The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture.

In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.

Implementing contingency management into rural recovery housing: recommendations of a professional advisory expert panel.

Background: Rural areas in the United States have been severely impacted by recent rises in substance use related mortality and psychosocial consequences. There is a dearth of treatment resources to address substance use disorder (SUD). Rural recovery houses (RRH) are important services that provide individuals with SUD with an environment where they can engage in recovery-oriented activities, but dropout rates are unacceptably high, and evidence-based interventions such as contingency management (CM) may reduce dropout and improve outcomes for RRH residents. In this paper, we describe the results of a national convening of experts that addressed important issues concerning the implementation of CM within the context of RRHs.Methods: Twelve experts (five female) in the areas of CM, RRH and rural health participated in a one-day facilitated meeting that used nominal group technique to identify expert consensus in three areas as they pertain to RRH: (a) facilitators and barriers to CM implementation, (b) elements necessary for successful program building based on group feedback, and (c) recommendations for future implementation of CM.Results: Several RRH- and system-level barriers and facilitators to implementing CM were identified by the panel, and these were categorized based on the level of importance for and ease of implementation. CM funding, staff and resident buy-in, set policies, education on CM, and consistent fidelity to CM procedures and tracking were identified as important requirements for implementing CM in RRH.Conclusions: We provide recommendations for the implementation of CM in RRH that may be useful in this context, as well as more broadly.

Recovery incentives program: California's contingency management benefit.

OBJECTIVE: The role of methamphetamine and cocaine use in California's drug poisoning (overdose) crisis has dramatically increased in the past five (5) years and has disproportionately affected American Indian, Alaska Native, and Black Californians. No FDA-approved medications currently exist for the treatment of individuals with stimulant use disorder (StimUD). Outside the Veteran's Administration, the Recovery Incentives Program: California's Contingency Management Benefit is the first large scale implementation of contingency management (CM). CM is the behavioral treatment with the most evidence and largest effect sizes for StimUD. METHODS: The Program uses a CM protocol where participants can receive a maximum of $599 over a six-month period, contingent upon 36 stimulant-negative urine test results. Urine tests are conducted using a set of approved, CLIA-waived, point-of-care urine drug tests (UDTs). To ensure fidelity to the CM protocol and to prevent fraud, waste, and abuse, all aspects of incentive accounting and distribution are managed electronically via a custom-developed software system. Incentive distribution utilizes electronic gift cards. A significant innovation of the project is the conceptualization of the CM Coordinator, a designated and highly trained and supervised individual responsible for all aspects of CM operation in a specific site. RESULTS AND CONCLUSIONS: The California Department of Health Care Services contracted with UCLA to develop and implement a robust evaluation of the Program; goals include evaluating the effectiveness of real-world implementation and facilitating quality improvement. The project will likely significantly impact the use of CM for StimUD nationally and may well reduce stimulant-related drug poisoning deaths.

The postrhinal cortex is not necessary for landmark control in rat head direction cells.

The rodent postrhinal cortex (POR), homologous to primate areas TH/TF and the human 'parahippocampal place area', has been implicated in processing visual landmark and contextual information about the environment. Head direction (HD) cells are neurons that encode allocentric head direction, independent of the animal's location or behavior, and are influenced by manipulations of visual landmarks. The present study determined whether the POR plays a role in processing environmental information within the HD circuit. Experiment 1 tested the role of the POR in processing visual landmark cues in the HD system during manipulation of a visual cue. HD cells from POR lesioned animals had similar firing properties, shifted their preferred firing direction following rotation of a salient visual cue, and in darkness had preferred firing directions that drifted at the same rate as controls. Experiment 2 tested the PORs involvement in contextual fear conditioning, where the animal learns to associate a shock with both a tone and a context in which the shock was given. In agreement with previous studies, POR lesioned animals were able to learn the tone-shock pairing, but displayed less freezing relative to controls when reintroduced into the environment previously paired with a shock. Therefore, HD cells from POR lesioned animals, with demonstrated impairments in contextual fear conditioning, were able to use a visual landmark to control their preferred direction. Thus, despite its importance in processing visual landmark information in primates, the POR in rats does not appear to play a pivotal role in controlling visual landmark information in the HD system. © 2016 Wiley Periodicals, Inc.

Visual landmark information gains control of the head direction signal at the lateral mammillary nuclei.

