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The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning 1-8 . Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations 9-14 . However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here we establish a mouse model that enables simultaneous genetic access to the brain's DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signalling and decrease 5HT signalling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioural deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive the acquisition of new associations and supported reinforcement more potently than either manipulation did alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement., Competing Interests: Competing interests: N.E. is a consultant for Boehringer Ingelheim. B.S.B. is a co-founder of Magnus Medical. R.C.M. is on the scientific advisory boards of MapLight Therapeutics, MindMed, Bright Minds Biosciences and Aelis Farma. D.F.C.P., M.B.P., M.Y.G., G.C.T. and A.P.F.C. declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT 1B R activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of ( R )-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo , increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT 2C R antagonist (SB242084), but not by the 5-HT 1B R antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, ( R )-MDMA is predicted to have prosocial effects and low abuse potential., Competing Interests: CONFLICT OF INTERESTS B.D.H. is on the scientific advisory boards of Journey Clinical and Osmind, and is a paid consultant to Arcadia Medicine, Inc. N.E. is a paid consultant for Boehringer Ingelheim. R.C.M. is now on leave from Stanford, functioning as Chief Scientific Officer at Bayshore Global Management. R.C.M. is on the scientific advisory boards of MapLight Therapeutics, Bright Minds, MindMed, and Aelis Farma.

Background: Patients with brain metastases (BrMs) from esophageal cancer have poor prognosis, the incidence of which is expected to rise due to improved survival from the primary tumor and increased neuroimaging. We aimed to identify patient and esophageal cancer characteristics associated with longer survival in patients with BrMs and, secondly, to compare the prognosis of patients with HER2 overexpression., Methods: We retrospectively reviewed patients with BrMs from esophageal cancer at a single institution from 2008-2021. We collected patient demographics, primary tumor and BrM characteristics, and treatment. Our primary outcome was median survival from the time of BrM., Results: The median age at primary diagnosis was 66.5 years and 86% were male. Of the 49 patients, 71% had adenocarcinoma, 20% squamous cell carcinoma and 8% other. In this group, 71% of patients presented with stage III or IV disease, including 16% with synchronous primary metastatis and BrM. The median time to BrM was 10.1 months (interquartile range 1.7-22.8) and the median survival from BrM was 8.4 months (95% CI 4.8-16.8 months). On multivariable analysis, treatment with stereotactic radiosurgery (hazard ratio [HR] = 0.19; P = 0.04), surgical resection (HR 0.24; P = 0.03), and immunotherapy (HR 0.19; P = 0.04) were associated with increased survival while Karnofsky Performance Status (KPS) ≤70 (HR = 13.2; P < 0.001) was associated with decreased survival. HER2 overexpression was found in 22% of patients, but we noted no survival difference (5.2 months HER2+ vs. 9.8 months HER2neg; P = 0.95)., Conclusions: The median survival from esophageal-to-brain metastasis was 8.4 months. Patients with a single lesion, KPS score >70, and treatment with surgical resection was correlated with improved survival. Further, HER2+ patients had distinct patient and BrM characteristics., (Copyright © 2024. Published by Elsevier Inc.)

Striatal dopamine (DA) release has long been linked to reward processing, but it remains controversial whether DA release reflects costs or benefits and how these signals vary with motivation. Here, we measure DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) while independently varying costs and benefits and apply behavioral economic principles to determine a mouse's level of motivation. We reveal that DA release in both structures incorporates both reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release. Furthermore, optogenetically evoked DA release was also heavily dependent on sunk cost. Our results reconcile previous disparate findings by demonstrating that striatal DA release simultaneously encodes cost, benefit, and motivation but in distinct manners over different timescales. Future work will be necessary to determine whether the reduction in phasic DA release in highly motivated animals is due to changes in tonic DA levels., Competing Interests: Declaration of interests N.E. is a consultant for Boehringer Ingelheim. R.C.M. is on the scientific advisory boards of MapLight Therapeutics, MindMed, Bright Minds Biosciences, Cyclerion, and AZ Therapies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Cervical fusion rates increased in the U.S. exponentially 1990-2014, but trends leading up to/during the COVID-19 pandemic have not been fully evaluated by patient socioeconomic status (SES). Here, we provide the most recent, comprehensive characterization of demographic and SES trends in cervical fusions, including during the pandemic., Methods: We collected the following variables on adults undergoing cervical fusions, 1/1/2004-3/31/2021, in Optum's Clinformatics Data Mart: age, Charlson Comorbidity Index, provider's practicing state, gender, race, education, and net worth. We performed multivariate linear and logistic regression to evaluate associations of cervical fusion rates with SES variables., Results: Cervical fusion rates increased 2004-2016, then decreased 2016-2020. Proportions of Asian, Black, and Hispanic patients undergoing cervical fusions increased (OR = 1.001,1.001,1.004, P < 0.01), with a corresponding decrease in White patients (OR = 0.996, P < 0.001) over time. There were increases in cervical fusions in higher education groups (OR = 1.006, 1.002, P < 0.001) and lowest net worth group (OR = 1.012, P < 0.001). During the pandemic, proportions of White (OR = 1.015, P < 0.01) and wealthier patients (OR ≥ 1.015, P < 0.01) undergoing cervical fusions increased., Conclusions: We present the first documented decrease in annual cervical surgery rates in the U.S. Our data reveal a bimodal distribution for cervical fusion patients, with racial-minority, lower-net-worth, and highly-educated patients receiving increasing proportions of surgical interventions. White and wealthier patients were more likely to undergo cervical fusions during the COVID-19 pandemic, which has been reported in other areas of medicine but not yet in spine surgery. There is still considerable work needed to improve equitable access to spine care for the entire U.S., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Laparoscopic cholecystectomy is frequently performed for acute cholecystitis and symptomatic cholelithiasis. Considerable variation in the execution of key steps of the operation remains. We conducted a systematic review of evidence regarding best practices for critical intraoperative steps for laparoscopic cholecystectomy., Methods: We identified 5 main intraoperative decision points in laparoscopic cholecystectomy: (1) number and position of laparoscopic ports; (2) identification of cystic artery and duct; (3) division of cystic artery and duct; (4) indications for subtotal cholecystectomy; and (5) retrieval of the gallbladder. PubMed, EMBASE, and Web of Science were queried for relevant studies. Randomized controlled trials and systematic reviews were included for analysis, and evidence quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation framework., Results: Fifty-two articles were included. Although all port configurations were comparable from a safety standpoint, fewer ports sometimes resulted in improved cosmesis or decreased pain but longer operative times. The critical view of safety should be obtained for identification of the cystic duct and artery but may be obtained through fundus-first dissection and augmented with cholangiography or ultrasound. Insufficient evidence exists to compare harmonic-shear, clipless ligation against clip ligation of the cystic duct and artery. Stump closure during subtotal cholecystectomy may reduce rates of bile leak and reoperation. Use of retrieval bag for gallbladder extraction results in minimal benefit. Most studies were underpowered to detect differences in incidence of rare complications., Conclusion: Key operative steps of laparoscopic cholecystectomy should be informed by both compiled data and surgeon preference/patient considerations., Competing Interests: No conflicts of interest are reported for any author. Dr Forrester has received unrestricted research funding from Varian for an investigator-initiated clinical trial (https://clinicaltrials.gov/ct2/show/NCT04482582) and received grant funding from the Surgical Infections Society. Neither of these leads to conflicts of interest for this work product., (© 2022 The Authors.)