Neuroimmune mechanisms connecting violence with internalizing symptoms: A high-dimensional multimodal mediation analysis.

Violence exposure is associated with worsening anxiety and depression symptoms among adolescents. Mechanistically, social defeat stress models in mice indicate that violence increases peripherally derived macrophages in threat appraisal regions of the brain, which have been causally linked to anxious behavior. In the present study, we investigate if there is a path connecting violence exposure with internalizing symptom severity through peripheral inflammation and amygdala connectivity. Two hundred and thirty-three adolescents, ages 12-15, from the Chicago area completed clinical assessments, immune assays and neuroimaging. A high-dimensional multimodal mediation model was fit, using violence exposure as the predictor, 12 immune variables as the first set of mediators and 288 amygdala connectivity variables as the second set, and internalizing symptoms as the primary outcome measure. 56.2% of the sample had been exposed to violence in their lifetime. Amygdala-hippocampus connectivity mediated the association between violence exposure and internalizing symptoms ( ζ ̂ Hipp π ̂ Hipp = 0.059 $$ {\hat{\zeta}}_{\mathrm{Hipp}}{\hat{\pi}}_{\mathrm{Hipp}}=0.059 $$ , 95 % CI boot = 0.009,0.134 $$ 95\%{\mathrm{CI}}_{\mathrm{boot}}=\left[\mathrm{0.009,0.134}\right] $$ ). There was no evidence that inflammation or inflammation and amygdala connectivity in tandem mediated the association. Considering the amygdala and the hippocampus work together to encode, consolidate, and retrieve contextual fear memories, violence exposure may be associated with greater connectivity between the amygdala and the hippocampus because it could be adaptive for the amygdala and the hippocampus to be in greater communication following violence exposure to facilitate evaluation of contextual threat cues. Therefore, chronic elevations of amygdala-hippocampal connectivity may indicate persistent vigilance that leads to internalizing symptoms.

Changes of creative ability and underlying brain network connectivity throughout the lifespan.

Creativity, or divergent thinking, is essential to and supported by cognitive functions necessary for everyday tasks. The current study investigates divergent thinking and its neural mechanisms from adolescence to late adulthood. To do this, 180 healthy participants completed a creativity task called the egg task including 86 adolescents (mean age (SD) = 13.62 (1.98)), 52 young adults (24.92 (3.60), and 42 older adults (62.84 (7.02)). Additionally, a subsample of 111 participants completed a resting-state fMRI scan. After investigating the impact of age on different divergent thinking metrics, we investigated the impact of age on the association between divergent thinking and resting-state functional connectivity within and between major resting-state brain networks associated with creative thinking: the DMN, ECN, and SN. Adolescents tended to be less creative than both young and older adults in divergent thinking scores related to expansion creativity, and not in persistent creativity, while young and older adults performed relatively similar. We found that adolescents' functional integrity of the executive control network (ECN) was positively associated with expansion creativity, which was significantly different from the negative association in both the young and older adults. These results suggest that creative performance and supporting brain networks change throughout the lifespan.

There is (probably) no (meaningful) difference in (most) outcomes between 'spinal' and 'general' anaesthesia for hip fracture surgery: time to move forward.

A meta-analysis influenced by two recent large randomised controlled trials (REGAIN and RAGA) concluded that little, if any, difference in commonly measured outcomes exists between patients administered spinal or general anaesthesia for their hip fracture surgery. We explore whether there is genuinely no difference, or what the methodological problems in research might be that prevent any real difference from being observed. We also discuss the need for greater nuance in future research to determine how anaesthetists might deliver perioperative care towards improving postoperative recovery trajectories in patients following hip fracture.

Low Socioeconomic Status Is Associated with a Greater Neural Response to Both Rewards and Losses.

