Fronto-limbic Connectivity Research Articles

Association between resting-state connectivity patterns in the defensive system network and treatment response in spider phobia—a replication approach

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.

Neighborhood Crime and Externalizing Behavior in Toddlers: A Longitudinal Study With Neonatal fMRI and Parenting

Prenatal exposure to neighborhood crime has been associated with weaker neonatal frontolimbic connectivity; however, associations with early childhood behavior remain unclear. We hypothesized that living in a high-crime neighborhood would be related to higher externalizing symptoms at age 1 and 2 years, over and above other adversities, and that neonatal frontolimbic connectivity and observed parenting behaviors at 1 year would mediate this relationship. Participants included 399 pregnant women, recruited as part of the Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders (eLABE) study. Geocoded neighborhood crime data was obtained from Applied Geographic Solution. A total of 319 healthy, non-sedated neonates underwent scanning using resting-state functional magnetic resonance imaging (fMRI) on a Prisma 3T scanner and had≥10 minutes of high-quality data. Infant-Toddler Socioemotional Assessment Externalizing T scores were available for 274 mothers of 1-year-olds and 257 mothers of 2-year-olds. Observed parenting behaviors were available for 202 parent-infant dyads at 1 year. Multilevel and mediation models tested longitudinal associations. Living in a neighborhood with high violent (β= 0.15, CI= 0.05-0.27, p= .004) and property (β= 0.10, CI= 0.01-0.20, p= .039) crime was related to more externalizing symptoms at 1 and 2 years, controlling for other adversities. Weaker frontolimbic connectivity was also associated with higher externalizing symptoms at 1 and 2 years. After controlling for other adversities, parenting behaviors mediated the specific association between crime and externalizing symptoms, but frontolimbic connectivity did not. These findings provide evidence that early exposure to neighborhood crime and weaker neonatal frontolimbic connectivity may influence later externalizing symptoms, and suggest that parenting may be an early intervention target for families in high-crime areas. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Maternal childhood maltreatment: associations to offspring brain volume and white matter connectivity.

The deleterious effects of adversity are likely intergenerational, such that one generation's adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children's behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

Patterns of experience, expression, and physiology of stress relate to depressive symptoms and self-injurious thoughts and behaviors in adolescents: a person-centered approach.

Preliminary evidence shows that discordance in stress experience, expression, and physiology (EEP) in adolescents is linked to depression, suicidal ideation (SI), non-suicidal self-injury (NSSI), and brain functioning. This study employs person-centered analysis to probe the relationship between stress responses, psychopathology, and neural patterns in female adolescents who are oversampled for engagement in NSSI. Adolescent females (N = 109, ages 12-17) underwent a social stress test from which self-report measures of stress experience, observer ratings of stress expression, and physiological metrics of stress (via salivary cortisol) were obtained. Multi-trajectory modeling was employed to identify concordant and discordant stress EEP groups. Depressive symptoms, SI and attempt, NSSI engagement, frontal and limbic activation to emotional stimuli, and resting state fronto-limbic connectivity were examined in the EEP groups derived from the multi-trajectory models. Four groups were identified, three of which demonstrated relatively concordant EEP and one which demonstrated discordant EEP (High Experience-High Expression-Low Physiology). Further, replicating past research, the High Experience-High Expression-Low Physiology discordant group exhibited higher depressive symptoms, SI, suicide attempt, and NSSI episodes (only for sensitivity analyses based on past year) relative to other EEP groups. No significant group differences in brain functioning emerged. Results indicate that within-person, multi-level patterns in stress responding capture risk for dysfunction including depression and self-injurious thoughts and behaviors. Further interrogating of system-level stress functioning may better inform assessment and intervention efforts.

Different brain functional network abnormalities between attention-deficit/hyperactivity disorder youth with and without familial risk for bipolar disorder.

