Reward contingency gates selective cholinergic suppression of amygdala neurons.

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward - even prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex. Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic receptor signaling, while also facilitating firing in BLA GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.

Single, Recurrent, Synchronous, and Metachronous Periprosthetic Joint Infections in Patients With Multiple Hip and Knee Arthroplasties.

BACKGROUND: The rate for periprosthetic joint infection (PJI) exceeds 1% for primary arthroplasties. Over 30% of patients who have a primary arthroplasty require an additional arthroplasty, and the impact of PJI on this population is understudied. Our objective was to assess the prevalence of recurrent, synchronous, and metachronous PJI in patients who had multiple arthroplasties and to identify risk factors for a subsequent PJI. METHODS: We identified 337 patients who had multiple arthroplasties and at least 1 PJI that presented between 2003 and 2021. The mean follow-up after revision arthroplasty was 3 years (range, 0 to 17.2). Patients who had multiple infected prostheses were categorized as synchronous (ie, presenting at the same time as the initial infection) or metachronous (ie, presenting at a different time as the initial infection). The PJI diagnosis was made using the MusculoSkeletal Infection Society (MSIS) criteria. RESULTS: There were 39 (12%) patients who experienced recurrent PJI in the same joint, while 31 (9%) patients developed PJI in another joint. Positive blood cultures were more likely in the second joint PJI (48%) compared to recurrent PJI (23%) or a single PJI (15%, P < .001). Synchronous PJI represented 42% of the second joint PJI cases (n = 13), while metachronous PJI represented 58% (n = 18). Tobacco users had 75% higher odds of metachronous PJI (odds ratio 1.75, 95% confidence interval: 1.1-2.9, P = .041). CONCLUSION: Over 20% of the patients with multiple arthroplasties and a single PJI will develop a subsequent PJI in another arthroplasty with 12% recurring in the initial arthroplasty and nearly 10% ocurring in another arthroplasty. Particular caution should be taken in patients who use tobacco, have bacteremia, or have Staphylococcus aureus isolation at time of their initial PJI. Optimizing the management of this high-risk patient population is necessary to reduce the additional burden of subsequent PJI. LEVEL OF EVIDENCE: Prognostic Level IV.

Association of Human Papillomavirus Status With Suicide Risk Among Patients With Head and Neck Cancer.

Importance: Human papillomavirus (HPV) is strongly associated with head and neck cancer, and HPV status is considered a prognostic factor. Being a sexually transmitted infection, HPV-related cancers may have greater risk of stigma and psychological distress; however, the potential association of HPV-positive status with psychosocial outcomes, such as suicide, is understudied in head and neck cancer. Objective: To investigate the association between HPV tumor status and suicide risk among patients with head and neck cancer. Design, Setting, and Participants: This population-based retrospective cohort study included adult patients with clinically confirmed cases of head and neck cancer based on HPV tumor status from the Surveillance, Epidemiology, and End Results database from January 1, 2000, to December 31, 2018. Data analysis was conducted from February 1 to July 22, 2022. Main Outcomes and Measures: The outcome of interest was death by suicide. Primary measure was HPV status of tumor site, dichotomized as positive or negative. Covariates included age, race, ethnicity, marital status, cancer stage at presentation, treatment modality, and type of residence. Cumulative risk of suicide among patients with HPV-positive and HPV-negative head and neck cancer was assessed using Fine and Gray competing risk models. Results: Of 60 361 participants, the mean (SD) age was 61.2 (13.65) years, and 17 036 (28.2%) were women; there were 347 (0.6%) American Indian, 4369 (7.2%) Asian, 5226 (8.7%) Black, 414 (0.7%) Native Hawaiian or Other Pacific Islander, and 49 187 (81.5%) White individuals. A competing risk analysis showed a significant difference in the cumulative incidence of suicide between HPV-positive cancers (5-year suicide-specific mortality, 0.43%; 95% CI, 0.33%-0.55%) and HPV-negative cancers (5-year suicide-specific mortality, 0.24%; 95% CI, 0.19%-0.29%). Tumor status that was HPV positive was associated with increased suicide risk in the unadjusted model (hazard ratio [HR], 1.76; 95% CI, 1.28-2.40), but not the fully adjusted model (adjusted HR, 1.18; 95% CI, 0.79-1.79). Among people with oropharyngeal cancer only, HPV status was associated with increased suicide risk, but the width of the confidence interval prevented definitive conclusion (adjusted HR, 1.61; 95% CI 0.88-2.94). Conclusions and Relevance: The results of this cohort study suggest that patients with HPV-positive head and neck cancer have similar risk of suicide as patients with HPV-negative cancer, despite differences in overall prognosis. Early mental health interventions may be associated with reduced suicide risk in all patients with head and neck cancer and should be assessed in future work.

Thyroid Cancer Incidence, Clinical Presentation, and Survival Among Native Hawaiian and Other Pacific Islanders.