Low socioeconomic status (SES) has been associated with distinct patterns of reward processing, which appear to have adverse implications for health outcomes, well-being, and human capital. However, most studies in this literature have used complex tasks that engage more than reward processing and/or retrospectively studied childhood SES in samples of adults. To clarify how SES relates to the development of reward processing tendencies, we measured income-to-poverty ratio (IPR) in 172 youth who subsequently underwent functional MRI while completing a passive avoidance task to assess neural responses to reward and loss information. Participants were 12-15 years old (mean = 13.94, SD = .52; 65.7% female) from a sample broadly representative of the Chicago area in terms of SES (IPR range = 0.1-34.53; mean = 3.90; SD = 4.15) and racial makeup (40.1% White 30.8% Black; 29.1% Hispanic). To the extent they had lower IPR, children displayed a trend toward worse behavioral performance on the passive avoidance task. Lower IPR also was associated with a greater response in attention brain regions to reward and loss cues and to reward and loss feedback. Lower IPR also was associated with reduced differentiation between reward and loss feedback in the ventromedial prefrontal and parietal cortex. The current data suggest that both increased salience of reward/loss information and reduced discrimination between reward and loss feedback could be factors linking SES with the development of human capital and health outcomes.

Cortisol changes in healthy children and adolescents during the COVID-19 pandemic.

The Coronavirus Disease 2019 (COVID-19) pandemic has caused massive disruptions to daily life in the United States, closing schools and businesses and increasing physical and social isolation, leading to deteriorations in mental health and well-being in people of all ages. Many studies have linked chronic stress with long-term changes in cortisol secretion, which has been implicated in many stress-related physical and mental health problems that commonly emerge in adolescence. However, the physiological consequences of the pandemic in youth remain understudied. Using hair cortisol concentrations (HCC), we quantified average longitudinal changes in cortisol secretion across a four-month period capturing before, during, and after the transition to pandemic-lockdown conditions in a sample of healthy youth (n = 49). Longitudinal changes in HCC were analyzed using linear mixed-effects models. Perceived levels of pandemic-related stress were measured and compared to the physiological changes in HCC. In children and adolescents, cortisol levels significantly increased across the course of the pandemic. These youth reported a multitude of stressors during this time, although changes in HCC were not associated with self-reported levels of COVID-19-related distress. We provide evidence that youth are experiencing significant physiological changes in cortisol activity across the COVID-19 pandemic, yet these biological responses are not associated with perceived stress levels. Youth may be especially vulnerable to the deleterious impacts of chronic cortisol exposure due to their current status in the sensitive periods for development, and the incongruency between biological and psychological stress responses may further complicate these developmental problems.

To snack or not to snack: Using fNIRS to link inhibitory control to functional connectivity in the toddler brain.

Inhibitory control (IC) emerges in infancy, continues to develop throughout childhood and is linked to later life outcomes such as school achievement, prosocial behavior, and psychopathology. Little, however, is known about the neural processes underpinning IC, especially in 2-year-olds. In this study, we examine functional connectivity (FC) in 2.5-year-olds while recording hemodynamic responses via functional infrared spectroscopy (fNIRS) during a traditional snack delay task. We found that functional connectivity strength between left frontal and parietal cortex and bilateral parietal cortex were positively associated with performance on this task. The current findings present the first neural data for toddlers during this IC task. Further, these data are the first to link this self-regulatory process to differences in brain development within this population. Implications for future directions and work with clinical populations are discussed.

Interaction of irritability and anxiety on emotional responding and emotion regulation: a functional MRI study.

