Person: Ressler, Kerry
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Ressler
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Kerry
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Ressler, Kerry
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Publication Treatment Outcomes of Electroconvulsive Therapy for Depressed Patients With and Without Borderline Personality Disorder: A Retrospective Cohort Study(Physicians Postgraduate Press, Inc, 2021-01-19) Yip, Agustin G.; Ressler, Kerry; Rodriguez-Villa, Fernando; Siddiqi, Shan H.; Seiner, Steven J.; SeinerBackground: Electroconvulsive therapy (ECT) is the gold-standard treatment for refractory depression. Borderline personality disorder (BPD) is generally considered a poor predictor of treatment response. We sought to assess symptom-severity outcomes among depressed patients, with and without BPD, undergoing acute phase ECT. Methods: The study sample consisted of at least moderately depressed patients who received an acute course of ECT from January 2011 to December 2016 at a freestanding psychiatric hospital. Participants completed a DSM-IV-validated BPD screening instrument (MSI-BPD) at baseline. Measures of DSM-IV depressive symptom severity (QIDS-SR) were taken serially on four occasions. Outcomes of interest comprised total QIDS-SR score trajectory, as well as QIDS-SR suicidality subscore and symptom clusters posited to differentiate response among antidepressant treatments. Results: 693 individuals met study inclusion criteria, 145 (20.9%) of whom screened positive for BPD. Overall, ECT was associated with significant improvement of depressive symptoms (χ2(1) = 504.8, p < 0.0001). Despite differing from BPD(-) individuals on key baseline features, BPD(+) individuals responded to ECT with similar improvement in overall depression severity (χ2(1) = 0.22, p = 0.64), suicidality (χ2(1) = 1.63, p = 0.20), and core emotional (χ2(1) = 0.63, p = 0.43), sleep (χ2(1) = 0.20, p = 0.65), and atypical (χ2(1) = 1.30, p = 0.25) symptoms after 15 treatments. Post hoc analysis indicates a slightly less robust overall response among BPD(+) by the 15th treatment. Conclusion: Acute course ECT benefits depressed patients, with or without co-morbid BPD, although patients with BPD may exhibit less pronounced improvement over time. Key words: electroconvulsive therapy, borderline personality disorder, depressionPublication Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally(BioMed Central, 2017) Barrett, Catherine E.; Hennessey, Thomas M.; Gordon, Katelyn M.; Ryan, Steve J.; McNair, Morgan L.; Ressler, Kerry; Rainnie, Donald G.Background: The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. Methods: Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. Results: Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. Conclusions: As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes. Electronic supplementary material The online version of this article (doi:10.1186/s13229-017-0160-x) contains supplementary material, which is available to authorized users.Publication F42. CHONDROTIN-6 SULFATE CLUSTERS: ASSOCIATION OF SYNAPTIC DOMAINS AND REGULATION OF SYNAPTIC PLASTICITY DURING FEAR LEARNING(Oxford University Press, 2018) Chelini, Gabriele; Berciu, Cristina; Pilobello, Kanoelani; Peter, Durning; Rachel, Jenkins; Kahn, Moazzzam; Ramikie, Teniel; Subramanian, Siva; Ressler, Kerry; Pantazopoulos, Charalampos; Berretta, SabinaAbstract Background: Emerging evidence from our group and others has brought the brain extracellular matrix (ECM) to the forefront of investigations on brain disorders. Our group has shown that organized perisynaptic ECM aggregates, i.e. perineuronal nets (PNNs) are decreased in several brain regions in people with schizophrenia (SZ) and bipolar disorder (BD). PNNs were detected by their expression of specific chondroitin sulfate proteoglycans (CSPGs), main components of the ECM, thought to play a key role in synaptic regulation during development and adulthood. Our studies have also shown that glial cells expressing CSPGs are altered in these disorders, suggesting a link between glial cell and PNN abnormalities. Finally, we have recently shown that novel CSPG structures, bearing a distinct CS-6 sulfation pattern and named CS-6 glial clusters, are decreased in the