OBJECTIVE:Episodic memory is one of the cognitive domains most affected after a traumatic brain injury (TBI), and memory decline is a hallmark of both normal aging and Alzheimer disease (AD). Although TBI is reported to accelerate age-related cognitive decline and brain atrophy, it is unclear how this trajectory is shaped by frequent co-occurring factors such as post-traumatic stress disorder (PTSD) and psychotropic medication use. This study tested whether age-related decline in delayed verbal memory is more pronounced among adults with a history of TBI than those without TBI. Analyses also explored PTSD status and use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) as independent moderators of verbal memory performance. SETTING:VA Medical Center and surrounding community. PARTICIPANTS:Sixty-two Veterans and civilians, ages 30-65, were enrolled. Participants who performed below established cutoffs on performance validity testing were excluded. Analyses (n = 56) included 28 adults with a history of TBI (82% mild, 18% moderate) and 28 demographically matched controls without TBI. MAIN MEASURES:Delayed recall on a standardized verbal memory task was the primary outcome measure. Analyses tested for main effects of TBI status, age, and their interaction, as well as interactions with the moderator variables (PTSD status and SSRI/SNRI use). DESIGN:Observational, cross-sectional design. RESULTS:Participants with a TBI history did not significantly differ from those without TBI in verbal memory performance. There was a trend toward poorer memory performance with age among participants with a TBI history not taking SSRIs/SNRIs, while participants with PTSD and TBI taking SSRIs/SNRIs demonstrated better performance with age. CONCLUSION:The findings underscore the importance of considering psychiatric comorbidities and medication use when examining cognition and aging effects in individuals with TBI. Larger, longitudinal studies are warranted to clarify how traumatic stress and psychotropic medications may mediate cognitive aging trajectories after TBI.

Non-specific Alzheimer's Disease (AD) biomarkers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (Nfl) are now included in the diagnosis and staging of AD, but more work is needed to fully understand their utility in early detection of AD. The present study examined plasma GFAP, Nfl, amyloid beta (Aβ) 40, and Aβ42 in individuals with AD, mild cognitive impairment (MCI) and subjective cognitive decline (SCD) who were either amyloid positive (A+) or negative (A-) according to florbetapir positron emission tomography scan neuroradiological read. The goal was to determine whether individuals with preclinical AD (SCD/A+) show biomarker profiles similar to those expected in AD and MCI (i.e., higher GFAP and Nfl and lower Aβ40 and Aβ42) compared to SCD individuals at lower risk (SCD/A-). Individuals with AD (24 A+, 5 A-), MCI (21 A+, 17 A-) and SCD (5 A+, 11 A-), as determined by clinician referral, completed a blood draw and neuropsychological testing. Blood samples were collected, processed, and stored per previously published guidelines. Plasma samples were assayed using the Neurology 4-Plex E+ assay on the HD-X analyzer (Quanterix, MA). Coefficients of variation for all assays were ≤5%. Generalized linear models (GLMs) with false discovery rate correction examined the effects of diagnosis severity (AD, MCI, SCD) and amyloid status (A+, A-) on plasma levels for each biomarker and the Aβ42/Aβ40 ratio, with covariates of age and sex. Associations between biomarkers and global cognitive functioning, as measured by the Montreal Cognitive Assessment (MoCA), were also examined. The Severity x Amyloid status interaction indicated that GFAP was higher (χ 2 (2)=6.9, p  = .032) and Aβ42/Aβ40 was lower (χ 2 (2)=13.1, p  = .001) in AD/A+ versus AD/A- and in SCD/A+ versus SCD/A-, but amyloid status did not moderate GFAP or Aβ42/Aβ40 in MCI. GLMs for Nfl, Aβ 40, and Aβ 42 did not yield significant effects. GFAP was negatively correlated with MoCA for MCI (ρ=-.61, p  <.001) and SCD (rρ=-.59, p  = .016) groups but not for AD (ρ =-.15, p  = .45). Individuals with preclinical AD (SCD/A+) showed biomarker profiles consistent with AD (higher GFAP; lower Aβ42/Aβ40) and GFAP was associated with poorer global cognition in MCI and SCD.