BACKGROUND: Irritability and anxiety frequently co-occur in pediatric populations. Studies separately looking at the neural correlates of these symptoms have identified engagement of similar neural systems - particularly those implicated in emotional processing. Both irritability and anxiety can be considered negative valence emotional states that might relate to emotion dysregulation. However, previous work has not examined the neural responding during the performance of an emotion regulation task as a function of interaction between irritability and anxiety simultaneously. METHODS: This fMRI study involved 155 participants (90 with significant psychopathologies and 92 male) who performed the Affective Stroop Task, designed to engage emotion regulation as a function of task demands. The Affective Reactivity Index (ARI) was used to index irritability and the Screen for Child Anxiety Related Emotional Disorders (SCARED) was used to index anxiety. RESULTS: Levels of irritability, but not anxiety, was positively correlated with responses to visual images within the right rostro-medial prefrontal cortex and left anterior cingulate cortex during view trials. The second region of ventral anterior cingulate cortex showed a condition-by-emotion-by-ARI score-by-SCARED score interaction. Specifically, anxiety level was significantly correlated with a decreased differential BOLD response to negative relative to neutral view trials but only in the presence of relatively high irritability. CONCLUSIONS: Atypical maintenance of emotional stimuli within the rostro-medial prefrontal cortex may exacerbate the difficulties faced by adolescents with irritability. Moreover, increased anxiety combined with significant irritability may disrupt an automatic emotional conflict-based form of emotion regulation that is particularly associated with the ventral anterior cingulate cortex.

Alcohol use disorder and cannabis use disorder symptomatology in adolescents is associated with dysfunction in neural processing of future events.

Two of the most commonly used substances by adolescents in the United States are cannabis and alcohol. Cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with impairments in decision-making processes. One mechanism for impaired decision-making in these individuals is thought to be an inability to adequately represent future events during decision-making. In the current study involving 112 adolescents, we used a comparative optimism task to examine the relationship between relative severity of CUD/AUD (as indexed by the CUD/AUD Identification Tests [CUDIT/AUDIT]) and atypical function within neural systems underlying affect-based neural represenation future events. Greater CUDIT scores were negatively related to responses within subgenual anterior and posterior cingulate cortex when processing high-intensity potential future positive and negative events. There was also a particularly marked negative relationship between CUD symptoms and blood oxygen level-dependent (BOLD) responses within visual and premotor cortices to high-intensity, negatively valenced potential future events. However, AUD symptom severity was not associated with dysfunction within these brain regions. These data indicate that relative risk/severity of CUD is associated with reduced responsiveness to future high-intensity events. This may impair decision-making where future significant consequences should guide response choice.

Moderation of prior exposure to trauma on the inverse relationship between callous-unemotional traits and amygdala responses to fearful expressions: an exploratory study.

BACKGROUND: Previous work has shown that amygdala responsiveness to fearful expressions is inversely related to level of callous-unemotional (CU) traits (i.e. reduced guilt and empathy) in youth with conduct problems. However, some research has suggested that the relationship between pathophysiology and CU traits may be different in those youth with significant prior trauma exposure. METHODS: In experiment 1, 72 youth with varying levels of disruptive behavior and trauma exposure performed a gender discrimination task while viewing morphed fear expressions (0, 50, 100, 150 fear) and Blood Oxygenation Level Dependent responses were recorded. In experiment 2, 66 of these youth performed the Social Goals Task, which measures self-reports of the importance of specific social goals to the participant in provoking social situations. RESULTS: In experiment 1, a significant CU traits-by-trauma exposure interaction was observed within right amygdala; fear intensity-modulated amygdala responses negatively predicted CU traits for those youth with low levels of trauma but positively predicted CU traits for those with high levels of trauma. In experiment 2, a bootstrapped model revealed that the indirect effect of fear intensity amygdala response on social goal importance through CU traits is moderated by prior trauma exposure. CONCLUSIONS: This study, while exploratory, indicates that the pathophysiology associated with CU traits differs in youth as a function of prior trauma exposure. These data suggest that prior trauma exposure should be considered when evaluating potential interventions for youth with high CU traits.

Neural correlates of conventional and harm/welfare-based moral decision-making.