Attention-deficit/hyperactivity disorder (ADHD) commonly precedes the initial onset of mania in youth with familial risk for bipolar disorder (BD). Although ADHD youth with and without BD familial risk exhibit different clinical features, associated neuropathophysiological mechanisms remain poorly understood. This study aimed to identify brain functional network abnormalities associated with ADHD in youth with and without familial risk for BD. Resting-state functional magnetic resonance imaging scans were acquired from 37 ADHD youth with a family history of BD (high-risk), 45 ADHD youth without a family history of BD (low-risk), and 32 healthy controls (HC). Individual whole-brain functional networks were constructed, and graph theory analysis was applied to estimate network topological metrics. Topological metrics, including network efficiency, small-worldness and nodal centrality, were compared across groups, and associations between topological metrics and clinical ratings were evaluated. Compared to HC, low-risk ADHD youth exhibited weaker global integration (i.e., decreased global efficiency and increased characteristic path length), while high-risk ADHD youth showed adisruption of localized network components with decreased frontoparietal and frontolimbic connectivity. Common topological deficits were observed in the medial superior frontal gyrus between low- and high-risk ADHD. Distinct network deficits were found in the inferior parietal lobule and corticostriatal circuitry. Associations between global topological metrics and externalizing symptoms differed significantly between the two ADHD groups. Different patterns of functional network topological abnormalities were found in high- as compared to low-risk ADHD, suggesting that ADHD in youth with BD familial risk may represent a phenotype that is different from ADHD alone.

Resting-state Fronto-limbic Connectivity in Unipolar Depressive Patients as a Predictor for Sporadic Conversion to (Hypo)mania

IntroductionPatients with a bipolar disorder (BD) may experience one or several episodes of major depression before transitioning into a manic phase. Given that treatment with common antidepressants may exacerbate symptoms of mania in patients with BD, initial diagnosis of major depressive disorder (MDD) is a significant issue affecting BD patients. Currently, a family history of BD is used as an early identifier for BD, but as genetic factors associated with BD confer susceptibility to a wide range of psychiatric illnesses, this approach lacks specificity. Thus, there is a pressing need for a biomarker which specifically predicts development of bipolar symptoms in patients with MDD, rather than a trait vulnerability to psychiatric disorderObjectives The aim of this study is to assess alterations in fronto-limbic function that exist prior to the manifestation of the first manic episode in BD patients without familial predisposition for BD.MethodsTo identify a biomarker for conversion to BD we performed a study in a naturalistic sample of MDD patients without a familial risk for BD, which were followed for 9 years. We used a seed-based functional connectivity analysis to assess differences in resting-state fronto-limbic connectivity between MDD patients who converted to BD during the follow-up period (n = 11), and non-converting MDD patients (n = 56).ResultsClusters of significantly reduced functional connectivity were found in the fronto-limbic network of prospective converters relative to non-converters.ConclusionsFindings suggest that alterations of fronto-limbic functional connectivity during episodes of depression predate and associate with conversion to BD later in life, in the absence of familial risk. These fronto-limbic functional connectivity disturbances may be of interest for diagnosing early-stage BD, and may offer insight in the mechanisms that drive conversion in the absence of familial predisposition. Findings from this study need to be verified through large-scale longitudinal imaging studies in naturalistic cohorts of MDD patients.Disclosure of InterestNone Declared

Aberrant cortical projections to amygdala GABAergic neurons contribute to developmental circuit dysfunction following early life stress

Early life stress (ELS) results in enduring dysfunction of the corticolimbic circuitry, underlying emotional and social behavior. However, the neurobiological mechanisms involved remain elusive. Here, we have combined viral tracing and electrophysiological techniques to study the effects of maternal separation (MS) on frontolimbic connectivity and function in young (P14-21) rats. We report that aberrant prefrontal inputs to basolateral amygdala (BLA) GABAergic interneurons transiently increase the strength of feed-forward inhibition in the BLA, which raises LTP induction threshold in MS treated male rats. The enhanced GABAergic activity after MS exposure associates with lower functional synchronization within prefrontal-amygdala networks invivo. Intriguingly, no differences in these parameters were detected in females, which were also resistant to MS dependent changes in anxiety-like behaviors. Impaired plasticity and synchronization during the sensitive period of circuit refinement may contribute to long-lasting functional changes in the prefrontal-amygdaloid circuitry that predispose to neuropsychiatric conditions later on in life.

