Exploring HD-tDCS Effect on µ-opioid Receptor and Pain Sensitivity in Temporomandibular Disorder: A Pilot Randomized Clinical Trial Study.

This study explored the association between experimentally-induced pain sensitivity and µ-opioid receptor (µOR) availability in patients with temporomandibular disorder (TMD) and further investigated any changes in the pain and µOR availability following high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) with pilot randomized clinical trials. Seven patients with TMD completed either active (n = 3) or sham treatment (n = 4) for 10 daily sessions and underwent positron emission tomography (PET) scans with [11C]carfentanil, a selective µOR agonist, a week before and after treatment. PET imaging consisted of an early resting and late phase with the sustained masseteric pain challenge by computer-controlled injection of 5% hypertonic saline. We also included 12 patients with TMD, obtained from our previous study, for baseline PET analysis. We observed that patients with more sensitivity to pain, indicated by lower infusion rate, had less µOR availability in the right amygdala during the late phase. Moreover, active M1 HD-tDCS, compared to sham, increased µOR availability post-treatment in the thalamus during the early resting phase and the amygdala, hippocampus, and parahippocampal gyrus during the late pain challenge phase. Importantly, increased µOR availability post-treatment in limbic structures including the amygdala and hippocampus was associated with decreased pain sensitivity. The findings underscore the role of the µOR system in pain regulation and the therapeutic potential of HD-tDCS for TMD. Nonetheless, large-scale studies are necessary to establish the clinical significance of these results. TRIAL REGISTRATION: ClinicalTrial.gov (NCT03724032) PERSPECTIVE: This study links pain sensitivity and µ-opioid receptors in patients with TMD. HD-tDCS over M1 improved µOR availability, which was associated with reduced pain sensitivity. Implications for TMD pain management are promising, but larger clinical trials are essential for validation.

Rapid, green disulphide bond formation in water using the corrin dicyanocobinamide.

Peptide chemists seek rapid methods combined with facile purification when producing disulphide bonds post solid-phase synthesis. Current methods typically require long reaction times of up to two days, can result in side-products from over-oxidation and/or degradation, require organic solvents, and/or require challenging purification. Herein, we describe a rapid, green, and facile oxidation of a series of peptides with up to three disulphide bonds. The method was conducted in aqueous solution, in air, utilizing the biocompatible corrin ring-containing compound dicyanocobinamide, and offers reaction times under 1 hour with simple one step removal of the catalyst.

Effect of High-Definition Transcranial Direct Current Stimulation on Headache Severity and Central µ-Opioid Receptor Availability in Episodic Migraine.

Objective: The current understanding of utilizing HD-tDCS as a targeted approach to improve headache attacks and modulate endogenous opioid systems in episodic migraine is relatively limited. This study aimed to determine whether high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) can improve clinical outcomes and endogenous µ-opioid receptor (µOR) availability for episodic migraineurs. Methods: In a randomized, double-blind, and sham-controlled trial, 25 patients completed 10-daily 20-min M1 HD-tDCS, repeated Positron Emission Tomography (PET) scans with a selective agonist for µOR. Twelve age- and sex-matched healthy controls participated in the baseline PET/MRI scan without neuromodulation. The primary endpoints were moderate-to-severe (M/S) headache days and responder rate (≥50% reduction on M/S headache days from baseline), and secondary endpoints included the presence of M/S headache intensity and the use of rescue medication over 1-month after treatment. Results: In a one-month follow-up, at initial analysis, both the active and sham groups exhibited no significant differences in their primary outcomes (M/S headache days and responder rates). Similarly, secondary outcomes (M/S headache intensity and the usage of rescue medication) also revealed no significant differences between the two groups. However, subsequent analyses showed that active M1 HD-tDCS, compared to sham, resulted in a more beneficial response predominantly in higher-frequency individuals (>3 attacks/month), as demonstrated by the interaction between treatment indicator and baseline frequency of migraine attacks on the primary outcomes. These favorable outcomes were also confirmed for the secondary endpoints in higher-frequency patients. Active treatment also resulted in increased µOR concentration compared to sham in the limbic and descending pain modulatory pathway. Our exploratory mediation analysis suggests that the observed clinical efficacy of HD-tDCS in patients with higher-frequency conditions might be potentially mediated through an increase in µOR availability. Conclusion: The 10-daily M1 HD-tDCS can improve clinical outcomes in episodic migraineurs with a higher baseline frequency of migraine attacks (>3 attacks/month). This improvement may be, in part, facilitated by the increase in the endogenous µOR availability. Clinical Trial Registration: www.ClinicalTrials.gov, identifier - NCT02964741.