The degree to which social norms are processed by a unitary system or dissociable systems remains debated. Much research on children's social-cognitive judgments has supported the distinction between "moral" (harm/welfare-based) and "conventional" norms. However, the extent to which these norms are processed by dissociable neural systems remains unclear. To address this issue, 23 healthy participants were scanned with functional magnetic resonance imaging (fMRI) while they rated the wrongness of harm/welfare-based and conventional transgressions and neutral vignettes. Activation significantly greater than the neutral vignette baseline was observed in regions implicated in decision-making regions including rostral/ventral medial frontal, anterior insula and dorsomedial frontal cortices when evaluating both harm/welfare-based and social-conventional transgressions. Greater activation when rating harm/welfare-based relative to social-conventional transgressions was seen through much of ACC and bilateral inferior frontal gyrus. Greater activation was observed in superior temporal gyrus, bilateral middle temporal gyrus, left PCC, and temporal-parietal junction when rating social-conventional transgressions relative to harm/welfare-based transgressions. These data suggest that decisions regarding the wrongness of actions, irrespective of whether they involve care/harm-based or conventional transgressions, recruit regions generally implicated in affect-based decision-making. However, there is neural differentiation between harm/welfare-based and conventional transgressions. This may reflect the particular importance of processing the intent of transgressors of conventional norms and perhaps the greater emotional content or salience of harm/welfare-based transgressions.

A neurocomputational investigation of reinforcement-based decision making as a candidate latent vulnerability mechanism in maltreated children.

Alterations in reinforcement-based decision making may be associated with increased psychiatric vulnerability in children who have experienced maltreatment. A probabilistic passive avoidance task and a model-based functional magnetic resonance imaging analytic approach were implemented to assess the neurocomputational components underlying decision making: (a) reinforcement expectancies (the representation of the outcomes associated with a stimulus) and (b) prediction error signaling (the ability to detect the differences between expected and actual outcomes). There were three main findings. First, the maltreated group (n = 18; mean age = 13), relative to nonmaltreated peers (n = 19; mean age = 13), showed decreased activity during expected value processing in a widespread network commonly associated with reinforcement expectancies representation, including the striatum (especially the caudate), the orbitofrontal cortex, and medial temporal structures including the hippocampus and insula. Second, consistent with previously reported hyperresponsiveness to negative cues in the context of childhood abuse, the maltreated group showed increased prediction error signaling in the middle cingulate gyrus, somatosensory cortex, superior temporal gyrus, and thalamus. Third, the maltreated group showed increased activity in frontodorsal regions and in the putamen during expected value representation. These findings suggest that early adverse environments disrupt the development of decision-making processes, which in turn may compromise psychosocial functioning in ways that increase latent vulnerability to psychiatric disorder.

Dysfunctional representation of expected value is associated with reinforcement-based decision-making deficits in adolescents with conduct problems.

BACKGROUND: Previous work has shown that patients with conduct problems (CP) show impairments in reinforcement-based decision-making. However, studies with patients have not previously demonstrated any relationships between impairment in any of the neurocomputations underpinning reinforcement-based decision-making and specific symptom sets [e.g. level of CP and/or callous-unemotional (CU) traits]. METHODS: Seventy-two youths [20 female, mean age = 13.81 (SD = 2.14), mean IQ = 102.34 (SD = 10.99)] from a residential treatment program and the community completed a passive avoidance task while undergoing functional MRI. RESULTS: Greater levels of CP were associated with poorer task performance. Reduced representation of expected values (EV) when making avoidance responses within bilateral anterior insula cortex/inferior frontal gyrus (AIC/iFG) and striatum was associated with greater levels of CP but not CU traits. CONCLUSIONS: The current data indicate that difficulties in the use of value information to motivate decisions to avoid suboptimal choices are associated with increased levels of CP (though not severity of CU traits). Moreover, they account for the behavioral deficits observed during reinforcement-based decision-making in youth with CP. In short, an individual's relative failure to utilize value information within AIC/iFG to avoid bad choices is associated with elevated levels of CP.

Type II1 factors satisfying the spatial isomorphism conjecture.

This paper addresses a conjecture in the work by Kadison and Kastler [Kadison RV, Kastler D (1972) Am J Math 94:38-54] that a von Neumann algebra M on a Hilbert space H should be unitarily equivalent to each sufficiently close von Neumann algebra N, and, moreover, the implementing unitary can be chosen to be close to the identity operator. This conjecture is known to be true for amenable von Neumann algebras, and in this paper, we describe classes of nonamenable factors for which the conjecture is valid. These classes are based on tensor products of the hyperfinite II(1) factor with crossed products of abelian algebras by suitably chosen discrete groups.

