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.

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.

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.

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.

Changing role of the amygdala in affective and cognitive traits between early and late adulthood.

Introduction: Healthy aging is typically associated with cognitive decline and lower negative affect. Previous studies have reported a significant and opposite role of the amygdala in relation to cognitive and affective processing in early adulthood. However, it remains unclear how aging impacts such relationships. Methods: Seventy-seven healthy participants including 40 young (mean age = 26.1 years) and 37 older (mean age = 61.8 years) adults completed a functional MRI Affective Stroop (AS) paradigm, a cognitive battery, and the state-trait anxiety inventory. The AS fMRI paradigm included "task trials," where participants saw a positively, negatively or neutrally valenced distractor image, followed by a numerical display, followed by another distractor image. We extracted signal in both amygdalas during the AS Task and compared it across all conditions and age group. We further conducted moderation analyses to investigate the impact of aging on the relationship between amygdala activation and anxiety or cognitive variables, respectively. Results: At the behavioral level, older participants showed lower trait anxiety than the younger adults (p = 0.002). While overall slower during the AS task, older adults achieved comparable accuracy during the AS task, relative to the younger adults. At the brain level, we revealed a significant interaction between age group and trial types in amygdala activation (F = 4.9, p = 0.03), with the older group showing stronger activation during the most complex trials compared to the passive view trials. We further found that age significantly modulated the relationship between anxiety and the left amygdala activation during negative stimuli, where the younger adults showed a positive association while the older adults showed a negative association. Age also significantly modulated the relationship between verbal fluency and left amygdala activation during incongruent versus view trials, with the younger adults showing a negative association and the older adults showing a positive association. Discussion: The current study suggests that the role of the amygdala on both emotional processing and cognitive traits changes between early and late adulthood.

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.

Assessing the relationship between maternal risk for attention deficit hyperactivity disorder and functional connectivity in their biological toddlers.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with increased risk for poor educational attainment and compromised social integration. Currently, clinical diagnosis rarely occurs before school-age, despite behavioral signs of ADHD in very early childhood. There is no known brain biomarker for ADHD risk in children ages 2-3 years-old. METHODS: The current study aimed to investigate the functional connectivity (FC) associated with ADHD risk in 70 children aged 2.5 and 3.5 years via functional near-infrared spectroscopy (fNIRS) in bilateral frontal and parietal cortices; regions involved in attentional and goal-directed cognition. Children were instructed to passively watch videos for approximately 5 min. Risk for ADHD in each child was assessed via maternal symptoms of ADHD, and brain data was evaluated for FC. RESULTS: Higher risk for maternal ADHD was associated with lower FC in a left-sided parieto-frontal network. Further, the interaction between sex and risk for ADHD was significant, where FC reduction in a widespread bilateral parieto-frontal network was associated with higher risk in male, but not female, participants. CONCLUSIONS: These findings suggest functional organization differences in the parietal-frontal network in toddlers at risk for ADHD; potentially advancing the understanding of the neural mechanisms underlying the development of ADHD.

Increases in Circulating Cortisol during the COVID-19 Pandemic are Associated with Changes in Perceived Positive and Negative Affect among Adolescents.

The Coronavirus Disease 2019 (COVID-19) pandemic has spread across the world and resulted in over 5 million deaths to date, as well as countless lockdowns, disruptions to daily life, and extended period of social distancing and isolation. The impacts on youth in particular are astounding, with shifts in learning platforms, limited social outlets, and prolonged uncertainty about the future. Surveys have shown that mental health among youth has severely suffered during the pandemic. However, limited research to date has reported on physiological indices of stress surrounding the pandemic, such as cortisol. Cortisol is a stress hormone that typically increases during stressful situations and can have deleterious effects on mental and physical health when chronically heightened. The present study leveraged hair cortisol concentration measurements, which allowed the retrospectiveinvestigation of circulating cortisol prior to- versus after pandemic-related local lockdowns during the first wave of the pandemic. A final sample of 44 youth ages 10- to 18-years-old provided hair samples and reported on their perceived affective well-being and level of concern regarding pandemic-related stressors between May and June of 2020. We found significant levels of concern and decreases in affective well-being following local lockdowns. Moreover, we saw that cortisol robustly increased following local lockdowns, and those increases were predictive of changes in affect. These findings provide critical insights into the underlying neuroendocrinology of stress during the pandemic and support the need for resources to support youths' mental health and well-being during this globally significant event.

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.

Raging Hormones: Why Age-Based Etiological Conceptualizations of the Development of Antisocial Behavior Are Insufficient.

Developmental science, particularly developmental neuroscience, has substantially influenced the modern legal system. However, this science has typically failed to consider the role of puberty and pubertal hormones on development when considering antisocial behavior. This review describes major theoretical positions on the developmental neuroscience of antisocial behavior and highlights where basic developmental neuroscience suggests that the role of puberty and pubertal hormones should be considered. The implications of the current state of the science with respect to developmental neuroscience is considered, particularly what is known in light of development beyond puberty. This review shows that development continues to an older age for many youth than the legal system typically acknowledges. The plasticity of the brain that this continued development implies has implications for the outcome of interventions in the legal system in ways that have not been explored. Future directions for both developmental scientists and legal professions are recommended.

Editorial: The Importance of Considering Multiple Factors Simultaneously to Advance Psychopathology Research.