Altered Reward Processing and Sex Differences in Chronic Pain.

Chronic pain and reward processing are understood to be reciprocally related to one another. Previous studies of reward processing in chronic pain patients have reported incongruent findings. While several factors likely contribute to these disparate findings, these previous studies did not stratify their analyses by sex-a factor previously shown to robustly impact reward-related responses. Thus, we examined sex as a factor of interest in level of striatal activation during anticipation of monetary incentives among patients with chronic non-specific back pain and healthy controls (HC). This study utilized functional magnetic resonance imaging during a monetary incentive delay task to evaluate reward and loss responsivity in the striatum among males and females with and without chronic pain (N = 90). Group, sex, and group-by-sex interactions were analyzed via repeated measures analysis of variance. Among HC, males exhibited significantly greater blood oxygen level dependent (BOLD) signal in the striatum during reward anticipation, particularly during large reward trials. By contrast, no significant sex differences were observed among patients. A significant group-by-sex interaction was also observed, revealing diminished BOLD responses among males with chronic pain relative to control males. These results provide novel evidence of sex-specific reductions in anticipatory responses to reward in patients with chronic pain. Altered striatal reward responsivity among males, but not females, suggests that the reward systems of males and females are uniquely disrupted by chronic pain, and highlights the value of including sex as a factor of interest in future studies of reward responsivity in the context of persistent pain.

Unique and joint associations of polygenic risk for major depression and opioid use disorder with endogenous opioid system function.

Major depressive disorder (MDD) and opioid use disorder (OUD) are common, potentially fatal, polygenic disorders that are moderately heritable and often co-occur. We examined the unique and shared associations of polygenic risk scores (PRS) for these disorders with µ-opioid receptor (MOR) concentration and endogenous opioid response during a stressful stimulus. Participants were 144 healthy European-ancestry (EA) subjects (88 females) who underwent MOR quantification scans with [11C]carfentanil and PET and provided DNA for genotyping. MOR non-displaceable binding potential (BPND) was measured in 5 regions of interest (ROIs) related to mood and addiction. We examined associations of PRS both at baseline and following opioid release calculated as the ratio of baseline and stress-challenge scans, first in the entire sample and then separately by sex. MOR availability at baseline was positively associated with MDD PRS in the amygdala and ventral pallidum. MDD and OUD PRS were significantly associated with stress-induced opioid system activation in multiple ROIs, accounting for up to 14.5% and 5.4%, respectively, of the variance in regional activation. The associations were most robust among females, where combined they accounted for up to 25.0% of the variance among the ROIs. We conclude that there is a pathophysiologic link between polygenic risk for MDD and OUD and opioid system activity, as evidenced by PRS with unique and overlapping regional associations with this neurotransmitter system. This link could help to explain the high rate of comorbidity of MDD and OUD and suggests that opioid-modulating interventions could be useful in treating MDD and OUD, both individually and jointly.

Photocatalytic turnover of CO2 under visible light by [Re(CO)3(1-(1,10) phenanthroline-5-(4-nitro-naphthalimide))Cl] in tandem with the sacrificial donor BIH.

Optimized photocatalytic conversion of CO2 requires new potent catalysts that can absorb visible light. The photocatalytic reduction of CO2 using rhenium(i) has been demonstrated but suffers from low turnover. Herein, we describe a [Re(CO)3(1-(1,10)phenanthroline-5-(4-nitro-naphthalimide))Cl] photocatalyst, which when combined with the sacrificial donor 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole, results in selective production of formic acid and a high turnover number of 533 and turnover frequency of 356 h-1. Single-crystal X-ray diffraction and DFT studies are also discussed.

Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation.

µ-Opioid receptors (MOR) are a major target of endogenous and exogenous opioids, including opioid pain medications. The µ-opioid neurotransmitter system is heavily implicated in the pathophysiology of chronic pain and opioid use disorder and, as such, central measures of µ-opioid system functioning are increasingly being considered as putative biomarkers for risk to misuse opioids. To explore the relationship between MOR system function and risk for opioid misuse, 28 subjects with chronic nonspecific back pain completed a clinically validated measure of opioid misuse risk, the Pain Medication Questionnaire (PMQ), and were subsequently separated into high (PMQ > 21) and low (PMQ ≤ 21) opioid misuse risk groups. Chronic pain patients along with 15 control participants underwent two separate [11C]-carfentanil positron emission tomography scans to explore MOR functional measures: one at baseline and one during a sustained pain-stress challenge, with the difference between the two providing an indirect measure of stress-induced endogenous opioid release. We found that chronic pain participants at high risk for opioid misuse displayed higher baseline MOR availability within the right amygdala relative to those at low risk. By contrast, patients at low risk for opioid misuse showed less pain-induced activation of MOR-mediated, endogenous opioid neurotransmission in the nucleus accumbens. This study links human in vivo MOR system functional measures to the development of addictive disorders and provides novel evidence that MORs and µ-opioid system responsivity may underlie risk to misuse opioids among chronic pain patients.

Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission.

Behavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain µ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed 37 healthy human volunteers to a standardized pain challenge on each of 2 days within a Positron Emission Tomography (PET) neuroimaging paradigm using the MOR selective radiotracer, 11C-Carfentanil (CFN). Each day volunteers received an intervention (placebo under analgesic expectation or no treatment), completed PET scanning, and rated their pain experience. MOR BPND parametric maps were generated from PET scans using standard methods. Results showed placebo reduced plasma IL-18 during pain (W74 = -3.7, p < 0.001), the extent correlating with reduction in pain scores. Placebo reduction in IL-18 covaried with placebo-induced endogenous opioid release in the left nucleus accumbens (T148 = 3.33; puncorr < 0.001) and left amygdala (T148 = 3.30; puncorr < 0.001). These findings are consistent with a modulating effect of placebo (under analgesic expectation in humans) on a potent nociceptive, pro-inflammatory cytokine (IL-18) and underlying relationships with endogenous opioid activity, a neurotransmitter system critically involved in pain, stress, and mood regulation.

Synthesis, Characterization, and Cellular Uptake of a Glycylglycine Chelate of Magnesium.

Human chronic latent magnesium deficiency is estimated to impact a substantive portion of the world's population. A number of magnesium compounds have been developed to combat this deficiency; however, none are ideal due to issues of solubility, absorption, side effects (e.g., laxation) and/or formulation. Here, we describe the pH-dependent synthesis, chemical characterization (inductively coupled plasma and thermal analysis, infrared and nuclear magnetic resonance (1D and 2D) spectroscopies, and electrospray mass spectrometry) and in vitro uptake (in a cell model of the large intestine (CaCo-2 cells)) of a magnesium complex of the glycine dimer (HG2). Results demonstrate that the HG2 ligand assumes a tridentate coordination mode with an N2O donor set and an octahedral coordination sphere completed with coordinated waters. The magnesium:HG2 complex exhibits significant solubility and cellular uptake.

Synthesis, Characterization, and Cellular Uptake of Magnesium Maltol and Ethylmaltol Complexes.

Magnesium deficiency and/or deficit (hypomagnesemia, <0.75 mmol/L in the blood) has become a recognized problem in healthcare and clinical settings. Concomitantly, supplementation has become recognized as the primary means of mitigating such deficiencies. Common magnesium supplements typically suffer from shortcomings: rapid dissociation and subsequent laxation (magnesium salts: e.g., magnesium chloride), poor water solubility (magnesium oxides and hydroxides), poor characterizability (magnesium chelates), and are/or use of non-natural ligands. To this end, there is a need for the development of fully characterized, water-soluble, all-natural magnesium compounds. Herein, we discuss the synthesis, solution and solid-state characterization, aqueous solubility, and cellular uptake of magnesium complexes of maltol and ethylmaltol, ligands whose magnesium complexes have yet to be fully explored.

Synthesis and Chemical and Biological Evaluation of a Glycine Tripeptide Chelate of Magnesium.

Magnesium (Mg2+) plays a crucial role in over 80% of all metabolic functions. It is becoming increasingly apparent that magnesium deficiency (hypomagnesemia) may play an important role in chronic disease. To counteract magnesium deficiency, there is an unmet clinical need to develop new fully characterized, highly bioavailable, and substantially water-soluble magnesium supplements. To this end, triglycine (HG3), a tripeptide of the amino acid glycine, was chosen as a chelating ligand for magnesium, given its natural occurrence and water solubility, and entropically-driven metal binding. Herein, we discuss the synthesis, chemical and physical characterization, and cellular uptake of a magnesium triglycine chelate (MgG3), an octahedral complex with extraordinary water solubility and improved cellular uptake in CaCo-2 cells than select commonly used magnesium supplements.

[Re(CO)3(5-PAN)Cl], a rhenium(I) naphthalimide complex for the visible light photocatalytic reduction of CO2.

