Medial Prefrontal Activity Research Articles

A Pilot Study of Neurobiological Mechanisms of Stress and Cardiovascular Risk.

Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk. Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress. Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

Abstract 14748: Genetic and Neurobiological Factors Link Chronic Stress to Earlier Onset Hypertension

Introduction: Chronic stress conditions associate with a greater incidence of hypertension (HTN). Hypothesis: We tested whether genetic risk for or neurobiological features of vulnerability to chronic stress associate with the risk for and timing of HTN. Methods: Data were obtained from Mass General Brigham Biobank participants. HTN was defined as > 2 International Classification of Disease codes at least one week apart. Those with secondary HTN and those diagnosed at age <18 years were excluded. Of this parent dataset, a validated polygenic risk score for neuroticism reflecting stress sensitivity (ssPRS) was assessed in 11,320 participants. Of the same parent dataset, stress-related neural network activity (SNNA), defined as a ratio of amygdalar to regulatory medial prefrontal cortical activity, was measured in 867 individuals who had undergone clinical 18 F-flurodeoxyglucose positron emission tomography imaging. Results: In the genetic subgroup, the median age [interquartile range] of participants was 60 [34-86] years and 56.3% were female. In a Cox regression model, standardized ssPRS predicted incident HTN (hazard ratio [95% confidence interval (CI)]: 1.05 [1.02, 1.08], p<0.001), when adjusted for principal components, age, and sex (Figure 1A). Similarly, standardized SNNA predicted incident HTN (1.44 [1.11, 1.85], p = 0.006) when adjusted for age and sex. The age of onset of HTN was significantly lower in those with high vs. low ssPRS (difference (years) [95% CI]: -1.65 (-2.45, -0.85], p < 0.001) and in those with high vs. low SNNA (-4.67 [-7.68, -1.66], p = 0.002, Figure 1B) in unadjusted models with findings of a similar magnitude and significance in multivariable models. Conclusions: This study identifies genetic and neurobiological factors linking chronic stress to HTN risk and its age of onset. Future studies should evaluate whether therapies targeting this neurobiological pathway may reduce HTN risk.

Medial prefrontal activity during self-other judgments is modulated by relationship need fulfillment

ABSTRACT The medial prefrontal cortex (MPFC) plays an important role in representing semantic self-knowledge. Studies comparing semantic self-judgments with judgments of close others suggest that interpersonal closeness may influence the degree to which the MPFC differentiates self and other. We used optical neuroimaging to examine if support for competence, relatedness, and autonomy from relationship partners moderates MPFC activity during a personality judgment task. Participants (N = 109) were asked to judge the descriptive accuracy of trait adjectives for both themselves and a friend. Participants who reported lower need fulfillment with their friend showed elevated activity only in the self-judgment condition; in contrast, participants who reported higher need fulfillment with their friend showed similarly high levels of MPFC activity across the conditions. These results are consistent with the idea that the MPFC differentially represents others on the basis of the need fulfillment experienced within the relationship.

Offset analgesia is associated with opposing modulation of medial versus dorsolateral prefrontal cortex activations: A functional near-infrared spectroscopy study.

Offset analgesia is defined by a dramatic drop in perceived pain intensity with a relatively small decrease in noxious input. Although functional magnetic resonance imaging studies implicate subcortical descending inhibitory circuits during offset analgesia, the role of cortical areas remains unclear. The current study identifies cortical correlates of offset analgesia using functional near infrared spectroscopy (fNIRS). Twenty-four healthy volunteers underwent fNIRS scanning during offset (OS) and control (Con) heat stimuli applied to the forearm. After controlling for non-neural hemodynamic responses in superficial tissues, widespread increases in cortical oxygenated hemoglobin concentration were observed, reflecting cortical activation during heat pain. OS–Con contrasts revealed deactivations in bilateral medial prefrontal cortex (mPFC) and bilateral somatosensory cortex (SSC) associated with offset analgesia. Right dorsolateral prefrontal cortex (dlPFC) showed activation only during OS. These data demonstrate opposing cortical activation patterns during offset analgesia and support a model in which right dlPFC underlies ongoing evaluation of pain intensity change. With predictions of decreasing pain intensity, right dlPFC activation likely inhibits ascending noxious input via subcortical pathways resulting in SSC and mPFC deactivation. This study identifies cortical circuitry underlying offset analgesia and introduces the use of fNIRS to study pain modulation in an outpatient clinical environment.

