Structural alterations within cerebellar circuitry are associated with general liability for common mental disorders.

Accumulating mental-health research encourages a shift in focus toward transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology-sometimes called the 'p factor'- that underlies shared risk for a wide range of mental disorders. Identifying neural correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the 'p factor' contributes to risk. Here we believe we first replicate the 'p factor' using cross-sectional data from a volunteer sample of 1246 university students, and then using high-resolution multimodal structural neuroimaging, we demonstrate that individuals with higher 'p factor' scores show reduced structural integrity of white matter pathways, as indexed by lower fractional anisotropy values, uniquely within the pons. Whole-brain analyses further revealed that higher 'p factor' scores are associated with reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, we observed a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher 'p factor' scores. The results of our analyses provide initial evidence that structural alterations in corticocerebellar circuitry supporting core functions related to the basic integration, coordination and monitoring of information may contribute to a general liability for common mental disorders.

Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

The association between cognitive function and subsequent depression: a systematic review and meta-analysis.

Despite a growing interest in understanding the cognitive deficits associated with major depressive disorder (MDD), it is largely unknown whether such deficits exist before disorder onset or how they might influence the severity of subsequent illness. The purpose of the present study was to conduct a systematic review and meta-analysis of longitudinal datasets to determine whether cognitive function acts as a predictor of later MDD diagnosis or change in depression symptoms. Eligible studies included longitudinal designs with baseline measures of cognitive functioning, and later unipolar MDD diagnosis or symptom assessment. The systematic review identified 29 publications, representing 34 unique samples, and 121 749 participants, that met the inclusion/exclusion criteria. Quantitative meta-analysis demonstrated that higher cognitive function was associated with decreased levels of subsequent depression (r = -0.088, 95% confidence interval. -0.121 to -0.054, p < 0.001). However, sensitivity analyses revealed that this association is likely driven by concurrent depression symptoms at the time of cognitive assessment. Our review and meta-analysis indicate that the association between lower cognitive function and later depression is confounded by the presence of contemporaneous depression symptoms at the time of cognitive assessment. Thus, cognitive deficits predicting MDD likely represent deleterious effects of subclinical depression symptoms on performance rather than premorbid risk factors for disorder.

Divergent responses of the amygdala and ventral striatum predict stress-related problem drinking in young adults: possible differential markers of affective and impulsive pathways of risk for alcohol use disorder.

Prior work suggests that there may be two distinct pathways of alcohol use disorder (AUD) risk: one associated with positive emotion enhancement and behavioral impulsivity, and another associated with negative emotion relief and coping. We sought to map these two pathways onto individual differences in neural reward and threat processing assessed using blood-oxygen-level-dependent functional magnetic resonance imaging in a sample of 759 undergraduate students (426 women, mean age 19.65±1.24 years) participating in the Duke Neurogenetics Study. We demonstrate that problem drinking is highest in the context of stress and in those with one of two distinct neural phenotypes: (1) a combination of relatively low reward-related activity of the ventral striatum (VS) and high threat-related reactivity of the amygdala; or (2) a combination of relatively high VS activity and low amygdala reactivity. In addition, we demonstrate that the relationship between stress and problem alcohol use is mediated by impulsivity, as reflected in monetary delay discounting rates, for those with high VS-low amygdala reactivity, and by anxious/depressive symptomatology for those with the opposite neural risk phenotype. Across both neural phenotypes, we found that greater divergence between VS and amygdala reactivity predicted greater risk for problem drinking. Finally, for those individuals with the low VS-high amygdala risk phenotype we found that stress not only predicted the presence of AUD diagnosis at the time of neuroimaging but also subsequent problem drinking reported 3 months following study completion. These results offer new insight into the neural basis of AUD risk and suggest novel biological targets for early individualized treatment or prevention.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology.

BACKGROUND: Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. METHOD: Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. RESULTS: Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. CONCLUSIONS: These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

Study of spectral linewidth in Ne-like Se x-ray laser.

Based on the modeling of the geometrically dependent gain coefficient (GDGC) and rate equations, this theoretical study explains the spectral linewidth behavior in an Se x-ray laser operating at 206.4 Å. The study used the reported experimental measurements for an Se target of 6.3 cm in length for the analysis. To obtain a finite value for the amplified spontaneous emission (ASE) intrinsic linewidth that initiates at the threshold length, we subtracted the ASE intensity background from the calculated ASE intensity to derive the corresponding FWHM. For homogeneously and Doppler broadened linewidths of 14 mÅ and 36 mÅ, we calculated the ASE Voigt profile linewidth to be 44 mÅ, initiated at the threshold length of 0.13 cm. The interaction is rather insensitive to the collision broadening; for the homogeneously broadened linewidth up to 21 mÅ, we could still explain the linewidth measurements. In this case, we calculated the related Voigt profile linewidth to be 48.5 mÅ. The current GDGC modeling approach greatly simplified the ASE analyses of these lasers.

A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology.

