflecting an emotion regulation-related modulation of learning. Our results show that cognitive emotion regulation reduced emotion-related brain activity, but increased prediction error-related activity in a network involving ventral tegmental area, hippocampus, insula and ventral striatum. While the reduction of response activity was related to behavioral measures of emotion regulation success, the enhancement of prediction error-related neural activity was related to learning performance. Furthermore, functional connectivity between the ventral tegmental area and ventrolateral prefrontal cortex, an area involved in regulation, was specifically increased during emotion regulation and likewise related to learning performance. Our data, therefore, provide first-time evidence that beyond reducing emotional responses, cognitive emotion regulation affects learning by enhancing prediction error-related activity, potentially via tegmental dopaminergic pathways.

The lower hippocampus global connectivity, the higher its local metabolism in Alzheimer disease.

OBJECTIVES: Based on the hippocampus disconnection hypothesis in Alzheimer disease (AD), which postulates that uncoupling from cortical inputs contributes to disinhibition-like changes in hippocampus activity, we suggested that in patients with AD, the more the intrinsic functional connectivity between hippocampus and precuneus is decreased, the higher hippocampal glucose metabolism will be. METHODS: Forty patients with mild AD dementia, 21 patients with mild cognitive impairment, and 26 healthy controls underwent simultaneous PET/MRI measurements on an integrated PET/MR scanner. (18)F-fluorodeoxyglucose-PET was used to measure local glucose metabolism as proxy for neural activity, and resting-state functional MRI with seed-based functional connectivity analysis was performed to measure intrinsic functional connectivity as proxy for neural coupling. Group comparisons and correlation analysis were corrected for effects of regional atrophy, partial volume effect, age, and sex. RESULTS: In both patient groups, intrinsic connectivity between hippocampus and precuneus was significantly reduced. Moreover, in both patient groups, glucose metabolism was reduced in the precuneus (AD < mild cognitive impairment < controls) while unchanged in the hippocampus. Critically, the lower connectivity between hippocampus and precuneus was in patients with AD dementia, the higher was hippocampus metabolism. CONCLUSION: Results provide evidence that in patients with AD dementia, stronger decrease of intrinsic connectivity between hippocampus and precuneus is linked with higher intrahippocampal metabolism (probably reflecting higher neuronal activity). These data support the hippocampus disconnection hypothesis, i.e., uncoupling from cortical inputs may contribute to disinhibition-like changes of hippocampal activity with potentially adverse consequences on both intrahippocampal physiology and clinical outcome.