Medial prefrontal and occipito-temporal activity at encoding determines enhanced recognition of threatening faces after 1.5years.

Studies demonstrated that faces with threatening emotional expressions are better remembered than non-threatening faces. However, whether this memory advantage persists over years and which neural systems underlie such an effect remains unknown. Here, we employed an individual difference approach to examine whether the neural activity during incidental encoding was associated with differential recognition of faces with emotional expressions (angry, fearful, happy, sad and neutral) after a retention interval of > 1.5years (N = 89). Behaviorally, we found a better recognition for threatening (angry, fearful) versus non-threatening (happy and neutral) faces after a delay of > 1.5years, which was driven by forgetting of non-threatening faces compared with immediate recognition after encoding. Multivariate principal component analysis (PCA) on the behavioral responses further confirmed the discriminative recognition performance between threatening and non-threatening faces. A voxel-wise whole-brain analysis on the concomitantly acquired functional magnetic resonanceimaging (fMRI) data during incidental encoding revealed that neural activity in bilateral inferior occipital gyrus (IOG) and ventromedial prefrontal/orbitofrontal cortex (vmPFC/OFC) was associated with the individual differences in the discriminative emotional face recognition performance measured by an innovative behavioral pattern similarity analysis (BPSA). The left fusiform face area (FFA) was additionally determined using a regionally focused analysis. Overall, the present study provides evidence that threatening facial expressions lead to persistent face recognition over periods of > 1.5years, and thatdifferential encoding-related activity in the medial prefrontal cortex and occipito-temporal cortex may underlie this effect.

Opposing Roles of the Dorsolateral and Dorsomedial Striatum in the Acquisition of Skilled Action Sequencing in Rats.

The shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift cooperatively or competitively remains unclear. Cortical inputs have also been implicated in the shift toward automaticity, but it is unknown whether they mirror their downstream striatal targets across this transition. We addressed these questions using a five step heterogeneous action sequencing task in male rats that is optimally performed by automated chains of actions. By optimizing automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly, the mPFC was not involved; however, the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to a model of competitive opposition, where the dorsomedial striatum interferes with the development of dorsolateral-striatum dependent behavior.SIGNIFICANCE STATEMENT We provide the most direct evidence to date that the dorsomedial and dorsolateral striatum compete for control in the acquisition of habitual action sequences. The dorsolateral striatum was critical for sequencing behavior, but loss of dorsomedial striatum function enhanced acquisition. In addition, we found that the mPFC was not required for the formation of automated actions. Using a task that optimizes habitual responding, we demonstrate that the arbitration of dorsomedial and dorsolateral control is not modulated by medial prefrontal cortical activity. However, we find evidence for the role of the lateral orbitofrontal cortex in action sequencing. These results have implications for our understanding of how habits and skills form.

Abstract 13203: Exercise Decreases Stress-Associated Neural Activity Predominantly by Upregulating Regulatory Medial Prefrontal Cortical Activity