The neural representation of directional heading is conveyed by head direction (HD) cells located in an ascending circuit that includes projections from the lateral mammillary nuclei (LMN) to the anterodorsal thalamus (ADN) to the postsubiculum (PoS). The PoS provides return projections to LMN and ADN and is responsible for the landmark control of HD cells in ADN. However, the functional role of the PoS projection to LMN has not been tested. The present study recorded HD cells from LMN after bilateral PoS lesions to determine whether the PoS provides landmark control to LMN HD cells. After the lesion and implantation of electrodes, HD cell activity was recorded while rats navigated within a cylindrical arena containing a single visual landmark or while they navigated between familiar and novel arenas of a dual-chamber apparatus. PoS lesions disrupted the landmark control of HD cells and also disrupted the stability of the preferred firing direction of the cells in darkness. Furthermore, PoS lesions impaired the stable HD cell representation maintained by path integration mechanisms when the rat walked between familiar and novel arenas. These results suggest that visual information first gains control of the HD cell signal in the LMN, presumably via the direct PoS → LMN projection. This visual landmark information then controls HD cells throughout the HD cell circuit.

California's Recovery Incentives Program: Implementation strategies.

INTRODUCTION: Due to the increasing role of psychostimulants in the US drug poisoning crisis, there is an increasing need to effectively implement evidence-based treatment for individuals with stimulant use disorder (StimUD). Contingency management is a behavioral strategy with robust evidence of support for the treatment of StimUD. In 2023, California initiated a large-scale effort to implement CM as a treatment for individuals with a stimulant use disorder (cocaine, methamphetamine, amphetamine) called the Recovery Incentives Program: California's Contingency Management Benefit. METHODS: The Recovery Incentives Program is being systematically implemented using the Becker et al. Science to Service Lab (SSL) implementation approach with several augmentations for this project. The SSL features three core components: didactic training, performance feedback, and external facilitation. We have augmented this approach with a readiness assessment process for sites prior to CM service launch, and an ongoing fidelity monitoring and feedback component post-launch. RESULTS: The present paper is a preliminary report describing the use of this augmented SSL strategy for CM implementation in a large-scale implementation effort. Data are presented to describe the implementation activities during the first ten months of the Recovery Incentives Program. CONCLUSION: The California Recovery Incentives Program has been systematically implemented and appears to be receiving a positive response from treatment program staff and enrolled members. Future papers and evaluation reports will continue to document member response to the Program and report on the ongoing training and implementation process.

Lifetime substance use and HIV sexual risk behaviors predict treatment response to contingency management among homeless, substance-dependent MSM.

Homeless, substance-dependent men who have sex with men (MSM) continue to suffer health disparities, including high rates of HIV. One-hundred and thirty one homeless, substance-dependent MSM were randomized into a contingency management (CM) intervention to increase substance abstinence and health-promoting behaviors. Participants were recruited from a community-based, health education/risk reduction HIV prevention program and the research activities were also conducted at the community site. Secondary analyses were conducted to identify and characterize treatment responders (defined as participants in a contingency management intervention who scored at or above the median on three primary outcomes). Treatment responders were more likely to be Caucasian/White (p < .05), report fewer years of lifetime methamphetamine, cocaine, and polysubstance use (p < or = .05), and report more recent sexual partners and high-risk sexual behaviors than nonresponders (p < .05). The application of evidence-based interventions continues to be a public health priority, especially in the effort to implement effective interventions for use in community settings. The identification of both treatment responders and nonresponders is important for intervention development tailored to specific populations, both in service programs and research studies, to optimize outcomes among highly impacted populations.

Delay-discounting among homeless, out-of-treatment, substance-dependent men who have sex with men.

BACKGROUND: Impulsivity is associated with substance use; however, to date, impulsivity has not been characterized among a sample of homeless, non-treatment seeking, substance-dependent men who have sex with men (MSM). OBJECTIVES: The aim of this study was to utilize the delay-discounting instrument to assess impulsive behaviors among a subsample of homeless, non-treatment seeking, substance-dependent men who have sex with men (S-D MSM) enrolled in a randomized, controlled, contingency management (CM) trial. METHODS: Twenty S-D MSM participants from the CM parent study were matched on age and ethnicity to 20 non-substance-dependent, non-homeless control participants using propensity scores (N=40) and were administered the delay-discounting procedure. RESULTS: Although discounting values decreased rapidly with time in both groups, the S-D MSM participants consistently discounted rewards more steeply than controls (p=.05), particularly at all intermediate measured timeframes. The S-D MSM participants also presented greater median discounting rates (k values) compared with the control group (m(S-D MSM)=2.39 (SD=3.72) vs. m(ctrl)=1.27 (SD=3.71), p≤.01). CONCLUSION: This work extends existing findings of increased delay-discounting among substance-dependent individuals to homeless, substance-dependent, non-treatment seeking MSM. SCIENTIFIC SIGNIFICANCE: A better understanding of the prevalence of delay-discounting type behaviors among homeless, substance-dependent MSM can be used to inform the development of tailored substance abuse interventions for this high-risk population.