Early (before age 6) potentially traumatic events (PTEs) may interact with hypothalamic-pituitary-adrenal (HPA) axis functioning to shape outcomes involving externalizing problems and anxiety. However, directions of effects remain unclear. This study examined associations between aspects of HPA axis reactivity, anxiety, and externalizing problems over two years by early PTE exposure history, while statistically capturing the co-occurrence of symptom domains. Youth (N = 189; Mage = 10.96 years, SD = 2.51, Range = 8-15; 52.4% female, 47.1% male; 50.3% White, 35.4% Black/African American, 6.4% Other; 7.4% Hispanic/Latine) were included if they had early PTE exposure (n = 107) or had never experienced a PTE (n = 82). HPA axis reactivity to social stress was calculated using area under the curve with respect to ground (AUCg) and increase (AUCi). For youth with early PTE exposure, higher AUCg was concurrently associated with more externalizing symptoms and greater predominance of externalizing over anxiety. Blunted AUCi predicted increasing predominance of externalizing for the early PTE group, but elevated AUCi predicted increases in anxiety for the no PTE group. Findings highlight distinct roles of overall and reactive HPA axis functioning in shaping outcomes following early trauma.

Objective: Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are common co-occurring conditions associated with a more severe clinical profile and poorer treatment outcomes than either disorder alone. To date, no medications have proven efficacious in the treatment of co-occurring PTSD/AUD. Methods: This randomized, double-blind, placebo-controlled trial examined the efficacy of N-acetylcysteine (NAC; 2,400 mg/day) among individuals (N=182, aged 21-65 years) who met DSM-5 criteria for current PTSD/AUD. Participants were randomized 1:1 to receive 12 weeks of NAC (n=93) or placebo (n=89). All participants received weekly, individual, cognitive behavioral therapy (CBT) for AUD. Follow-up visits occurred at 3-, 6-, and 12-months posttreatment. Primary outcomes included the Clinician Administered PTSD Scale for DSM-5 (CAPS-5), PTSD Checklist for DSM-5 (PCL-5), Timeline Follow-Back (TLFB), and the Obsessive Compulsive Drinking Scale at 12 weeks. The TLFB evaluated the frequency and amount of alcohol consumption. A secondary measure evaluated depression symptoms. Results: Intent-to-treat analyses showed that participants in both the NAC and placebo groups evidenced significant reductions in the CAPS-5 (B=-0.19, P<.001) and PCL-5 (B=-0.20, P<.001) during treatment, with no significant group differences. Both groups also showed significant reductions in alcohol use (drinks per drinking day [B=-0.02, P<.001], percent heavy drinking days [B=-0.14, P<.001], percent days abstinent [B=0.29, P=.022]) and craving (B=-0.12, P<.001) during treatment, but with no significant group differences. There were no group differences in retention or adverse events. Conclusions: Although NAC was well tolerated, it was not more effective than placebo in improving symptoms of PTSD or AUD when added to individual CBT for AUD. Trial Registration: ClinicalTrials.gov identifier: NCT02966873.

Though half of people with posttraumatic stress disorder (PTSD) develop alcohol use disorder (AUD), co-occurring PTSD and AUD (PTSD + AUD) is associated with more severe clinical outcomes relative to either alone and little remains known about the pathophysiology of PTSD + AUD. PTSD and AUD have each been associated with marked dysfunction in brain glutamate and GABA systems, making these systems promising targets for pharmacological intervention, including N-acetylcysteine (NAC), which restores extracellular glutamate concentrations via GLT-1 and System Xc-. Based on promising results from our pilot study of NAC, we recently completed a 12-week, randomized, double-blind, placebo-controlled clinical trial of NAC for PTSD + AUD. As part of this trial, we acquired proton MR spectroscopy (1H-MRS) data at pretreatment and 8-weeks posttreatment in a subsample of (n = 44) participants to evaluate whether NAC significantly affects frontal glutamate levels (i.e., represented by Glx, glutamate + glutamine), with exploratory evaluation of GABA and glutathione levels, and whether NAC-related changes in neurometabolite levels correspond to decreased drinking and/or PTSD symptoms, in people with PTSD + AUD. We found that NAC was associated with significantly higher frontal Glx (t = 2.45, p = 0.017), and significantly lower GABA (t = -2.82, p = 0.007) but equivalent glutathione (t = -1.00, p = 0.321), levels relative to placebo. Finally, lower NAC-related GABA, but not Glx or glutathione, levels were significantly associated with decreased drinks per drinking day (t = 2.57, p = 0.014), but not percent drinking days or PTSD symptoms (ps > 0.10). Though preliminary, these findings are consistent with the mechanistic hypothesis that NAC reduces drinking quantity through its effects on excitatory and inhibitory neurotransmission in people with PTSD + AUD.