Introduction: Exercise associates with dose-dependent decreases in stress-associated neural activity (SNA) which, in part, mediate exercise’s beneficial impact on major adverse cardiovascular event (MACE) risk. SNA can be assessed as a ratio of the resting metabolic activity of the brain’s fear centers (i.e., the amygdala [Amyg]), to that of regulatory centers (i.e., the medial prefrontal cortex [PFC]). However, it is unknown whether exercise reduces SNA by impacting the activity of Amyg, mPFC, or both. Hypothesis: We tested whether exercise reduces SNA primarily through enhancing the activity of the mPFC. We further hypothesize that it is the regulatory effect of the mPFC on SNA that contributes to MACE risk reduction. Methods: Self-reported physical activity data were obtained from Partners Biobank participants and total metabolic equivalents-minutes per week (MET-min/wk) were calculated. In a subset with clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, Amyg and mPFC activity were measured and corrected by whole cerebrum activity. SNA was calculated (Amyg/mPFC activity). MACE and cardiovascular risk factors were obtained using International Classification of Diseases codes. Results: Out of 684 subjects with both physical activity and imaging data (median age 68 years [IQR 60,75]), 275 (40.2%) developed MACE. Physical activity (as tertiles) associated with a dose-dependent increase in mPFC activity (Figure 1A; standardized β [95% CI]: 0.087 [0.002,0.036], p=0.025). Moreover, while SNA predicted MACE in adjusted analysis, the activities of the Amyg or PFC alone did not (Figure 1B). Conclusions: Exercise associates with dose dependent increases in mPFC activity. This effect does not directly reduce MACE risk; however, it may reduce MACE risk via its regulatory action on SNA. These observations may also have relevance in the impact of exercise on depression/anxiety disorders and cognitive function.

Facing successfully high mental workload and stressors: An fMRI study.

The present fMRI study aimed at highlighting patterns of brain activations and autonomic activity when confronted with high mental workload and the threat of auditory stressors. Twenty participants performed a complex cognitive task in either safe or aversive conditions. Our results showed that increased mental workload induced recruitment of the lateral frontoparietal executive control network (ECN), along with disengagement of medial prefrontal and posterior cingulate regions of the default mode network (DMN). Mental workload also elicited an increase in heart rate and pupil diameter. Task performance did not decrease under the threat of stressors, most likely due to efficient inhibition of auditory regions, as reflected by a large decrement of activity in the superior temporal gyri. The threat of stressors was also accompanied with deactivations of limbic regions of the salience network (SN), possibly reflecting emotional regulation mechanisms through control from dorsal medial prefrontal and parietal regions, as indicated by functional connectivity analyses. Meanwhile, the threat of stressors induced enhanced ECN activity, likely for improved attentional and cognitive processes toward the task, as suggested by increased lateral prefrontal and parietal activations. These fMRI results suggest that measuring the balance between ECN, SN, and DMN recruitment could be used for objective mental state assessment. In this sense, an extra recruitment of task‐related regions and a high ratio of lateral versus medial prefrontal activity may represent a relevant marker of increased but efficient mental effort, while the opposite may indicate a disengagement from the task due to mental overload and/or stressors.

Multivariate Encoding Analysis of Medial Prefrontal Cortex Cortical Activity during Task Learning.

Studies have shown that medial prefrontal cortex (mPFC) is responsible for outcome evaluation. Some recent studies also suggest that mPFC may play an important role in goal planning and action execution when performing a task. If the information encoded in mPFC can be accurately extracted and identified, it can improve the design of brain-machine interfaces by better reconstructing subjects' motion intention guided by reward information. In this paper, we investigate whether mPFC neural signals simultaneously encode information of goal planning, action execution and outcome evaluation. Linear-nonlinear-Poisson (LNP) model is applied for encoding analysis on mPFC neural spike data when a rat is learning a two-lever-press discrimination task. We use the L2-norm of tuning parameter in LNP model to indicate the importance of the encoded information and compare the spike train prediction performance of LNP model using all information, the most significant information and reward information only. The preliminary results indicate that mPFC activity can encode simultaneously the information of goal planning, action execution and outcome evaluation and that all the relevant information could be reconstructed from mPFC spike trains on a single trial basis.