Pain modulates dopamine neurons via a spinal-parabrachial-mesencephalic circuit.

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.

Characterization of transgenic mouse models targeting neuromodulatory systems reveals organizational principles of the dorsal raphe.

The dorsal raphe (DR) is a heterogeneous nucleus containing dopamine (DA), serotonin (5HT), γ-aminobutyric acid (GABA) and glutamate neurons. Consequently, investigations of DR circuitry require Cre-driver lines that restrict transgene expression to precisely defined cell populations. Here, we present a systematic evaluation of mouse lines targeting neuromodulatory cells in the DR. We find substantial differences in specificity between lines targeting DA neurons, and in penetrance between lines targeting 5HT neurons. Using these tools to map DR circuits, we show that populations of neurochemically distinct DR neurons are arranged in a stereotyped topographical pattern, send divergent projections to amygdala subnuclei, and differ in their presynaptic inputs. Importantly, targeting DR DA neurons using different mouse lines yielded both structural and functional differences in the neural circuits accessed. These results provide a refined model of DR organization and support a comparative, case-by-case evaluation of the suitability of transgenic tools for any experimental application.

Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors.

Chronic stress (CS) is a major risk factor for the development of depression. Here, we demonstrate that CS-induced hyperactivity in ventral tegmental area (VTA)-projecting lateral habenula (LHb) neurons is associated with increased passive coping (PC), but not anxiety or anhedonia. LHb→VTA neurons in mice with increased PC show increased burst and tonic firing as well as synaptic adaptations in excitatory inputs from the entopeduncular nucleus (EP). In vivo manipulations of EP→LHb or LHb→VTA neurons selectively alter PC and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show CS-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics, we reveal a set of genes that can collectively serve as biomarkers to identify mice with increased PC and differentiate LHb→VTA from LHb→DR neurons. Together, we provide a set of biological markers at the level of genes, synapses, cells, and circuits that define a distinctive CS-induced behavioral phenotype.

A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System.

Ventral tegmental area (VTA) dopamine (DA) neurons play a central role in mediating motivated behaviors, but the circuitry through which they signal positive and negative motivational stimuli is incompletely understood. Using in vivo fiber photometry, we simultaneously recorded activity in DA terminals in different nucleus accumbens (NAc) subnuclei during an aversive and reward conditioning task. We find that DA terminals in the ventral NAc medial shell (vNAcMed) are excited by unexpected aversive outcomes and to cues that predict them, whereas DA terminals in other NAc subregions are persistently depressed. Excitation to reward-predictive cues dominated in the NAc lateral shell and was largely absent in the vNAcMed. Moreover, we demonstrate that glutamatergic (VGLUT2-expressing) neurons in the lateral hypothalamus represent a key afferent input for providing information about aversive outcomes to vNAcMed-projecting DA neurons. Collectively, we reveal the distinct functional contributions of separate mesolimbic DA subsystems and their afferent pathways underlying motivated behaviors. VIDEO ABSTRACT.

Questionable Use of "Nonorganic" in Norrix et al. (2017), "Estimating Nonorganic Hearing Thresholds".

PURPOSE: The author of this letter to the editor expresses concern about the use of the word "nonorganic" as a source of confusion in terminology. Specifically, this is in response to the December 2017 American Journal of Audiology article, "Estimating Nonorganic Hearing Thresholds Using Binaural Auditory Stimuli" (Norrix, Rubiano, & Mueller, 2017). "Nonorganic" is a source of confusion in terminology, because it can be used in two different ways. One way can mean to say there is no hearing loss. When used in this sense, it is illogical because it is qualifying a hearing loss believed not to exist. The second usage means there is a real disorder of function, but the organs themselves are not damaged and the basis is unknown. In the place of "nonorganic," I have proposed "false hearing loss." "Nonorganic" might carry a negative connotation that "false" might not. Many instances of false hearing loss stem from physical-mental health disturbances. Audiologists must stay alert to signs of psychosocial difficulty and refer for further evaluation accordingly. CONCLUSION: "False" hearing loss is a more appropriate term than "nonorganic" hearing loss.

Nucleus Accumbens Subnuclei Regulate Motivated Behavior via Direct Inhibition and Disinhibition of VTA Dopamine Subpopulations.