A rhenium(i) naphthalimide complex [Re(CO)3(5-PAN)Cl] (Re(5-PAN); 5-PAN = 1-(1,10-phenanthroline)-4-nitro-naphthalimide) was synthesized, characterized, and evaluated as a photocatalyst for CO2 reduction. Characterization included use of MALDI-ToF mass spectrometry, FT-IR, RAMAN, 1H and 13C NMR, elemental analysis, electronic absorption and emission spectroscopy, single crystal X-ray diffraction, DFT and cyclic voltammetry. Photocatalytic (406 nm) reduction of 13CO2 to formate (H13COO) in the presence of this catalyst was tracked via13C NMR. Results support Re5-PAN (φ = 0.021) functioning as a catalyst for the reduction of CO2 (maximum turn-over 48-50 at 300 equiv. triethylamine as the sacrificial electron donor).

The Coordination Chemistry of Bio-Relevant Ligands and Their Magnesium Complexes.

The coordination chemistry of magnesium (Mg2+) was extensively explored. More recently; magnesium; which plays a role in over 80% of metabolic functions and governs over 350 enzymatic processes; is becoming increasingly linked to chronic disease-predominantly due to magnesium deficiency (hypomagnesemia). Supplemental dietary magnesium utilizing biorelevant chelate ligands is a proven method for counteracting hypomagnesemia. However, the coordination chemistry of such bio-relevant magnesium complexes is yet to be extensively explored or elucidated. It is the aim of this review to comprehensively describe what is currently known about common bio-relevant magnesium complexes from the perspective of coordination chemistry.

Memory differences by sex, but not by previous diagnosis of major depressive disorder.

Memory difficulties are consistently reported in Major Depressive Disorder (MDD). Nonetheless, it has not been thoroughly investigated as to whether these deficits persist during remission from MDD. A group of 32 healthy young adults with no history of a mood disorder (Mage = 20.8, SD = 2.1) and 62 remitted depressed young adults (Mage = 21.1, SD = 1.9) completed a neuropsychological battery. The test battery included two measures of nonverbal memory, two measures of verbal memory, and a measure of performance validity. The testing session was repeated three to six weeks later to determine performance stability. No differences were found between healthy controls and remitted depressed patients in either memory domain (all ps > .05) and improvement in performance was exhibited over time for both groups (p = 0.004). Potential practice effects are examined. We found a stronger performance for women than men (p = 0.003), particularly for the Semantic List Learning Task (SLLT) (p = .047). Verbal and nonverbal memory and effort may not be impacted in those who are in a remitted state of MDD, early in the course of the illness. Women demonstrated auditory memory superiority over men, similar to prior research.

Impaired frontostriatal functional connectivity among chronic opioid using pain patients is associated with dysregulated affect.

Preclinical studies have shown effects of chronic exposure to addictive drugs on glutamatergic-mediated neuroplasticity in frontostriatal circuitry. These initial findings have been paralleled by human functional magnetic resonance imaging (fMRI) research demonstrating weaker frontostriatal resting-state functional connectivity (rsFC) among individuals with psychostimulant use disorders. However, there is a dearth of human imaging literature describing associations between long-term prescription opioid use, frontostriatal rsFC, and brain morphology among chronic pain patients. We hypothesized that prescription opioid users with chronic pain, as compared with healthy control subjects, would evidence weaker frontostriatal rsFC coupled with less frontostriatal gray matter volume (GMV). Further, those opioid use-related deficits in frontostriatal circuitry would be associated with negative affect and drug misuse. Prescription opioid users with chronic pain (n = 31) and drug-free healthy controls (n = 30) underwent a high-resolution anatomical and an eyes-closed resting-state functional scan. The opioid group, relative to controls, exhibited weaker frontostriatal rsFC, and less frontostriatal GMV in both L.NAc and L.vmPFC. Frontostriatal rsFC partially mediated group differences in negative affect. Within opioid users, L.NAc GMV predicted opioid misuse severity. The current study revealed that prescription opioid use in the context of chronic pain is associated with functional and structural abnormalities in frontostriatal circuitry. These results suggest that opioid use-related abnormalities in frontostriatal circuitry may undergird disturbances in affect that may contribute to the ongoing maintenance of opioid use and misuse. These findings warrant further examination of interventions to treat opioid pathophysiology in frontostriatal circuitry over the course of treatment.

Positron emission tomography imaging of endogenous mu-opioid mechanisms during pain and migraine.