amygdala of people with SZ and BD. The morphology and function of CS-6 glial clusters is not currently known, but evidence from rodents and on the role of CSPGs in regulating synaptic functions strongly suggest that they may affect synaptic plasticity. We tested this hypothesis using a combination of human postmortem and rodent brain studies. Methods: High Resolution electron microscopy was used to investigate the ultrastructural organization of CS-6 glia clusters. A transgenic mouse model expressing green fluorescent protein in a subset of excitatory pyramidal neurons was used to investigate dendritic spines association with CS-6 glia clusters. Mice were exposed to a single session of auditory fear conditioning for a total of 15 minutes. Animals were euthanized 4 hours after behavioral test. Multiplex immunocytochemistry was used to visualize CS-6 clusters. Results: In human tissue, we show that CS-6 glia clusters are widespread in several brain regions, including the amygdala, entorhinal cortex, thalamus and hippocampus. Ultrastructural results show that CS-6 glia clusters are formed by CS-6 accumulations surrounding several dendrites. CS-6 expression was dected in astrocytes surrounding the dendrites, particularly in astrocytic endfeet enveloping dendritic spines, and within spines postsynaptic densities. Following auditory fear conditioning, marked changes of CS-6 glia clusters were observed in hippocampus regions dentate gyrus (g>1.5) and CA2 (g>1.5) and basolateral amygdala (g>1). Discussion These findings suggest that CS-6 glia clusters may represent segregated microdomains, dynamically regulated during learning and contributing to the modulation of synaptic regulation machinery. Specifically, we postulate that astrocytes synthesize CS-6 CSPG and secrete it through their endfeet around dendrites, modulating structural plasticity of dendritic spines. These results suggest a relationship between the abnormalities in CSPGs expression and alteration in dendritic spines, two pathological landmarks observed in postmortem brains of people with SZ and BD.Publication Quantified Coexpression Analysis of Central Amygdala Subpopulations(Society for Neuroscience, 2018) McCullough, Kenneth; Morrison, Filomene G.; Hartmann, Jakob; Carlezon, William; Ressler, KerryAbstract Molecular identification and characterization of fear controlling circuitries is a promising path towards developing targeted treatments of fear-related disorders. Three-color in situ hybridization analysis was used to determine whether somatostatin (SOM, Sst), neurotensin (NTS, Nts), corticotropin-releasing factor (CRF, Crf), tachykinin 2 (TAC2, Tac2), protein kinase c-δ (PKC-δ, Prkcd), and dopamine receptor 2 (DRD2, Drd2) mRNA colocalize in male mouse amygdala neurons. Expression and colocalization was examined across capsular (CeC), lateral (CeL), and medial (CeM) compartments of the central amygdala. The greatest expression of Prkcd and Drd2 were found in CeC and CeL. Crf was expressed primarily in CeL, while Sst-, Nts-, and Tac2-expressing neurons were distributed between CeL and CeM. High levels of colocalization were identified between Sst, Nts, Crf, and Tac2 within the CeL, while little colocalization was detected between any mRNAs within the CeM. These findings provide a more detailed understanding of the molecular mechanisms that regulate the development and maintenance of fear and anxiety behaviors.Publication A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder(BioMed Central, 2017) Polimanti, Renato; Amstadter, Ananda B.; Stein, Murray B.; Almli, Lynn M.; Baker, Dewleen G.; Bierut, Laura J.; Bradley, Bekh; Farrer, Lindsay A.; Johnson, Eric O.; King, Anthony; Kranzler, Henry R.; Maihofer, Adam X.; Rice, John P.; Roberts, Andrea L.; Saccone, Nancy L.; Zhao, Hongyu; Liberzon, Israel; Ressler, Kerry; Nievergelt, Caroline M.; Koenen, Karestan; Gelernter, JoelBackground: The nature and underlying mechanisms of the observed increased vulnerability to posttraumatic stress disorder (PTSD) in women are unclear. Methods: We investigated the genetic overlap of PTSD with anthropometric traits and reproductive behaviors and functions in women. The analysis was conducted using female-specific summary statistics from large genome-wide association studies (GWAS) and a cohort