The increased risk for psychopathology associated with interpersonal violence exposure (IPV, e.g., physical abuse, sexual assault) is partially mediated by neurobiological alterations in threat-related processes. Evidence supports parsing neural circuitry related to transient and sustained threat, as they appear to be separable processes with distinct neurobiological underpinnings. Although childhood is a sensitive period for neurodevelopment, most prior work has been conducted in adult samples. Further, it is unknown how IPV exposure may impact transient-sustained threat neural interactions. The current study tested the moderating role of IPV exposure on sustained vmPFC-transient amygdala co-activation during an fMRI task during which threat and neutral cues were predictably or unpredictably presented. Analyses were conducted in a sample of 212 community-recruited youth (M/SDage = 11.77/2.44 years old; 51.9% male; 56.1% White/Caucasian). IPV-exposed youth evidenced a positive sustained vmPFC-transient amygdala co-activation, while youth with no IPV exposure did not show this association. Consistent with theoretical models, effects were specific to unpredictable, negative trials and to exposure to IPV (i.e., unrelated to non-IPV traumatic experiences). Although preliminary, these findings provide novel insight into how childhood IPV exposure may alter neural circuity involved in specific facets of threat processing.

BACKGROUND AND PURPOSE:Understanding sex differences in typical development of the face processing network is important for elucidating disruptions during atypical development in sex-linked developmental disorders like autism spectrum disorder. Based on prior sex difference studies in other cognitive domains, this study examined whether females show increased integration of core and extended face regions with age for face viewing, while males would show increased segregation. METHODS:This study used a cross-sectional design with typically developing children and adults (n = 133) and a functional MRI face localizer task. Psychophysiological interaction (PPI) analysis examined functional connectivity between canonical and extended face processing network regions with age, with greater segregation indexed by decreased core-extended region connectivity with age and greater integration indexed by increased core-extended region connectivity with age. RESULTS:PPI analysis confirmed increased segregation for males-right fusiform face area (FFA) coupling to right inferior frontal gyrus (IFG) opercular when viewing faces and left amygdala when viewing objects decreased with age. Females showed increased integration with age (increased coupling of the right FFA to right IFG opercular region and right occipital face area [OFA] to right IFG orbital when viewing faces and objects, respectively) and increased segregation (decreased coupling with age of the right OFA with IFG opercular region when viewing faces). CONCLUSIONS:Development of core and extended face processing network connectivity follows sexually dimorphic paths. These differential changes mostly occur across childhood and adolescence, with males experiencing segregation and females both segregation and integration changes in connectivity.

Importance In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Stressful social experiences play an important role in increasing vulnerability to substance use, including cocaine. Oxytocin (OXT), known for its anxiolytic properties and involvement in social functioning, has been suggested as a potential therapeutic for cocaine use disorder (CUD). However, limited research has explored OXT’s influence on social stress in CUD, and no study has examined its effects on neural response to subconscious (implicit) social threat cues in this population. To address this gap, the present study administered intranasal OXT (24 IU) or placebo (PBO) to participants with CUD (CUD+, N = 76) or without CUD (CUD-, N = 61) in a randomized parallel design. Participants then completed a functional magnetic resonance imaging (fMRI) task involving briefly presented facial fear and anger (i.e., threat) cues, followed by neutral face stimuli. Whole-brain activation and amygdala functional connectivity (using psychophysiological interaction modeling) were examined in response to the facial threat cues. OXT reduced activation in the thalamus and pontine reticular formation in response to fear cues, and in the supplementary motor area for both fear and anger cues, regardless of CUD status. Additionally, under PBO, amygdala-medial prefrontal cortex connectivity to fear stimuli was negative for the CUD+ group, but under OXT, this coupling was positive, similar to the positive coupling observed for the CUD- group under both PBO and OXT administration. The finding of OXT-mediated reversal of amygdala-prefrontal coupling was specific to CUD+ and suggests that OXT alters circuitry related to threat surveillance and implicit emotion regulation in CUD. However, additional research is needed to determine whether these alterations due to OXT have clinical significance in CUD.