Fetal Frontolimbic Connectivity Prospectively Associates With Aggression in Toddlers

BackgroundAggression is a major public health concern that emerges early in development and lacks optimized treatment, highlighting need for improved mechanistic understanding regarding the etiology of aggression. The present study leveraged fetal resting-state functional magnetic resonance imaging to identify candidate neurocircuitry for the onset of aggressive behaviors before symptom emergence. MethodsPregnant mothers were recruited during the third trimester of pregnancy to complete a fetal resting-state functional magnetic resonance imaging scan. Mothers subsequently completed the Child Behavior Checklist to assess child aggression at 3 years postpartum (n = 79). Independent component analysis was used to define frontal and limbic regions of interest. ResultsChild aggression was not related to within-network connectivity of subcortical limbic regions or within–medial prefrontal network connectivity in fetuses. However, weaker functional coupling between the subcortical limbic network and medial prefrontal network in fetuses was prospectively associated with greater maternal-rated child aggression at 3 years of age even after controlling for maternal emotion dysregulation and toddler language ability. We observed similar, but weaker, associations between fetal frontolimbic functional connectivity and toddler internalizing symptoms. ConclusionsNeural correlates of aggressive behavior may be detectable in utero, well before the onset of aggression symptoms. These preliminary results highlight frontolimbic connections as potential candidate neurocircuitry that should be further investigated in relation to the unfolding of child behavior and psychiatric risk.

Structural connectome-based prediction of trait anxiety.

Neurobiological research on anxiety has shown that trait-anxious individuals may be characterized by weaker structural connectivity of the amygdala-prefrontal circuitry, representing a reduced capacity for efficient communication between the two brain regions. However, comparison of available studies has been inconsistent, possibly related to factors such as aging that influences both trait anxiety and structural connectivity of the brain. To help clarify the nature of brain-anxiety relationship, we applied a connectome-based predictive modeling framework on 148 diffusion-weighted imaging data from the Leipzig Study for Mind-Body Emotion Interactions dataset and identified multivariate patterns of whole-brain structural connectivity that predicted trait anxiety. Results showed that networks predictive of trait anxiety differed across age groups. Specifically, an isolated negative network, which shared overlapping features with the amygdala-prefrontal circuitry, was found in younger adults (20-30 years of age), whereas a widespread positive network highlighted by frontotemporal and frontolimbic connectivity was identified when both younger and older adults (20-80 years of age) were examined. No predictive network was observed when only older adults (30-80 years of age) were considered. Our findings highlight an important age-dependent effect on the structural connectome-based prediction of trait anxiety, supporting ongoing efforts to develop potential neural biomarkers of anxiety.

The Effects of Prenatal Exposure to Neighborhood Crime on Neonatal Functional Connectivity

BackgroundMaternal exposure to adversity during pregnancy has been found to affect infant brain development; however, the specific effect of prenatal crime exposure on neonatal brain connectivity remains unclear. Based on existing research, we hypothesized that living in a high-crime neighborhood during pregnancy would affect neonatal frontolimbic connectivity over and above other individual- and neighborhood-level adversity and that these associations would be mediated by maternal psychosocial stress. MethodsParticipants included 399 pregnant women, recruited as part of the eLABE (Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders) study. In the neonatal period, 319 healthy, nonsedated infants were scanned using resting-state functional magnetic resonance imaging (repetition time = 800 ms; echo time = 37 ms; voxel size = 2.0 × 2.0 × 2.0 mm3; multiband = 8) on a Prisma 3T scanner and had at least 10 minutes of high-quality data. Crime data at the block group level were obtained from Applied Geographic Solution. Linear regressions and mediation models tested associations between crime, frontolimbic connectivity, and psychosocial stress. ResultsLiving in a neighborhood with high property crime during pregnancy was related to weaker neonatal functional connectivity between the thalamus–anterior default mode network (aDMN) (β = −0.15, 95% CI = −0.25 to −0.04, p = .008). Similarly, high neighborhood violent crime was related to weaker functional connectivity between the thalamus-aDMN (β = −0.16, 95% CI = −0.29 to −0.04, p = .01) and amygdala-hippocampus (β = −0.16, 95% CI = −0.29 to −0.03, p = .02), controlling for other types of adversity. Psychosocial stress partially mediated relationships between the thalamus-aDMN and both violent and property crime. ConclusionsThese findings suggest that prenatal exposure to crime is associated with weaker neonatal limbic and frontal functional brain connections, providing another reason for targeted public policy interventions to reduce crime.