Mesolimbic dopamine (DA) neurons play a central role in motivation and reward processing. Although the activity of these mesolimbic DA neurons is controlled by afferent inputs, little is known about the circuits in which they are embedded. Using retrograde tracing, electrophysiology, optogenetics, and behavioral assays, we identify principles of afferent-specific control in the mesolimbic DA system. Neurons in the medial shell subdivision of the nucleus accumbens (NAc) exert direct inhibitory control over two separate populations of mesolimbic DA neurons by activating different GABA receptor subtypes. In contrast, NAc lateral shell neurons mainly synapse onto ventral tegmental area (VTA) GABA neurons, resulting in disinhibition of DA neurons that project back to the NAc lateral shell. Lastly, we establish a critical role for NAc subregion-specific input to the VTA underlying motivated behavior. Collectively, our results suggest a distinction in the incorporation of inhibitory inputs between different subtypes of mesolimbic DA neurons.

Using ECHO Clinics to Promote Capacity Building in Clinical Supervision.

INTRODUCTION: Project Extension for Community Healthcare Outcomes (ECHO™) is a hub-and-spoke knowledge-sharing network, led by expert teams who use multipoint videoconferencing to conduct virtual clinics with community providers in order to improve the quality of care. For this project, members of the Addiction Technology Transfer Center network applied this model in order to enhance workforce capacity to deliver clinical supervision for the treatment of substance use disorders. METHODS: Clinical supervisors (n=66) employed in substance use disorder treatment programs were recruited to participate in this pilot study. The virtual ECHO clinic consisted of 12 total sessions, each lasting 1 hour and comprising a 15-minute mini-lecture on a clinical supervision topic and a 45-minute case presentation and review. All data were collected and analyzed between September 2016 and June 2017. RESULTS: Forty-eight staff attended at least one ECHO session (mean=6.38) and results are presented for 20 staff who completed the follow-up survey. Participants were highly satisfied with the overall intervention, organization of the clinic and the facilitation of Hub experts, relevance of the technical assistance to their work, and with the impact of the intervention on their effectiveness as a supervisor. Results also indicate that there were significant self-reported improvements in clinical supervision self-efficacy following participation in the ECHO clinic. CONCLUSIONS: Results from this pilot study suggest that ECHO virtual clinics are feasible to implement for the purpose of workforce development, are well liked by participants, and can enhance clinical supervision self-efficacy among participants. Further research should explore the impact of self-efficacy on the effective implementation of clinical supervision practices. SUPPLEMENT INFORMATION: This article is part of a supplement entitled The Behavioral Health Workforce: Planning, Practice, and Preparation, which is sponsored by the Substance Abuse and Mental Health Services Administration and the Health Resources and Services Administration of the U.S. Department of Health and Human Services.

Mesiodistal root angulation using panoramic and cone beam CT.

OBJECTIVE: To determine if the panoramic projection can accurately determine mesiodistal root angulations. MATERIALS AND METHODS: A plaster study model of the dentition of each of five patients was prepared. A radiographic stent containing radiopaque markers was fabricated for each of the models. Panoramic and cone beam computed tomography (CBCT) scans were taken on each patient with the radiographic stent seated on the dentition. Root angulations for each of the radiographic images were measured and compared. RESULTS: Root angulation was measured by three independent individuals and good reliability between measurements was demonstrated. Compared to plaster model measurements (the gold standard), the CBCT scan produced very accurate measurements of root angulation. Compared to CBCT images, panoramic projections did not provide reliable data on root angulation. CONCLUSION: Panoramic images did not accurately represent the mesiodistal root angulations on clinical patients.

Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence.

OBJECTIVE: To conduct a 16-week, randomized, placebo-controlled, double-blind trial of two GABAergic medications, baclofen (20 mg tid) and gabapentin (800 mg tid), for the treatment of methamphetamine dependence. METHODS: Adults with methamphetamine dependence were randomized to one of three conditions for 16 weeks: baclofen (n = 25), gabapentin (n = 26) or placebo (n = 37). All participants attended clinic thrice weekly to receive study medication and psychosocial counseling, complete study assessments, and provide urine samples. RESULTS: No statistically significant main effects for baclofen or gabapentin in reducing methamphetamine use were observed using a generalized estimating equation (GEE). A significant treatment effect was found in post hoc analyses for baclofen, but not gabapentin, relative to placebo among participants who reported taking a higher percentage of study medication (significant treatment group and medication adherence interaction in GEE model of methamphetamine use). CONCLUSIONS: While gabapentin does not appear to be effective in treating methamphetamine dependence, baclofen may have a small treatment effect relative to placebo. Future studies evaluating the effectiveness of baclofen and other GABAergic agents for treatment of methamphetamine may be warranted.