Subjective Cognitive Decline (SCD) is considered an early preclinical stage of Alzheimer’s Disease and related dementias (ADRD) which may show promise for targeted preventative treatments. Subtle changes in functional connectivity and white matter integrity (WMI) may occur in SCD. Few studies have applied both functional graph theory (GT) and diffusional kurtosis imaging (DKI) techniques in tandem to identify differences in vulnerable network hubs. We addressed these issues by applying GT and DKI to study differences in intercommunity brain hubs. The hypothesis was that in hubs identified in healthy controls, SCD subjects’ hubs would show decreased GT diversity coefficient (DC) and DKI mean kurtosis (MK). Images were acquired on a Siemens PRISMA scanner. Matlab was used to calculate DC and identify 5 hubs in 107 healthy controls (HC) and DC in 30 SCD (93 females, mean age = 67.51). SCD classification was determined by a comprehensive clinician evaluation or Everyday Cognition average item score>1.6, with objectively healthy cognitive performance (Montreal Cognitive Assessment score>22). Hub DC was the target in GLMM analysis, with diagnosis as predictor. Mean Kurtosis (MK) was analyzed in DSI Studio’s cross-sectional connectometry using the hubs as seeds. Only the covariate of gray matter volume approached significance (p = .059), and was included in analysis. Mean age, education, head motion, and sex balance did not significantly differ between groups. All hubs had lower DC in SCD compared to HC (p ≤ .006). Connectometry identified positive correlation between MK and diagnosis in Left hemisphere tracts associated with two hubs: Inferior Fronto-Occipital, Extreme capsule, and Uncinate tracts from Insular cortex, and Superior Longitudinal, Superior Corticalstriatal, Arcuate, Frontal Aslant, and Corticalspinal tracts from Middle Frontal gyrus. Conclusion Rs-fMRI findings show that intercommunity functional hubs are weaker in SCD compared to healthy individuals. Furthermore, the study identified a relationship of higher MK values in SCD for hubs located in insular cortex and middle frontal gyrus, all left hemisphere biased. Higher MK in SCD also runs counter to our hypothesis but is supported by recent paradoxical increase theories of decline. WMI differences between groups may be subtler than functional changes, warranting examination of the 2 modalities’ relationship.

Episodic memory (EM) impairment is an important feature of early Alzheimer’s Disease and is related to well accepted biomarkers of AD. Monitoring healthy individuals for EM impairment may allow for early detection of risk for AD or a better understanding of resilience to cognitive decline. The present study used a functional magnetic resonance imaging (fMRI) EM task to examine whether neural substrates of EM are associated with classic features of AD. Healthy adults (n = 120, 84 females, 45-85 years of age) completed a 5-minute fMRI EM encoding task which presented photographs of unfamiliar faces and objects with instructions to remember the items for later recognition. Following fMRI preprocessing using FSL, first-level statistical analysis (using Feat) included an explanatory variable that modeled Items that were correctly remembered in the recognition phase to reflect successful encoding. Group-level voxel-wise analysis then examined which of a number of different AD features independently moderated fMRI response during successful encoding, including amyloid deposition from PET, hippocampal volume from MRI, APOE e4 status, and performance on neuropsychological tests (Craft story recall, Multi-Lingual Naming Test: MINT, global cognition: MOCA). Age, sex and education were included as covariates in all voxel-wise analyses and activation maps were cluster-corrected using Z > 3.1, p = .05. The only AD marker that significantly moderated EM successful encoding was amyloid status. Amyloid+ individuals (n = 25) recruited an area of the left antero-lateral temporal cortex (MNI coordinates: x = -68, y = -30, z = -14) more strongly than Amyloid- individuals (n = 94). A post-hoc exploratory analysis (controlling for age, sex and education) revealed that in Amyloid+ individuals, activation in the dorsal aspect of this temporal region was associated with better delayed memory performance (partial r = .426, p = .048) and activation in the ventral aspect of this region was associated with greater left hippocampal volume (partial r = .489, p = .021). In contrast, in Amyloid- individuals, activation in the dorsal aspect of this temporal region was associated with better performance on the MINT (partial r = .288, p = .006). Recruitment of left lateral temporal cortex during successful encoding in Amyloid+ individuals was associated with better delayed memory recall performance and greater hippocampal volume, suggesting a potential profile of resilience to AD.