Medial prefrontal brain activity correlates with emerging symptoms of anxiety and depression in late adolescence: A fNIRS study

The brain undergoes dramatic changes over the course of the adolescent years, and these developmental changes are implicated in the emergence of disorders that involve negative emotionality. Late adolescence might be the window within which brain networks manifest vulnerabilities to depressive and anxiety symptomology; particularly within the prefrontal cortex (PFC), which houses emotional control (dorsolateral) and emotional processing (medial) nodes. Given the comorbidity of depressive and anxious symptomology, it may be that the neural signature is similar for both within the developing PFC. In a sample of 67 adolescents (M=15.97 years, SD=1.36), we used functional near-infrared spectroscopy (fNIRS) to examine the neural signature of emergent anxiety and depressive symptoms among younger and older adolescents. We further examined the extent to which neural signatures of anxiety and depressive symptoms within the PFC were similar or different. Findings revealed that self-reported anxiety and depressive symptoms were highly correlated, and that the neural signatures of both within the PFC were similar, corresponding with the medial subregions of the PFC (i.e., those involved in evaluative processing). These findings were evident only in later adolescence, suggesting the possibility of a common vulnerability for anxiety and depressive disorders emerging around this developmental window.

Leading indicators of mental representation in construction hazard recognition

ABSTRACT Hazard recognition is mainly a visual search and cognitive process. Mental representations of hazards may impact mental states of hazard recognition. We assessed the effects of critical indicators of mental presentations of construction hazards on prefrontal cortex activation, a proxy for the mental states of hazard recognition. Students participated in a hazard inspection experiment, with near-infrared spectroscopy (NIRS) used to record prefrontal cortex activation. The effects of critical indicators of the hazards’ mental representations on prefrontal activation were analyzed. Results demonstrated that site familiarity, risk tolerance and safety knowledge have significant effects on medial prefrontal activation for hazards at a low visual clutter level. High levels of site familiarity and risk tolerance reduced medial prefrontal activation and saved cognitive resources. Theoretically, the findings supplement the knowledge of safety hazards’ mental representations; and practically, the findings guide provision of individual-specific guidance for improving workers’ hazard inspection performance.

Neuronal activation and performance changes in working memory induced by chronic sleep restriction in adolescents.

Most adolescents get less than the recommended 8-10hr of sleep per night. Functional deficits from lack of sleep include disruption of working memory. Adult neuroimaging studies of sleep deprivation suggest diminished responses in task-related brain networks if performance degrades, but compensatory increased responses with maintained performance. This study utilized functional magnetic resonance imaging to examine compensatory and diminished brain responses in adolescents during working memory performance, comparing chronic sleep restriction and healthy sleep duration. Thirty-six healthy adolescents, 14-17years old, experienced a 3-week protocol: (a) sleep phase stabilization; (b) sleep restriction (~6.5hr nightly); and (c) healthy sleep duration (~9hr nightly). After each sleep manipulation, we acquired functional magnetic resonance imaging with an NBack working memory task with four difficulty levels (0 to 3-back). NBack performance degraded with higher task difficulty, but without a detectable effect of sleep duration. ANOVA revealed main effects of both NBack difficulty and sleep in widespread brain networks. Planned contrasts showed that, compared with healthy sleep, sleep restriction resulted in greater medial prefrontal activation and weaker activation in the precuneus for the most difficult task condition. During sleep restriction, we found compensatory functional responses in brain regions that process sensory input and vigilance. However, adolescents also showed impaired performance and diminished brain responses during the hardest task level under a week of chronic sleep restriction. Chronic sleep restriction during adolescence is common. Understanding the impact of ongoing functional compensation and performance breakdown during this developmental period can have important implications for learning and educational strategies.

Phosphodiesterase type 1 inhibition alters medial prefrontal cortical activity during goal-driven behaviour and partially reverses neurophysiological deficits in the rat phencyclidine model of schizophrenia

Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in Lister Hooded rats treated with the PDE1B inhibitor Lu AF64386 and tested in the 5-choice serial reaction time task (5-CSRTT). We also asked whether PDE1B inhibition modulates neurophysiological deficits produced by subchronic phencyclidine (PCP) treatment, a rat pharmacological model of schizophrenia. Lu AF64386 significantly affected behavioural parameters consistent with a reduction in goal-directed behaviour, however without affecting accuracy. Additionally, it reduced mPFC neuronal activity. Pre-treatment with PCP did not affect behavioural parameters, however it significantly disrupted overall neuronal firing while increasing phasic responses to reward-predicting cues and disrupting mPFC-NAc cross-talk. The latter two effects were reversed by Lu AF64386. These findings suggest PDE1B inhibition may be beneficial in disorders implicating a dysfunction of the mPFC-NAc network.