The enormous advancements in the medical imaging methods witnessed in the past decades have allowed clinical researchers to study the function of the human brain in vivo, both in health and disease. In addition, a better understanding of brain responses to different modalities of stimuli such as pain, reward, or the administration of active or placebo interventions has been achieved through neuroimaging methods. Although magnetic resonance imaging has provided important information regarding structural, hemodynamic, and metabolic changes in the central nervous system related to pain, magnetic resonance imaging does not address modulatory pain systems at the molecular level (eg, endogenous opioid). Such important information has been obtained through positron emission tomography, bringing insights into the neuroplastic changes that occur in the context of the pain experience. Positron emission tomography studies have not only confirmed the brain structures involved in pain processing and modulation but also have helped elucidate the neural mechanisms that underlie healthy and pathological pain regulation. These data have shown some of the biological basis of the interindividual variability in pain perception and regulation. In addition, they provide crucial information to the mechanisms that drive placebo and nocebo effects, as well as represent an important source of variability in clinical trials. Positron emission tomography studies have also permitted exploration of the dynamic interaction between behavior and genetic factors and between different pain modulatory systems. This narrative review will present a summary of the main findings of the positron emission tomography studies that evaluated the functioning of the opioidergic system in the context of pain.

Mindfulness-Oriented Recovery Enhancement remediates hedonic dysregulation in opioid users: Neural and affective evidence of target engagement.

Addiction neuroscience models posit that recurrent drug use increases reactivity to drug-related cues and blunts responsiveness to natural rewards, propelling a cycle of hedonic dysregulation that drives addictive behavior. Here, we assessed whether a cognitive intervention for addiction, Mindfulness-Oriented Recovery Enhancement (MORE), could restructure reward responsiveness from valuation of drug-related reward back to valuation of natural reward. Before and after 8 weeks of MORE or a support group control, prescription opioid users (N = 135) viewed opioid and natural reward cues while an electroencephalogram biomarker of target engagement was assessed. MORE was associated with decreased opioid cue-reactivity and enhanced capacity to regulate responses to opioid and natural reward cues. Increased positive affective responses to natural reward cues were associated with decreased craving and mediated MORE's therapeutic effects on opioid misuse. This series of randomized experiments provide the first neurophysiological evidence that an integrative behavioral treatment can remediate hedonic dysregulation among chronic opioid users.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

Association between smoking, and hospital readmission among inpatients with psychiatric illness at an academic inpatient psychiatric facility, 2000-2015.

INTRODUCTION: Smoking rates are up to 2-4 times higher among individuals with mental illness. Hospital readmissions for patients with psychiatric illness within a year of discharge are also high, and there is limited evidence of associations between smoking and these readmissions. METHODS: This study was a secondary data analysis using clinical data of psychiatric inpatients with initial admissions between the years 2000 and 2015. Following a descriptive analysis, logistic regression models were fitted to explore relationships between smoking and psychiatric hospital readmission within 30 days and a year of discharge. RESULTS: A total of 5439 patients with average age of 30.18 ±â€¯15.97 were identified. Of this number, 47.0% were current smokers and 53.0% were never smokers. Within 30 days of discharge, 11% of the current smokers were readmitted compared to 9% of never smokers. The primary diagnoses with highest proportion of smokers were, opioid or substance use disorders (80.0%), schizophrenia (70.7%), alcohol dependence (68.2%), and bipolar disorders (50.8%). About 31% of current smokers were readmitted within one year of discharge compared to 26% of never smokers. Adjusted odds ratios for readmission within 1-year of discharge were, bipolar disorders (1.41, p = 0.01), schizophrenia (2.33, p < 0.001), and opioid/substance dependence (1.55, p = 0.01). CONCLUSION: Significant relationships exist between smoking and readmission for patients with psychiatric illness. Smokers are more likely to be readmitted within 30 days or one year after discharge. Interaction of smoking and certain specific diagnoses significantly increases readmission.

Influence of childhood adversity, approach motivation traits, and depression on individual differences in brain activation during reward anticipation.

Reward anticipation dysfunction is associated with major depressive disorder (MDD), but is not universally observed in individuals with MDD. Reward anticipation deficits have also been linked to childhood adversity (CA) and approach/avoidance traits. The present study evaluated whether severity of CA (as measured by the Childhood Trauma Questionnaire) and approach/avoidance traits predict individual differences in blood oxygen level dependent (BOLD) response to reward anticipation beyond MDD diagnosis alone. Participants were individuals with MDD (n = 23) and healthy controls (n = 27). Multiple regression was conducted using CTQ scores, trait approach/avoidance scores, and diagnosis to predict activation during reward anticipation in a monetary incentive delay fMRI task. Across groups, higher trait reward responsiveness predicted increased activation in the hippocampus, cingulate cortex, and medial frontal gyrus. Greater CTQ scores predicted increased reward network activation. Overall, CTQ and reward responsiveness scores predicted more variance in reward anticipation activation than diagnosis. These findings suggest that clinicians should assess history of childhood adversity and trait reward responsiveness when treating individuals with MDD.