The ability to anticipate and process predictable unpleasant events, while also regulating emotional reactivity, is an adaptive skill. The current article and a companion in this issue test for potential changes in predictable event processing across the childhood-to-adolescence transition, a key developmental period for biological systems that support cognitive/emotional abilities. While the companion article focuses on emotion regulation and peripheral attention modulation in predictable unpleasant contexts, the current paper presents neurophysiological markers of predictable event processing itself. 315 third-, sixth-, or ninth-grade individuals saw 5-s cues predicting "scary," "every day," or uncertain image content; in this paper, cue- and picture-locked event-related potentials (ERPs) are analyzed. During the cue, early ERP positivities were increased and later slow-wave negativities were reduced when predicted content was scary as compared with mundane. After picture onset, a picture processing-related positivity was then increased for scary compared with everyday images regardless of predictability. Cue-interval data suggest enhanced processing of scary cues and reduced anticipatory processing of scary images-opposite to adults. After event onset, meanwhile, emotional ERP enhancement regardless of predictability is similar to adults and suggests that even preadolescent individuals maintain preferential engagement with unpleasant events when they are predictable.

The ability to anticipate and process predictable unpleasant events, while also regulating emotional reactivity, is an adaptive skill. The current article and a companion in this issue test for potential changes in predictable event processing across the childhood-to-adolescence transition, a key developmental period for biological systems that support cognitive/ emotional abilities. While the companion article focuses on neurophysiology of predictable event processing itself, the present article examines peripheral emotional response regulation and attention modulation that coincides with event processing. A total of 315 third-, sixth-, or ninth-grade individuals saw 5-s cues predicting "scary," "every day," or uncertain pictures, and here, blink reflexes and brain event-related potentials (ERPs) elicited by peripheral noise probes are analyzed. During the cue, blink reflexes and probe ERP (P200) amplitudes were increased when the cue predicted scary, compared to everyday, content. After picture onset, reflex enhancement by scary content then disappeared for predictable images, whereas ERP modulation was similar regardless of predictability. Patterns are similar to those in adults and suggest (1) sustained defensive response priming and enhancement of peripheral attention during aversive anticipation, and (2) an ability, even in pre-adolescents, to downregulate defensive priming while maintaining attentional modulation once an awaited predictable aversive event occurs.

Objective: The aim of this study was to determine the efficacy of doxazosin, an α1-adrenergic antagonist, for the treatment of co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD).Methods: This 12-week, double-blind, randomized controlled trial of doxazosin (16 mg/d) was conducted between June 2016 and December 2019 at the Ralph H. Johnson VA Medical Center in Charleston, South Carolina. Participants were military veterans (N = 141) who met DSM-5 criteria for current PTSD and AUD and were randomly assigned to receive doxazosin (n = 70) or placebo (n = 71). Primary outcome measures were the Clinician Administered PTSD Scale (CAPS-5), the PTSD Checklist for DSM-5 (PCL-5), and the Timeline Follow-Back (TLFB).Results: Findings from the intent-to-treat analyses revealed that participants in both groups demonstrated statistically significant reductions in CAPS-5 and PCL-5 scores (P < .0001), but, contrary to hypotheses, no significant differences were observed between groups. Percent drinking days and percent heavy drinking days also decreased significantly during treatment, but there were no differences between groups (P < .0001). Abstinence during treatment was significantly higher in the doxazosin versus the placebo group (22% vs 7%, P = .017); however, participants in the doxazosin group consumed a greater number of drinks on drinking days (6.15 vs 4.56, P = .0096). A total of 74.5% of the sample completed the treatment phase, and there were no group differences in retention or adverse events.Conclusions: Doxazosin was safe and tolerable but was not more effective than placebo in reducing PTSD or AUD severity in this dually diagnosed sample. Clinical considerations such as heterogeneity of PTSD and AUD presentation and potential moderators are discussed in the context of future research directions.Trial Registration: ClinicalTrials.gov Identifier: NCT02500602.