Resting-state fronto-limbic connectivity in unipolar depressive patients as a predictor for sporadic conversion to (hypo)mania

Resting-state fronto-limbic connectivity in unipolar depressive patients as a predictor for sporadic conversion to (hypo)mania

P.0677 Fronto-limbic functional connectivity associated with childhood maltreatment in adults with depression

P.0677 Fronto-limbic functional connectivity associated with childhood maltreatment in adults with depression

Reduced prefrontal cortex response to own vs. unknown emotional infant faces in mothers with bipolar disorder

Motherhood involves functional brain adaptations within a broad neural network purported to underlie sensitive caregiving behavior. Bipolar disorder (BD) is associated with aberrant brain response to emotional faces within a similar network, which may influence BD mothers’ sensitivity to infant faces. This functional magnetic resonance imaging (fMRI) study aimed to investigate whether mothers with BD display aberrant neural responses to own infant faces compared to healthy mothers. Twenty-six mothers with BD in remission and 35 healthy mothers underwent fMRI during which they viewed happy and distressed still facial photographs of their own and of unknown infants. After the scan, mothers viewed the pictures again on a computer screen and rated the intensity of infants’ facial emotions and their own emotional response to infant face images. Mothers with BD displayed lower left dorsolateral prefrontal cortex (dlPFC) response compared to healthy mothers to own vs. unknown infant faces specifically and abnormal positive functional connectivity between the left and right amygdala and prefrontal regions. BD mothers further displayed stronger deactivation of precuneus and occipital regions to all happy vs. distressed infant faces. After the scan, they rated their infants’ distress and own response to their infants’ distressed faces less negatively than healthy mothers. Blunted dlPFC response and aberrant fronto-limbic connectivity while viewing own infant faces and less negative ratings of own infants’ distress in BD mothers may affect their responses to their own infants in real-life mother-infant interactions.

The processing of angry faces in schizophrenia patients with a history of suicide: An fMRI study examining brain activity and connectivity

BackgroundThe high rate of suicidal behaviours (SBs) in psychiatric populations remain an important preoccupation to address. The literature reveals emotional instability as an important risk factor for SBs. However, the neural mechanisms underpinning this risk factor have never been investigated in schizophrenia patients with SBs. The following study implemented a task-based emotional processing functional magnetic resonance imaging (fMRI) paradigm to evaluate the activation and connectivity differences exhibited by schizophrenia patients with a history of suicide attempt (SA). MethodA sample of 62 schizophrenia patients with and without SA and 22 controls completed an fMRI emotional processing task, which included the visualization of dynamic angry facial expressions. Task-based connectivity was assessed using generalized psychophysical interaction analyses. ResultsDuring the processing of angry faces, suicidal schizophrenia patients displayed increased activation of the left median cingulate gyrus, left middle frontal gyrus, and left precuneus when compared to nonsuicidal schizophrenia patients and healthy controls. Whole-brain connectivity analyses yielded an increased coupling of the right amygdala and right superior frontal gyrus, as well as between the left precuneus and median cingulate gyrus, in suicidal schizophrenia patients. Schizophrenia patients' hostility scores on the Positive and Negative Symptom Scale (PANSS) were significantly and positively correlated with the activity of the left median cingulate gyrus. ConclusionWhen exposed to angry faces, suicidal schizophrenia patients demonstrate elevated activation of brain regions associated to executive functioning and self-processing, as well as aberrant fronto-limbic connectivity involved in emotion regulation. Our results highlight the neglected role of anger when investigating the neural alterations underpinning SBs in schizophrenia.