OBJECTIVE: To assess the incidence, clinical presentation, and survival in Native Hawaiian and other Pacific Islander (NHPI) patients with well-differentiated thyroid cancer. STUDY DESIGN: This population-based incidence analysis and retrospective cohort study utilized data from the Surveillance, Epidemiology, and End Results database. SETTING: Incidence analysis included patients diagnosed between 1990 and 2014, while the cohort to study clinical presentation and survival comprised patients diagnosed between 2004 and 2015. METHODS: Incidence rates and trends were compared among NHPI, Asian, and non-Hispanic White (NHW) populations. Clinical presentation was assessed via multivariable logistic regression. Survival was assessed per Cox regression. RESULTS: Recent incidence trends (2009-2014) show that the rate of increase remained consistent among NHPI patients (annual percentage change, 3.67%; 95% CI, 2.66%-4.69%), while it slowed in the NHW population and plateaued among Asians as compared with previous years. NHPI patients were more likely to present with distant metastasis than NHW patients (odds ratio, 3.37; 95% CI, 1.97-5.36) and Asian patients (odds ratio, 1.82; 95% CI, 1.05-2.97). NHPI race was also associated with advanced T stage and nodal metastasis as compared with the NHW race. Survival outcomes were similar among NHPI, NHW, and Asian patients. CONCLUSION: Well-differentiated thyroid cancer incidence has increased at a higher rate for the NHPI population as opposed to the NHW and Asian populations in recent years. NHPI patients are more likely to present with advanced disease when compared with NHW and Asian patients. These results highlight the importance of disaggregating the often-combined Asian/Pacific Islander group in epidemiologic studies.

A functional topography within the cholinergic basal forebrain for encoding sensory cues and behavioral reinforcement outcomes.

Basal forebrain cholinergic neurons (BFCNs) project throughout the cortex to regulate arousal, stimulus salience, plasticity, and learning. Although often treated as a monolithic structure, the basal forebrain features distinct connectivity along its rostrocaudal axis that could impart regional differences in BFCN processing. Here, we performed simultaneous bulk calcium imaging from rostral and caudal BFCNs over a 1-month period of variable reinforcement learning in mice. BFCNs in both regions showed equivalently weak responses to unconditioned visual stimuli and anticipated rewards. Rostral BFCNs in the horizontal limb of the diagonal band were more responsive to reward omission, more accurately classified behavioral outcomes, and more closely tracked fluctuations in pupil-indexed global brain state. Caudal tail BFCNs in globus pallidus and substantia innominata were more responsive to unconditioned auditory stimuli, orofacial movements, aversive reinforcement, and showed robust associative plasticity for punishment-predicting cues. These results identify a functional topography that diversifies cholinergic modulatory signals broadcast to downstream brain regions.

Appetitive and aversive sensory preconditioning in rats is impaired by disruption of the postrhinal cortex.

Episodic memory involves binding stimuli and/or events together in time and place. Furthermore, memories become more complex when new experiences influence the meaning of stimuli within the original memory. Thus collectively, complex episodic memory formation and maintenance involves processes such as encoding, storage, retrieval, updating and reconsolidation, which can be studied using animal models of higher-order conditioning. In the present study aversive and appetitive sensory preconditioning paradigms were used to test the hypothesis that the postrhinal cortex (POR), which is a component of the hippocampal memory system, is involved in higher-order conditioning. Drawing on the known role of the POR in contextual learning, Experiment 1 employed a four-phase sensory preconditioning task that involved fear learning and context discrimination in rats with or without permanent lesions of the POR. In parallel, to examine POR function during higher-order conditioning in the absence of a particular spatial arrangement, Experiments 2 and 3 used a three-phase sensory preconditioning paradigm involving phasic stimuli. In Experiment 2, bilateral lesions of the POR were made and in Experiment 3, a chemogenetic approach was used to temporarily inactivate POR neurons during each phase of the paradigm. Evidence of successful sensory preconditioning was observed in sham rats which, during the critical context discrimination test, demonstrated higher levels of freezing behavior when re-exposed to the paired versus the unpaired context, whereas POR-lesioned rats did not. Data from the appetitive sensory preconditioning paradigm also confirmed the hypothesis in that during the critical auditory discrimination test, sham rats showed greater food cup responding following presentations of the paired compared to the unpaired auditory stimulus, whereas POR-lesioned rats did not. Lastly, in Experiment 3, when the POR was inactivated only during preconditioning or only during conditioning, discrimination during the critical auditory test was impaired. Thus, regardless of whether stimulus-stimulus associations were formed between static or phasic stimuli or whether revaluation of the paired stimulus occurred through association with an aversive or an appetitive unconditioned stimulus, the effects were the same; POR lesions disrupted the ability to use higher-order conditioned stimuli to guide prospective behavior.