Punishing unfairness: rewarding or the organization of a reactively aggressive response?

OBJECTIVES: The neural correlates of human cooperative behavior remain poorly understood. Previous work has suggested that increases in striatal activation while punishing unfair offers represents reward signaling. However, other regions are also implicated when punishing others, for example dorsomedial frontal cortex (dmFC), anterior insula cortex (AIC), and periaqueductal gray (PAG). Moreover, the response of other regions implicated in signaling reward, for example ventromedial prefrontal cortex (vmPFC) or posterior cingulate cortex (PCC), has not been systematically examined. EXPERIMENTAL DESIGN: Functional magnetic resonance imaging utilizing parametric modulation was conducted on 21 healthy adults participating in a social exchange paradigm. PRINCIPAL OBSERVATIONS: Participants showed significant positive modulation of activity as a function of delivered punishment in caudate, dmFC, AIC, and PAG; that is, higher punishments by participants of unsatisfactory offers were associated with increasing activity within these regions. However, participants showed significant negative modulation of activity as a function of delivered punishment in vmPFC and PCC; increases in punishment level by participants were associated with decreases in activity within these regions. CONCLUSIONS: The current data question whether caudate activity when punishing unfair offers should be considered to indicate the reward value of this punishment. Instead, this activity, in conjunction with activity within dmFC, AIC, and PAG, may represent the organization of an untypical, punishing response that represents a reactive aggressive response to provocation. Notably, an inverse, regulatory relationship between vmPFC and PAG activity has been previously implicated in the context of another stimulus for reactive aggression; looming threat (Mobbs et al. [2007]: Science 317:1079-1083).

A retrospective, observational, single-centre, cohort database analysis of the haemodynamic effects of low-dose spinal anaesthesia for hip fracture surgery.

Background: Careful administration of either spinal (intrathecal) or general anaesthesia probably has a greater impact on outcomes after hip fracture surgery than which method is used per se. Intraoperative hypotension is associated with poorer outcomes, but appears less prevalent using lower doses of spinal anaesthesia. Methods: In this observational single-centre study, intraoperative noninvasive blood pressure data were analysed from 280 patients undergoing unilateral hip fracture surgery after the administration of hyperbaric spinal bupivacaine 0.5%, 1.3 ml (0.65 mg). Results: Mean cohort mean arterial pressure (MAP) remained within 10% of baseline (spinal injection) MAP for 97/98 (99.0%) subsequent aggregated 1-min recording intervals. The prevalences of lowest MAP <70 mm Hg and <55 mm Hg were significantly lower than historical equivalents (Anaesthesia Sprint Audit of Practice 1 and 2) (52.9% and 10.4% vs 71.9% and 23.8%, respectively, both <0.0001). The proportions of 10 551 MAP readings <70 mm Hg and <55 mm Hg were 6.7% and 0.4%, respectively. Forty-five (16.1%) patients had relatively persistent hypotension (MAP ≤70 mm Hg for five or more intraoperative readings), and were statistically more likely to be frail (Nottingham Hip Fracture Score ≥7/10, 37.8% vs 19.6%, P=0.0109) and be taking alpha-/beta-blockers (44.4% vs 24.3%, P=0.0099) than the remaining 'normotensive' cohort. Surgical anaesthesia remained effective for up to 190 min, with only one patient requiring supplemental local anaesthesia during skin closure. Conclusions: Low doses of hyperbaric spinal 0.5% bupivacaine (1.3 ml, 6.5 mg) are associated with minimal reductions in blood pressure during surgery and provide adequate duration of surgical anaesthesia. Randomised comparisons of lower vs higher/standard doses of spinal anaesthesia are now required to confirm outcome benefits in this vulnerable patient group. Clinical trial registration: NCT05799300.

Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement.

BACKGROUND: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation. METHODS: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. RESULTS: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri). CONCLUSIONS: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.