Self-esteem and cultural worldview buffer mortality salience effects on responses to self-face: Distinct neural mediators

Terror management theory proposes cultural worldview and self-esteem as two buffers against death anxiety. The neural mediators of these buffering effects, however, have not been fully understood. The present work investigated neural mediation mechanisms between self-esteem/cultural trait (self-construal) and mortality salience (MS) effects on self-face processing. We found that MS (vs. NA) priming eliminated self-face advantage in behavioral judgments of face-orientation in low self-esteem individuals and reduced self-face advantage in behavioral judgments of facial-familiarity in individuals with high interdependent self-construals. Our functional magnetic resonance imaging (fMRI) results showed that, following MS priming, insular activities mediated the relationship between self-esteem and self-face advantage in face-orientation judgments, whereas dorsal medial prefrontal activity mediated the relationship between interdependent self-construal and self-face advantage in face-familiarity judgments. Our findings suggest that distinct neural mechanisms are engaged in mediating the relationships between self-esteem/cultural trait and MS effects on the emotional and cognitive processes of self-relevant information.

Alterations of medial prefrontal cortex bioelectrical activity in experimental model of isoprenaline-induced myocardial infarction.

BackgroundClinical and animal studies have found that anxiety and depression are significantly more common after acute myocardial infarction (AMI). The medial prefrontal cortex (PFC) has a dual role: in higher brain functions and in cardiovascular control, making it a logical candidate for explaining the perceived bidirectional heart-brain connection. We used parallel Electrocardiography (ECG) and Electrocorticography (ECoG) registration to investigate AMI-induced changes in medial PFC bioelectrical activity in a rat model of AMI.Materials and methodsAdult male Wistar albino rats were used in the study. Gold-plated recording electrodes were implanted over the frontal cortex for ECoG recording. ECG was recorded via two holter electrodes attached on the skin of the back fixed in place by a jacket. Induction of AMI was performed by isoprenaline (150 mg/kg, i.p.). ECoG and ECG signals were registered at baseline, during 3 hours after isoprenaline administration and at 24 hours after isoprenaline administration.ResultsSignificant increases of theta, alpha, and beta electroencephalographic (EEG) band power were observed in different time intervals after isoprenaline administration. Significant increase of theta band peak frequency was also observed during the first hour after isoprenaline administration. No statistically significant differences in band-power activity were found between the pre-isoprenaline measurements and 24 hours after administration.ConclusionOur results demonstrate significant increases in EEG band power of alpha beta and theta bands during isoprenaline-induced AMI model. These are the first findings to connect heart damage during isoprenaline- induced AMI to disturbances in the cortical bioelectrical activity.

Keeping an eye on pain expression in primary somatosensory cortex

Facial expressions of pain are composed of a subset of pain-indicative muscle movements. Amongst this subset, contracting the muscles surrounding the eyes (orbicularis oculi muscle) is the most frequent response and has been linked specifically to pain intensity, a fundamental aspect of the sensory dimension of pain. To further explore this link, the present study used functional magnetic resonance imaging (fMRI) to test the hypothesis that orbicularis oculi activation during pain reflects the magnitude of brain responses in areas being involved in processing the sensory dimension of pain.Facial and brain (BOLD) responses to experimentally-induced heat pain applied to the left lower leg were assessed in twenty-two healthy participants after verbal suggestions were given to specifically increase perceived pain intensity and in control conditions involving no suggestion.Increases in pain intensity produced the expected changes in facial responses characterized by a stronger contraction of the orbicularis oculi muscle. A regression model further demonstrated that stronger increases in orbicularis oculi activity reflected a larger increase in the BOLD response to the noxious stimulus in the leg area of the primary somatosensory cortex (S1) and a larger decrease in medial prefrontal activity consistent with previous finding suggesting disinhibition. Importantly, the positive coupling of orbicularis oculi with S1 activity was not accounted for by changes in other facial muscles.These results are consistent with the notion that facial expressions of pain differentially encode the multi-dimensional pain experience and reflect, at least partly, the activity of the spino-thalamo-cortical pathway targeting the primary somatosensory cortex.