Coordination between frontolimbic resting state connectivity and hypothalamic–pituitary–adrenal axis functioning in adolescents with and without depression

Depression is associated with abnormalities in Hypothalamic–Pituitary–Adrenal (HPA) axis functioning and neural circuitry that underlie the stress response. Resting-state functional connectivity (RSFC) between frontolimbic brain regions captures intrinsic connections that may set the stage for the rallying and regulating of the HPA axis system. This study examined the association between cortisol stress response and frontolimbic (amygdala and ventral and dorsal medial prefrontal cortex [vmPFC and dmPFC respectively]) RSFC in 88 (Age: M = 15.95, SD = 2.04; 71.60% female) adolescents with (N = 55) and without (N = 33) major depressive disorder (MDD). We collected salivary cortisol in the context of a modified Trier Social Stress Test (TSST) paradigm. Key findings were that adolescents with depression and healthy controls showed different patterns of association between amygdala and vmPFC RSFC and HPA functioning: while healthy controls showed a positive relationship between frontolimbic connectivity and cortisol levels that may indicate coordination across neural and neuroendocrine systems, adolescents with depression showed a minimal or inverse relationship, suggesting poor coordination of these systems. Results were similar when examining non-suicidal self-injury subgroups within the MDD sample. These findings suggest that the intrinsic quality of this frontolimbic connection may be related to HPA axis functioning. In MDD, inverse associations may represent a compensatory response in one system in response to dysfunction in the other. Longitudinal multilevel research, however, is needed to disentangle how stress system coordination develops in normal and pathological contexts and how these systems recover with treatment.

Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning.

It is currently unclear whether early life stress (ELS) affects males and females differently. However, a growing body of work has shown that sex moderates responses to stress and injury, with important insights into sex-specific mechanisms provided by work in rodents. Unfortunately, most of the ELS studies in rodents were conducted only in males, a bias that is particularly notable in translational work that has used human imaging. Here we examine the effects of unpredictable postnatal stress (UPS), a mouse model of complex ELS, using high resolution diffusion magnetic resonance imaging. We show that UPS induces several neuroanatomical alterations that were seen in both sexes and resemble those reported in humans. In contrast, exposure to UPS induced fronto-limbic hyper-connectivity in males, but either no change or hypoconnectivity in females. Moderated-mediation analysis found that these sex-specific changes are likely to alter contextual freezing behavior in males but not in females.

Threat-induced anxiety during goal pursuit disrupts amygdala\u2013prefrontal cortex connectivity in posttraumatic stress disorder

To investigate how unpredictable threat during goal pursuit impacts fronto-limbic activity and functional connectivity in posttraumatic stress disorder (PTSD), we compared military veterans with PTSD (n = 25) vs. trauma-exposed control (n = 25). Participants underwent functional magnetic resonance imaging (fMRI) while engaged in a computerized chase-and-capture game task that involved optimizing monetary rewards obtained from capturing virtual prey while simultaneously avoiding capture by virtual predators. The game was played under two alternating contexts—one involving exposure to unpredictable task-irrelevant threat from randomly occurring electrical shocks, and a nonthreat control condition. Activation in and functional connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) was tested across threat and nonthreat task contexts with generalized psychophysiological interaction (gPPI) analyses. PTSD patients reported higher anxiety than controls across contexts. Better task performance represented by successfully avoiding capture by predators under threat compared with nonthreat contexts was associated with stronger left amygdala–vmPFC functional connectivity in controls and greater vmPFC activation in PTSD patients. PTSD symptom severity was negatively correlated with vmPFC activation in trauma-exposed controls and with right amygdala–vmPFC functional connectivity across all participants in the threat relative to nonthreat contexts. The findings showed that veterans with PTSD have disrupted amygdala–vmPFC functional connectivity and greater localized vmPFC processing under threat modulation of goal-directed behavior, specifically related to successfully avoiding loss of monetary rewards. In contrast, trauma survivors without PTSD relied on stronger threat-modulated left amygdala–vmPFC functional connectivity during goal-directed behavior, which may represent a resilience-related functional adaptation.