Randomized, placebo-controlled trial of sertraline and contingency management for the treatment of methamphetamine dependence.

BACKGROUND: Methamphetamine dependence and associated medical and psychiatric concerns are significant public health issues. This project evaluated the efficacy of sertraline (50mg bid) and contingency management (CM) for the treatment of methamphetamine dependence. METHOD: In this randomized, placebo-controlled, double-blind trial, participants completed a 2-week non-medication baseline and were randomized to one of four conditions for 12 weeks: sertraline plus CM (n=61), sertraline-only (n=59), matching placebo plus CM (n=54), or matching placebo-only (n=55). All participants attended clinic thrice-weekly for data collection, medication dispensing, and relapse prevention groups. Outcomes included methamphetamine use (urine drug screening and self-reported days of use), retention (length of stay), drug craving (visual analogue scale), and mood symptoms (Beck Depression Inventory). RESULTS: No statistically significant main or interaction effects for sertraline or CM in reducing methamphetamine use were observed using a generalized estimating equation (GEE), although post hoc analyses showed the sertraline-only condition had significantly poorer retention than other conditions (chi(2) (3)=8.40, p<0.05). Sertraline conditions produced significantly more adverse events than placebo conditions. A significantly higher proportion of participants in CM conditions achieved three consecutive weeks of methamphetamine abstinence than those in non-CM conditions. CONCLUSIONS: These data do not demonstrate improved outcomes for sertraline versus placebo for treatment of methamphetamine dependence; indeed, they suggest sertraline is contraindicated for methamphetamine dependence. Findings provide support for the use of contingency management for treatment of methamphetamine dependence.

Behavioral treatment approaches for methamphetamine dependence and HIV-related sexual risk behaviors among urban gay and bisexual men.

BACKGROUND: Methamphetamine-dependent gay and bisexual men (GBM) are at high risk for HIV transmission, largely due to drug-associated sexual risk behaviors. This project evaluated the efficacy of four behavioral drug abuse treatments for reducing methamphetamine use and sexual risk behaviors among this population. METHODS: In this randomized controlled trial, 162 methamphetamine-dependent (SCID-verified) GBM in Los Angeles County were randomly assigned to one of four treatment conditions for 16 weeks: standard cognitive behavioral therapy (CBT, n=40), contingency management (CM, n=42), combined cognitive behavioral therapy and contingency management (CBT+CM, n=40), and a culturally tailored cognitive behavioral therapy (GCBT, n=40). Stimulant use was assessed thrice-weekly during treatment using urine drug screens (48 measures). Sexual risk behaviors were monitored monthly (four measures). Follow-up assessments were conducted at 6 (80.0%) and 12 months (79.9%). RESULTS: Statistically significant differences in retention (F(3,158)=3.78, p<.02), in longest period of consecutive urine samples negative for methamphetamine metabolites (F(3,158)=11.80, p<.001), and in the Treatment Effectiveness Score were observed by condition during treatment (F(3,158)=7.35, p<.001) with post hoc analyses showing the CM and CBT+CM conditions to perform better than standard CBT. GEE modeling results showed GCBT significantly reduced unprotected receptive anal intercourse (URAI) during the first 4 weeks of treatment (X2=6.75, p<.01). During treatment between-group differences disappeared at follow-up with overall reductions in outcomes sustained to 1-year. CONCLUSIONS: Among high-risk methamphetamine-dependent GBM, drug abuse treatments produced significant reductions in methamphetamine use and sexual risk behaviors. Drug abuse treatments merit consideration as a primary HIV prevention strategy for this population.

HIV-associated medical, behavioral, and psychiatric characteristics of treatment-seeking, methamphetamine-dependent men who have sex with men.

This paper examines medical and psychiatric symptoms and disorders associated with reported HIV serostatus among methamphetamine-dependent, treatment-seeking men who have sex with men (MSM) in Los Angeles. Baseline data from a NIDA-funded, randomized clinical trial of behavioral drug abuse therapies included medical examinations and behavioral interviews of the 162 randomized participants. Variables identified as significantly associated with HIV infection were entered into a multivariate, hierarchical logistic regression analysis to optimally predict HIV serostatus. The disturbingly high 61% of the sample with reported HIV-seropositive status represents 3-4 times the prevalence for all MSM in Los Angeles County. HIV infection status strongly associated with prior treatment for methamphetamine dependence; unprotected receptive anal intercourse; history of sexually transmitted infections; and health insurance status. Findings demonstrate the powerful connection between methamphetamine dependence and HIV infection, and strongly suggest a need for development of interventions that function as both substance abuse treatment and HIV prevention for this population.