A neurobiological association of revenge propensity during intergroup conflict.

Revenge during intergroup conflict is a human universal, but its neurobiological underpinnings remain unclear. We address this by integrating functional MRI and measurements of endogenous oxytocin in participants who view an ingroup and an outgroup member's suffering that is caused mutually (Revenge group) or by a computer (Control group). We show that intergroup conflict encountered by the Revenge group is associated with an increased level of oxytocin in saliva compared to that in the Control group. Furthermore, the medial prefrontal activity in response to ingroup pain in the Revenge group but not in the Control group mediates the association between endogenous oxytocin and the propensity to give painful electric shocks to outgroup members, regardless of whether they were directly involved in the conflict. Our findings highlight an important neurobiological correlate of revenge propensity, which may be implicated in conflict contagion across individuals in the context of intergroup conflict.

Macaques Exhibit Implicit Gaze Bias Anticipating Others’ False-Belief-Driven Actions via Medial Prefrontal Cortex

The ability to infer others' mental states is essential to social interactions. This ability, critically evaluated by testing whether one attributes false beliefs (FBs) to others, has been considered to be uniquely hominid and to accompany the activation of a distributed brain network. We challenge the taxon specificity of this ability and identify the causal brain locus by introducing an anticipatory-looking FB paradigm combined with chemogenetic neuronal manipulation in macaque monkeys. We find spontaneous gaze bias of macaques implicitly anticipating others' FB-driven actions. Silencing of the medial prefrontal neuronal activity with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) specifically eliminates the implicit gaze bias while leaving the animals' visually guided and memory-guided tracking abilities intact. Thus, neuronal activity in the medial prefrontal cortex could have a causal role in FB-attribution-like behaviors in the primate lineage, emphasizing the importance of probing the neuronal mechanisms underlying theory of mind with relevant macaque animal models.

S67. Suicidal Behavior is Associated With Greater Medial Prefrontal and Fusiform Activation During Risky Decision Making in Youth With Disruptive Behavior Disorders

Suicide rates among youth are increasing; while research on adults has identified endophenotypes characterized by deficits in decision-making in risk for suicidality, less is known regarding neurobiological markers of suicide risk among youth. Understanding of neural mechanisms characteristic of youth with a history of suicidal ideation or attempts may inform screening, prevention, and intervention. We examined neural mechanisms underlying decision-making among 11-12 year-olds with and without suicidality.

Neural mechanisms of face emotion processing in youths and adults with bipolar disorder.

Little is known about potential differences in the pathophysiology of bipolar disorder (BD) across development. The present study aimed to characterize age-related neural mechanisms of BD. Youths and adults with and without BD (N=108, age range=9.8-55.9years) completed an emotional face labeling task during fMRI acquisition. We leveraged three different fMRI analytic tools to identify age-related neural mechanisms of BD, investigating (a) change in neural responses over the course of the task, (b) neural activation averaged across the entire task, and (c) amygdala functional connectivity. We found converging Age Group × Diagnosis patterns across all three analytic methods. Compared to healthy youths vs adults, youths vs adults with BD show an altered pattern in response to repeated presentation of emotional faces in medial prefrontal, amygdala, andtemporoparietal regions, as well as amygdala-temporoparietal connectivity. Specifically, medial prefrontal and lingual activation decreases over the course of repeated emotional face presentations in healthy youths vs adults but increases in youths with BD compared to adults with BD. Moreover, youths vs adults with BD show less medial prefrontal activation and amygdala-temporoparietal junction connectivity averaged over the task, but this difference is not found for healthy youths vs adults. Although longitudinal confirmation and replication will be necessary, these findings suggest that neural development may be aberrant in BD and that some neural mechanisms mediating BD may differ in adults vs children with the illness.