Stable inhibition-related inferior frontal hypoactivation and fronto-limbic hyperconnectivity in obsessive–compulsive disorder after concentrated exposure therapy

Response inhibition has previously been suggested as an endophenotype for obsessive–compulsive disorder (OCD), evidenced by studies showing worse task performance, and altered task-related activation and connectivity. However, it’s unclear if these measures change following treatment. In this study, 31 OCD patients and 28 healthy controls performed a stop signal task during 3 T functional magnetic resonance imaging before treatment, while 24 OCD patients and 17 healthy controls were rescanned one week and three months after concentrated exposure and response prevention over four consecutive days using Bergen 4-Day Format. To study changes over time we performed a longitudinal analysis on stop signal reaction time and task-related activation and amygdala connectivity during successful and failed inhibition. Results showed that there was no group difference in task performance. Before treatment, OCD patients compared to controls showed less inhibition-related activation in the right inferior frontal gyrus, and increased functional connectivity between the right amygdala and the right inferior frontal gyrus and pre-supplementary motor area. During error-processing, OCD patients versus controls showed less activation in the pre-SMA before treatment. These group differences did not change after treatment. Pre-treatment task performance, brain activation, and connectivity were unrelated to the degree of symptom improvement after treatment. In conclusion, inferior frontal gyrus hypoactivation and increased fronto-limbic connectivity are likely trait markers of OCD that remain after effective exposure therapy.

Brain signatures of threat-safety discrimination in adolescent chronic pain.

Approximately 1.7 million youth suffer from debilitating chronic pain in the US alone, conferring risk of continued pain in adulthood. Aberrations in threat-safety (T-S) discrimination are proposed to contribute to pain chronicity in adults and youth by interacting with pain-related distress. Yet, few studies have examined the neural circuitry underlying T-S discrimination in patients with chronic pain or how T-S discrimination relates to pain-related distress. In this study, 91 adolescents (10-24 years; 78 females) including 30 chronic pain patients with high pain-related distress, 29 chronic pain patients with low pain-related distress, and 32 healthy peers without chronic pain completed a developmentally appropriate T-S learning paradigm. We measured self-reported fear, psychophysiology (skin conductance response), and functional magnetic resonance imaging responses (N = 72 after functional magnetic resonance imaging exclusions). After controlling for age and anxiety symptoms, patients with high pain-related distress showed altered self-reported fear and frontolimbic activity in response to learned threat and safety cues compared with both patients with low pain-related distress and healthy controls. Specifically, adolescent patients with high pain-related distress reported elevated fear and showed elevated limbic (hippocampus and amygdala) activation in response to a learned threat cue (CS+). In addition, they showed decreased frontal (vmPFC) activation and aberrant frontolimbic connectivity in response to a learned safety cue (CS-). Patients with low pain-related distress and healthy controls appeared strikingly similar across brain and behavior. These findings indicate that altered T-S discrimination, mediated by frontolimbic activation and connectivity, may be one mechanism maintaining pain chronicity in adolescents with high levels of pain-related distress.

Intrinsic Frontolimbic Connectivity and Mood Symptoms in Young Adult Cannabis Users.

Objective: The endocannbinoid system and cannabis exposure has been implicated in emotional processing. The current study examined whether regular cannabis users demonstrated abnormal intrinsic (a.k.a. resting state) frontolimbic connectivity compared to non-users. A secondary aim examined the relationship between cannabis group connectivity differences and self-reported mood and affect symptoms.Method: Participants included 79 cannabis-using and 80 non-using control emerging adults (ages of 18–30), balanced for gender, reading ability, and age. Standard multiple regressions were used to predict if cannabis group status was associated with frontolimbic connectivity after controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis.Results: After controlling for research site, past month alcohol and nicotine use, and days of abstinence from cannabis, cannabis users demonstrated significantly greater connectivity between left rACC and the following: right rACC (p = 0.001; corrected p = 0.05; f2 = 0.55), left amygdala (p = 0.03; corrected p = 0.47; f 2 = 0.17), and left insula (p = 0.03; corrected p = 0.47; f 2 = 0.16). Among cannabis users, greater bilateral rACC connectivity was significantly associated with greater subthreshold depressive symptoms (p = 0.02).Conclusions: Cannabis using young adults demonstrated greater connectivity within frontolimbic regions compared to controls. In cannabis users, greater bilateral rACC intrinsic connectivity was associated with greater levels of subthreshold depression symptoms. Current findings suggest that regular cannabis use during adolescence is associated with abnormal frontolimbic connectivity, especially in cognitive control and emotion regulation regions.