Recent advances in scientific techniques, particularly in psychoneuroendocrinology and functional neuroimaging, have made it clear that clinically significant antisocial behavior, such as that seen in conduct disorder, cannot be understood without reference to multiple biological systems.1 However, the additional complexity arising from the interaction between the multiple biological systems implicated in conduct disorder has not typically been reflected in the complexity of experimental designs. Most often, studies examine only one system or subsystem at a time. Furthermore, the majority of studies of conduct disorder have not included female participants, have included few female participants, and/or have not explicitly considered biological sex in analytic strategies.2 Particularly in the context of endocrinological functioning, biological sex is an important but understudied biological variable.3 Greater complexity in experimental design, incorporating data from different biological systems, and factoring in important variables such as sex will be needed moving forward to adequately model data from all of the relevant levels of analysis. This is true with respect not just to conduct disorder but to all psychopathology. The paper by Bernhard et al4 published in this issue is an excellent example of the types of studies that are required to grapple with the complexity of any psychiatric illness. Their study is notable for its examination of multiple endocrine systems simultaneously and for adequately incorporating biological sex as a variable into the study.

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.

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.

Increases in Stressors Prior to-Versus During the COVID-19 Pandemic in the United States Are Associated With Depression Among Middle-Aged Mothers.

Working parents in are struggling to balance the demands of their occupation with those of childcare and homeschooling during the COVID-19 pandemic. Moreover, studies show that women are shouldering more of the burden and reporting greater levels of psychological distress, anxiety, and depression relative to men. However, research has yet to show that increases in psychological symptoms are linked to changes in stress during the pandemic. Herein, we conduct a small-N study to explore the associations between stress and psychological symptoms during the pandemic among mothers using structural equation modeling, namely latent change score models. Thirty-three mothers completed questionnaires reporting current anxious and depressive symptoms (Beck Anxiety and Depression Index, respectively), as well as stressful life experiences prior to-versus during the pandemic (Social Readjustment Rating Scale). Women endorsed significantly more stressful events during the pandemic, relative to the pre-pandemic period. Additionally, 58% of mothers scored as moderate-to-high risk for developing a stress-related physical illness in the near future because of their pandemic-level stress. Depressive symptoms were associated with the degree of change in life stress, whereas anxiety symptoms were more related to pre-pandemic levels of stress. The present study preliminarily sheds light on the nuanced antecedents to mothers' experiences of anxious and depressive symptoms during the COVID-19 pandemic. Although further work is needed in larger, more diverse samples of mothers, this study highlights the potential need for appropriate policies, and prevention and intervention programs to ameliorate the effects of pandemics on mothers' mental health.

Lower neural value signaling in the prefrontal cortex is related to childhood family income and depressive symptomatology during adolescence.

Lower family income during childhood is related to increased rates of adolescent depression, though the underlying mechanisms are poorly understood. Evidence suggests that individuals with depression demonstrate hypoactivation in brain regions involved in reward learning and decision-making processes (e.g., portions of the prefrontal cortex). Separately, lower family income has been associated with neural alterations in similar regions. Motivated by this research, we examined associations between family income, depression, and brain activity during a reward learning and decision-making fMRI task in a sample of adolescents (full n = 94; usable n = 78; mean age = 15.2 years). We focused on brain activity for: 1) expected value (EV), the learned subjective value of an object, and 2) prediction error, the difference between EV and the actual outcome received. Regions of interest related to reward learning were examined in connection to childhood family income and parent-reported adolescent depressive symptoms. As hypothesized, lower activity in the subgenual anterior cingulate (sACC) for EV in response to approach stimuli was associated with lower childhood family income, as well as greater symptoms of depression measured one-year after the neuroimaging session. These results are consistent with the hypothesis that lower early family income leads to disruptions in reward and decision-making brain circuitry, contributing to adolescent depression.

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.

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.

Association of Inflammatory Activity With Larger Neural Responses to Threat and Reward Among Children Living in Poverty.

OBJECTIVE: Children exposed to severe, chronic stress are vulnerable to mental and physical health problems across the lifespan. To explain how these problems develop, the neuroimmune network hypothesis suggests that early-life stress initiates a positive feedback loop between peripheral inflammatory cells and networked brain regions involved in threat and reward processing. The authors sought to test this hypothesis by studying a sample of urban children from diverse socioeconomic backgrounds. METHODS: The authors examined the basic predictions of the neuroimmune network hypothesis in 207 children (mean age=13.9 years, 63% female; 33% Black; 30% Hispanic), focusing on poverty as a stressor. The children had fasting blood drawn to quantify five inflammatory biomarkers-C-reactive protein, tumor necrosis factor-α, and interleukins-6, -8, and -10-which were averaged to form a composite score. Children also completed two functional MRI tasks, which measured amygdala responsivity to angry facial expressions and ventral striatum responsivity to monetary rewards. RESULTS: Poverty status and neural responsivity interacted statistically to predict inflammation. Among children living in poverty, amygdala threat responsivity was positively associated with inflammation, and the same was true for ventral striatum responsivity to reward. As children's socioeconomic conditions improved, these brain-immune associations became weaker. In sensitivity analyses, these patterns were robust to alternative measures of socioeconomic status and were independent of age, sex, racial and ethnic identity, and pubertal status. The associations were also condition specific; no interactions were apparent for amygdala responsivity to neutral faces, or striatal responsivity to monetary losses. CONCLUSIONS: These findings suggest that childhood poverty is associated with accentuated neural-immune signaling, consistent with the neuroimmune network hypothesis.