BACKGROUND:A significant proportion of individuals with alcohol use disorder (AUD) also meet criteria for posttraumatic stress disorder (PTSD). Military veterans are at increased risk for developing co-occurring AUD/PTSD, with prevalence rates 2-4 times higher than the general population. Research is needed to develop more effective treatments for this common comorbidity. The current investigation addresses this need by examining the synergistic effects of a novel pharmacotherapy combined with psychotherapy for co-occurring AUD/PTSD among veterans. Accumulating evidence suggests that the neuropeptide oxytocin (OT) is a promising pharmacotherapy to augment psychotherapy for AUD/PTSD. OT targets neurobiological and behavioral dysregulation common to both AUD and PTSD, in particular, corticolimbic connectivity. Human and animal studies show OT reduces alcohol self-administration, tolerance, and withdrawal; enhances fear extinction; and promotes prosocial behaviors. The current study builds on previous work by examining OT among veterans with AUD/PTSD receiving Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE), an evidence-based integrated treatment. METHODS:This paper describes the rationale, design, and methodology of a Stage II, 12-week, double-blind, randomized clinical trial of intranasal OT (40 IU) versus placebo combined with COPE among veterans (N = 180) with current AUD/PTSD. In addition, the effects of treatment on corticolimbic connectivity will be examined using functional magnetic resonance imaging (fMRI) at pre- and post-treatment. CONCLUSIONS:The proposed study will provide new knowledge and mechanistic insights to accelerate research in this understudied area and may lead to improved treatment outcomes for co-occurring AUD/PTSD. CLINICALTRIALS:gov: NCT04523922.

Background: Expedient diagnosis of incipient dementia is often hindered by time constraints in primary care visits, shortage of dementia specialists, and extended waitlists for comprehensive neuropsychological evaluations. Methods: We developed the Rapid Access Memory Program (RAMP) to improve access of neuropsychological services for older adults presenting to our institutional primary care clinics with concerns of cognitive decline. RAMP provides abbreviated neurocognitive assessment, same-day patient feedback, expedited reporting to referring providers, and is financially selfsupported. Here, we describe development of RAMP and clinical outcomes from the first 3 years. Results: Of 160 patients seen, dementia was diagnosed in 30% and Mild Cognitive Impairment in 50%; Alzheimer ' s disease was the most common suspected etiology. New psychiatric diagnosis was made in about one-third (n = 54). Most frequent recommendations involved medication adjustments (initiating cholinesterase inhibitors, deprescribing anticholinergics), safety (driving, decision-making), and specialist referrals. Additionally, 27 (17%) subsequently enrolled in local research. Conclusions: Results support feasibility and utility of RAMP for connecting older adults in primary care with neuropsychological services.

Social stress can contribute to the development of substance use disorders (SUDs) and increase the likelihood of relapse. Oxytocin (OT) is a potential pharmacotherapy that may buffer the effects of social stress on arousal and reward neurocircuitry. However, more research is needed to understand how OT moderates the brain’s response to social stress in SUDs. The present study examined the effect of intransasal OT (24 IU) versus placebo (PBO) on corticolimbic functional connectivity associated with acute social stress in individuals with cocaine use disorder (CUD; n = 67) and healthy controls (HC; n = 52). Psychophysiological interaction modeling used the left and right amygdala as seed regions with the left and right orbitofrontal and anterior cingulate cortex as a priori regions of interest. Moderators of the OT response included childhood trauma history and biological sex, which were examined in independent analyses. The main finding was that OT normalized corticolimbic connectivity (left amygdala-orbitofrontal and left amygdala-anterior cingulate) as a function of childhood trauma such that connectivity was different between trauma-present and trauma-absent groups on PBO, but not between trauma groups on OT. Effects of OT on corticolimbic connectivity were not different as a function of diagnosis (CUD vs HC) or sex. However, OT reduced subjective anxiety during social stress for CUD participants who reported childhood trauma compared to PBO and normalized craving response as a function of sex in CUD. The present findings add to some prior findings of normalizing effects of OT on corticolimbic circuitry in individuals with trauma histories and provide some initial support that OT can normalize subjective anxiety and craving in CUD.