Neurogenetics research has begun to advance our understanding of how genetic variation gives rise to individual differences in brain function, which, in turn, shapes behavior and risk for psychopathology. Despite these advancements, neurogenetics research is currently confronted by three major challenges: (1) conducting research on individual variables with small effects, (2) absence of detailed mechanisms, and (3) a need to translate findings toward greater clinical relevance. In this review, we showcase techniques and developments that address these challenges and highlight the benefits of a neurogenetics approach to understanding brain, behavior and psychopathology. To address the challenge of small effects, we explore approaches including incorporating the environment, modeling epistatic relationships and using multilocus profiles. To address the challenge of mechanism, we explore how non-human animal research, epigenetics research and genome-wide association studies can inform our mechanistic understanding of behaviorally relevant brain function. Finally, to address the challenge of clinical relevance, we examine how neurogenetics research can identify novel therapeutic targets and for whom treatments work best. By addressing these challenges, neurogenetics research is poised to exponentially increase our understanding of how genetic variation interacts with the environment to shape the brain, behavior and risk for psychopathology.

Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity.

Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.

Healing patient, harming planet? A drive towards sustainable surgery: review of waste production and recyclability of surgical instrument packaging.

INTRODUCTION: Healthcare contributes more than 1% of all domestic waste in the United Kingdom (UK), with operating theatre waste alone accounting for approximately 50% of all hospital waste. In November 2022, the UK Surgical Royal Colleges issued an Intercollegiate Climate Emergency Declaration and called for urgent action. We review waste production and the recyclability of surgical instrument packaging used in a common ear, nose and throat procedure (thyroidectomy) and suggest strategies to make this surgery more sustainable,. These strategies can be generalised to other surgeries. METHODS: We prospectively audited packaging waste from 20 thyroidectomies performed at the Royal Marsden Hospital in the UK between July and December 2022. All packaging was weighed, categorised and analysed after the operation. RESULTS: On average, each thyroidectomy produced packaging waste comprising 183g (34%) of plain paper/cardboard, 167g (31%) of soft plastic film, 142g (26%) of laminated paper, 37g (7%) of hard plastic and 11g (2%) of metal foil. Of all the packaging collected, only one item had a recycling label. When extrapolated to the 7,851 thyroidectomies performed in the National Health Service during the fiscal year 2021/2022, the estimated total weight of packaging waste would be 4.2 tonnes, of which only 31.4kg would be indicated as recyclable. When converted to an estimated carbon footprint, total carbon emissions would be 1,048kg CO2e, equivalent to three round trips from London to Edinburgh in a petrol car. CONCLUSION: This audit demonstrates the different categories and vast amount of packaging waste from a common operation. Manufacturers should place clear recyclability labels on packaging, and switch to recyclable materials and a digital information booklet where possible. Local waste audit and analysis can be simple first steps towards making surgery more sustainable.

Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients.

Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.

Impact of COVID-19 pandemic on head-neck cancer referral and treatment pathway in North East London.

INTRODUCTION: The COVID-19 pandemic has led to wide-ranging disruption of head-neck cancer (HNC) service provision in the UK. Early reports suggest delays in referral, diagnosis and initiation of treatment for new cancer cases compared with before the pandemic. METHODS: The HNC service was studied retrospectively for the time-periods between 1 January 2020 to 31 October 2020 (hereafter 'post-COVID') and 1 January 2019 to 31 October 2019 (hereafter 'pre-COVID'). We analysed: (1) the number of cases treated at our centre, (2) stage of disease at presentation and (3) treatment delivery times. RESULTS: In the post-COVID period, the total number of HNC cases treated decreased (48 vs 56 pre-COVID). There was increase in advanced stage at presentation (58% vs 42% pre-COVID) and a significant increase in the need for airway stabilisation (13 vs 5 pre-COVID; p=0.03). Average time from referral to treatment was significantly prolonged (72.5 days vs 49.23 days pre-COVID; p=0.03). Two-week wait referrals were seen in HNC clinics at median time of 11.9 days, compared with 7.1 days during the pre-COVID period (p=0.07). However, there was no delay in the initiation of first treatment after the decision to treat (29.2 days vs 24.7 days pre-COVID; p=0.58). CONCLUSION: The results of this study call for early referral at the primary care level and rapid radiopathological confirmation at the tertiary level to prevent delays in diagnosis of new HNC cases.

Rethinking the 'one-stop' neck lump clinic: a novel pathway beyond coronavirus disease 2019.

OBJECTIVES: UK guidelines advocate 'one-stop' neck lump assessment for cancer referrals. This paper reports the pilot of a novel pre-clinic ultrasound pathway, presents outcomes, and discusses strengths and limitations in the context of the coronavirus disease 2019 pandemic. METHODS: Two-week-wait cancer referral patients with a neck lump were allocated a pre-clinic ultrasound scan followed by a clinic appointment. Demographic, patient journey and outcome data were collected and analysed. RESULTS: Ninety-nine patients underwent ultrasound assessment with or without biopsy on average 8 days following referral. Patients were followed up on average 14.1 days (range, 2-26 days) after initial referral. At the first clinic appointment, 45 patients were discharged, 10 were scheduled for surgery, 12 were diagnosed with cancer, 6 were referred to another specialty and cancer was excluded in 19 patients. Retrospectively, four ultrasounds were performed unnecessarily. CONCLUSION: Pre-clinic ultrasound scanning is an alternative to the one-stop neck lump pathway. This study demonstrates fewer clinic visits, faster diagnosis and a low proportion of unnecessary scans, whilst minimising face-to-face consultations and aerosol-generating procedures.

