ABSTRACT IMPACT: Our research has the potential to impact human health by identifying gender specific neural markers of emotion regulation in alcohol use disorder. OBJECTIVES/GOALS: Emotion dysregulation is known to be mediated by altered functional organization of the limbic system in addiction. This preliminary study sought to identify gender effects in the association between emotion regulation and resting-state functional connectivity (rsFC) of a negative affect network. METHODS/STUDY POPULATION: 55 individuals receiving treatment for alcohol use disorder (˜2 weeks of abstinence) were recruited for this study and included in this analysis (N=55; Age: M=41.78, SD=10.66; 21 females). RsFC within a network involved in the withdrawal/negative affect stage of addiction and Personality Inventory for DSM-5 (PID-5) metrics were collected from all participants. RsFC data were preprocessed using the Human Connectome Project pipelines. Correlations between (a) rsFC within the withdrawal/negative affect network and the (b) scores of the negative affect subscale of the PID-5 instrument were conducted for each gender separately. RESULTS/ANTICIPATED RESULTS: Independent samples t-test showed a statistically significant gender difference in the PID-5 negative affect scores (Males: M=1.02, SD=0.66; Females: M=1.53, SD=0.51); t(55)=-3.002, p=0.004. Only females showed a significant correlation between rsFC within the withdrawal/negative affect network and negative affect scores of the PID-5 (r=0.51, p<0.05). Fisher r-to-z test showed significant gender differences (z=-1.91; p=0.03, 1-tailed) in correlations coefficients representing the relationship between rsFC of the withdrawal/negative affect network and negative affect (PID-5 subscale). DISCUSSION/SIGNIFICANCE OF FINDINGS: Preliminary findings suggest that the relationship between neural networks mediating emotion regulation and negative affect is only found in females. These results provide valuable data to inform personalized chemical dependency treatment that targets emotion regulation specific to females.

OBJECTIVES/SPECIFIC AIMS: Given the heightened risk for suicide seen in individuals with PTSD+MDD, this report explored the effect of repeated ketamine infusions on SI in a cohort of veterans. METHODS/STUDY POPULATION: Veterans with PTSD+MDD (n = 15) received six intravenous infusions of 0.5 mg/kg ketamine on a Monday-Wednesday-Friday schedule over a 12-day period. All subjects endorsed SI at baseline. Outcome measures included the Montgomery-Asberg Depression Rating Scale (MADRS) total score, MADRS suicidal ideation item, and PTSD symptom Checklist for DSM-5 (PCL-5) subscales (intrusion, avoidance, negative alterations in cognition and mood, and marked alterations in arousal and reactivity), and visual analog scale of pain. Measures were collected immediately before and 24-hours after each infusion. RESULTS/ANTICIPATED RESULTS: Significant improvement in SI was observed 24-hours after the first infusion (Z = 3.21; p = .001) and remained significantly improved at all other post-infusion time points. Improvement in SI at the conclusion of the infusion series was significantly correlated with PTSD subscales of avoidance (r(12) = .610, p = .021), negative alterations in cognition and mood (r(12) = .786, p = .001), alterations in arousal and reactivity (r(12) = .729, p = .003), and pain (r(12) = .591, p = .013), even when controlling for improvement in symptoms of depression. DISCUSSION/SIGNIFICANCE OF IMPACT: The present analysis provides evidence of improvement in SI in a cohort of veterans with PTSD+MDD. Improvements in suicidality were correlated with PTSD symptom subscales and pain independent of improvement in depression. This report extends the interpersonal theory of suicide as it applies to posttraumatic pathology by demonstrating a significant association between improvements in all subclusters of PTSD, improvement in pain and improvement in suicidal ideation.

OBJECTIVES/SPECIFIC AIMS: -Transmit learning and wisdom from past scholars -Predispose new scholars towards a receptive attitude -Normalize struggle and failure on the road to success -Encourage a community of accomplishment and celebration -Connect the scholar METHODS/STUDY POPULATION: The exit presentations were given by NCATS funded junior faculty in the CTSI KL2 Scholars Program who had graduated. All KL2 Scholars take part in the K Scholar Multidisciplinary Seminar Series that meets weekly during the academic calendar. The departed scholars returned for the presentations the following semester. The audience was made up of KL2 who had started with a later cohort, the CTSI KL2 program is a 3-year program, and newly appointed scholars. Scholars were given 12-15 minutes to cover: 1) What was learned, 2) Accomplishments on specific aims, 3) Next steps for project and career, and 4) Recommendations for other scholars. Presentations were collected and reviewed for recurring themes. Themes were grouped and quotes were included to identify nuance. RESULTS/ANTICIPATED RESULTS: From the 17 exit presentations, six themes were identified: 1) Don’t miss the forest for the trees (x10) – “the KL2 program helps to fill in gaps scholars don’t realize they have – it is about more than just the research project, trust in the process and let the program help keep you on track.” 2) Diversify and keep an open mind (x7) – “focus is important but diversifying research and reorganizing priorities is ok.” 3) Don’t be discouraged by failure (x6) –” perseverance is key, all success comes on the heels of many failures.” 4) Importance of building network inside and outside of Scholar program (x6) – “importance of exploring and establishing collaborations” 5) Learn to say no and yes (x5) – “protect your time but be open to opportunities” 6) Seek advice and criticism but don’t follow blindly (x4) DISCUSSION/SIGNIFICANCE OF IMPACT: The use of exit presentations for graduating KL2 Scholars is a useful tool in transmitting wisdom and enhancing subsequent KL2 cohorts. The Scholar’s experience and trajectory, share personal insights and recommendations to help other Scholars get the most out of their KL2 experience, give the community a chance to celebrate the Scholar’s accomplishments, and provide the Scholar with a sense of closure in their KL2 journey. Within the exit presentations, six common themes emerged relating to best practices on making good use of resources and guidance, and learning to interact and navigate within networks and responsibilities in a mature way. Scholars in the audience benefit from hearing the insights and advice from their predecessors. The identification of themes helps the program to understand where it adds value.

Integrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12–19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.

The N-methyl-D-aspartate glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive aspects in TRD has started to be explored. This study aims to (1) examine baseline neurocognitive performance and change in severity of depressive symptoms through six ketamine infusions, (2) examine the neurocognitive effects after completion of serial infusions and whether changes were associated to relapse to depression. Six IV infusions of 0.5 mg/Kg ketamine over 40 min were conducted on a Monday–Wednesday–Friday schedule during a 12-d period on 15 patients with TRD followed by a 4-wk observational period. Neurocognitive functioning was assessed using the CogState battery at baseline and at each follow-up visit. Tasks were designed to test attention, memory (working, visual, and verbal), speed of processing, and set shifting. The likelihood of response through six infusions was greater among depressed subjects with lower attention at baseline (F(1,13) = 5.59, p = 0.034). Significant improvement was found in scores of visual memory (F(4,33.82) = 5.12, p = 0.002), simple working memory (F(4, 24.85) = 3.29, p = 0.027) and complex working memory (F(4, 32.76) = 4.18, p = 0.008) after the last ketamine infusion. However, neurocognitive changes were accounted for by improvement in the severity of depressive symptom. The acute neurocognitive effect after completion of repeated infusions was not associated with the likelihood of subsequent relapse during follow-up. Our findings suggest a potential baseline neurocognitive predictor of ketamine response and the apparently lack of short-term neurocognitive impairment after completion of six ketamine infusions in TRD.

Diffusion tensor imaging was used to investigate white matter (WM) integrity in adults with traumatic brain injury (TBI) and healthy adults as controls. Adults with TBI had sustained severe vehicular injuries on the average of 7 years earlier. A multivariate analysis of covariance with verbal IQ as the covariate revealed that adults with TBI had lower fractional anisotropy and higher mean diffusivity than controls, specifically in the three regions of interest (ROIs), the centrum semiovale (CS), the superior frontal (SPF), and the inferior frontal (INF). Adults with TBI averaged in the normal range in motor speed and two of three executive functions and were below average in delayed verbal recall and inhibition, whereas controls were above average. Time since injury, but not age, was associated with WM changes in the SPF ROI, whereas age, but not time since injury, was associated with WM changes in the INF ROI, suggesting that the effects of WM on time since injury may interact with age. To understand the utility of WM changes in chronic recovery, larger sample sizes are needed to investigate associations between cognition and WM integrity of severely injured individuals who have substantial cognitive impairment compared to severely injured individuals with little cognitive impairment. (JINS, 2009, 15, 130–136.)

Neuroimaging and lesion studies have demonstrated that hippocampal volume correlates with memory performance, but material-specific lateralization of this structure-function relationship has been inconsistent. This MRI study examined the relative contributions of left and right temporal lobe volumes to verbal and nonverbal recognition memory in a group of 20 Alzheimer's disease (AD) patients. There was a significant relationship between extent of right hippocampal and right temporal gray matter tissue volume deficit and performance on the face recognition subtest of the Warrington Recognition Memory Test. The face recognition test correlated with right hemisphere volume but not to left, indicating a material-specific relationship between brain structure and function in this patient group. Right temporal horn volume did not account for a significant proportion of variance in face recognition memory. Although word recognition was not significantly correlated with either left or right hippocampal volume in the total group, there was a strong correlation between left hippocampal volume and word recognition memory in the female AD patients. Thus, face recognition shows a material specific relationship with select lateralized hippocampal and temporal cortical volumes in AD patients, regardless of gender, whereas the verbal recognition–left-hippocampal volume relationship may be mediated by gender. (JINS, 1998, 4, 106–114.)

This study examined the relationships between regional cortical and hippocampal brain volumes and components of remote memory (recall, recognition, sequencing, and photo naming of presidential candidates) in 13 individuals with Alzheimer's disease (AD). Recognition and sequencing of remote memory for public figures were associated with regional cortical volumes. Specifically, lower recognition and sequencing scores were associated with smaller parietal–occipital cortical volumes; poorer sequencing was also associated with smaller prefrontal cortical volumes. By contrast, poorer anterograde but not remote memory scores were correlated with smaller hippocampal volumes. Within the constraints of the brain regions measured, these findings highlight the importance of the posterior cortical areas for selective remote memory processes and provide support for the dissociation between cortically mediated remote memory and hippocampally mediated anterograde memory. (JINS, 2001, 7, 384–390.)

The Clock Drawing Test (CDT) is widely used in the assessment of dementia and is known to be sensitive to the detection of deficits in neurodegenerative disorders such as Alzheimer's disease (AD). CDT performance is dependent not only on visuospatial and constructional abilities, but also on conceptual and executive functioning; therefore, it is likely to be mediated by multiple brain regions. The purpose of the present study was to identify component cognitive processes and regional cortical volumes that contribute to CDT performance in AD. In 29 patients with probable AD, CDT performance was significantly related to right-, but not left-hemisphere, regional gray matter volume. Specifically, CDT score correlated significantly with the right anterior and posterior superior temporal lobe volumes. CDT scores showed significant relationships with tests of semantic knowledge, executive function, and visuoconstruction, and receptive language. These results suggest that in AD patients, CDT performance is attributable to impairment in multiple cognitive domains but is related specifically to regional volume loss of right temporal cortex. (JINS, 1999, 5, 502–509.)