Theoretical application of z-dependent gain coefficient to describe amplified spontaneous emission.

Based on the geometrical modeling of the unified gain coefficient and the reported amplified spontaneous emission (ASE) output energy measurement ε(ASE) versus amplifying excitation length, l(AMP) in a KrF laser oscillator, we managed, as an example, to explain the ASE output energy behavior both numerically and analytically. In this approach, introducing the ASE gain-coefficient profile for the KrF laser, g(0,KrF)(ASE), was not avoidable. It was found that while the g(0,KrF)(ASE) profile follows the introduced gain-modeling formulation, it is, however, slightly lower than the KrF laser gain profile, g(0,KrF)(exp), deduced from the measurements reported by different researchers. The present approach, up to the present time, is able to explain all of the existing ambiguities on understanding the ASE behavior.

Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission.

A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.

Obstructive Sleep Apnea in Obese Patients: a UK Population Analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is an increasingly common disorder associated with increased cardiovascular disease, mortality, reduced productivity, and an increased risk of road traffic accidents. A significant proportion of patients with OSA in the UK are undiagnosed. This study aims to identify risk factors for OSA in an obese cohort. METHOD: A population-based study was conducted of obese patients (BMI ≥ 30 kg/m2) from the Clinical Practice Research Datalink (CPRD). A logistic regression model was used to calculate odds ratios (ORs) for developing OSA according to other clinicopathological characteristics. Multivariate analysis was conducted of individual factors that affect the propensity to develop OSA. Statistical significance was defined as p < 0.050. RESULTS: From 276,600 obese patients identified during a data extraction of the CPRD in July 2017, the prevalence of OSA was 5.4%. The following risk factors were found to be independently associated with increased likelihood of OSA: male sex (OR = 3.273; p < 0.001), BMI class II (OR = 1.640; p < 0.001), BMI class III (OR = 3.768; p < 0.001), smoking (OR = 1.179; p < 0.001), COPD (OR = 1.722; p < 0.001), GERD (OR = 1.557; p < 0.001), hypothyroidism (OR = 1.311; p < 0.001), acromegaly (OR = 3.543; p < 0.001), and benzodiazepine use (OR = 1.492; p < 0.001). Bariatric surgery was associated with reduced risk of OSA amongst this obese population (OR = 0.260; p < 0.001). CONCLUSIONS: In obese patients, there are numerous comorbidities that are associated with increased likelihood of OSA. These factors can help prompt clinicians to identify undiagnosed OSA. Bariatric surgery appears to be protective against developing OSA.

Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity.

Individual differences in traits such as impulsivity involve high reward sensitivity and are associated with risk for substance use disorders. The ventral striatum (VS) has been widely implicated in reward processing, and individual differences in its function are linked to these disorders. Dopamine (DA) plays a critical role in reward processing and is a potent neuromodulator of VS reactivity. Moreover, altered DA signaling has been associated with normal and pathological reward-related behaviors. Functional polymorphisms in DA-related genes represent an important source of variability in DA function that may subsequently impact VS reactivity and associated reward-related behaviors. Using an imaging genetics approach, we examined the modulatory effects of common, putatively functional DA-related polymorphisms on reward-related VS reactivity associated with self-reported impulsivity. Genetic variants associated with relatively increased striatal DA release (DRD2 -141C deletion) and availability (DAT1 9-repeat), as well as diminished inhibitory postsynaptic DA effects (DRD2 -141C deletion and DRD4 7-repeat), predicted 9-12% of the interindividual variability in reward-related VS reactivity. In contrast, genetic variation directly affecting DA signaling only in the prefrontal cortex (COMT Val158Met) was not associated with variability in VS reactivity. Our results highlight an important role for genetic polymorphisms affecting striatal DA neurotransmission in mediating interindividual differences in reward-related VS reactivity. They further suggest that altered VS reactivity may represent a key neurobiological pathway through which these polymorphisms contribute to variability in behavioral impulsivity and related risk for substance use disorders.

Capacity for 5-HT1A-mediated autoregulation predicts amygdala reactivity.

We examined the contribution of 5-HT1A autoreceptors (with [11C]WAY100635 positron emission tomography) to amygdala reactivity (with blood oxygenation level-dependent functional magnetic resonance imaging) in 20 healthy adult volunteers. We found a significant inverse relationship wherein 5-HT1A autoreceptor density predicted a notable 30-44% of the variability in amygdala reactivity. Our data suggest a potential molecular mechanism by which a reduced capacity for negative feedback regulation of 5-HT release is associated with increased amygdala reactivity.