of 3577 European American women (966 PTSD cases and 2611 trauma-exposed controls). We applied a high-resolution polygenic score approach and Mendelian randomization analysis to investigate genetic correlations and causal relationships. Results: We observed an inverse association of PTSD with genetically determined anthropometric traits related to body shape, independent of body mass index (BMI). The top association was related to BMI-adjusted waist circumference (WCadj; R = –0.079, P < 0.001, Q = 0.011). We estimated a relative decrease of 64.6% (95% confidence interval = 27.5–82.7) in the risk of PTSD per 1-SD increase in WCadj. MR-Egger regression intercept analysis showed no evidence of pleiotropic effects in this association (Ppleiotropy = 0.979). We also observed associations of genetically determined WCadj with age at first sexual intercourse and number of sexual partners (P = 0.013 and P < 0.001, respectively). Conclusions: There is a putative causal relationship between genetically determined female body shape and PTSD, which could be mediated by evolutionary mechanisms involved in human sexual behaviors. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0491-4) contains supplementary material, which is available to authorized users.Publication Molecular characterization of Thy1 expressing fear-inhibiting neurons within the basolateral amygdala(Nature Publishing Group, 2016) McCullough, Kenneth; Choi, Dennis; Guo, Jidong; Zimmerman, Kelsey; Walton, Jordan; Rainnie, Donald G.; Ressler, KerryMolecular characterization of neuron populations, particularly those controlling threat responses, is essential for understanding the cellular basis of behaviour and identifying pharmacological agents acting selectively on fear-controlling circuitry. Here we demonstrate a comprehensive workflow for identification of pharmacologically tractable markers of behaviourally characterized cell populations. Thy1-eNpHR-, Thy1-Cre- and Thy1-eYFP-labelled neurons of the BLA consistently act as fear inhibiting or ‘Fear-Off' neurons during behaviour. We use cell-type-specific optogenetics and chemogenetics (DREADDs) to modulate activity in this population during behaviour to block or enhance fear extinction. Dissociated Thy1-eYFP neurons are isolated using FACS. RNA sequencing identifies genes strongly upregulated in RNA of this population, including Ntsr2, Dkk3, Rspo2 and Wnt7a. Pharmacological manipulation of neurotensin receptor 2 confirms behavioural effects observed in optogenetic and chemogenetic experiments. These experiments identify and validate Ntsr2-expressing neurons within the BLA, as a putative ‘Fear-Off' population.Publication DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression(Nature Publishing Group, 2015) Wingo, Aliza P.; Almli, Lynn M.; Stevens, Jennifer J.; Klengel, Torsten; Uddin, Monica; Li, Yujing; Bustamante, Angela C.; Lori, Adriana; Koen, Nastassja; Stein, Dan J.; Smith, Alicia K.; Aiello, Allison E.; Koenen, Karestan C.; Wildman, Derek E.; Galea, Sandro; Bradley, Bekh; Binder, Elisabeth B.; Jin, Peng; Gibson, Greg; Ressler, KerryDICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.Publication Emotion Dysregulation and Inflammation in African-American Women with Type 2 Diabetes(Hindawi Publishing Corporation, 2016) Powers, Abigail; Michopoulos, Vasiliki; Conneely, Karen; Gluck, Rachel; Dixon, Hayley; Wilson, Joseph; Jovanovic, Tanja; Pace, Thaddeus W. W.; Umpierrez, Guillermo E.; Ressler, Kerry; Bradley, Bekh; Gillespie, Charles F.C-reactive protein (CRP), a marker of systemic inflammation, has been associated with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state. The objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus (T2DM). We examined associations between trauma exposure, MDD, PTSD, emotion dysregulation, and CRP among 40 African-American women with T2DM recruited from an urban hospital. Emotion dysregulation was measured using the Difficulties in Emotion Regulation Scale. PTSD and MDD were measured with structured clinical interviews. Child abuse and lifetime trauma load were also assessed. Analyses showed that both emotion dysregulation and current MDD were significantly associated with higher levels of CRP (p < 0.01). Current PTSD was not significantly related to CRP. In a regression model, emotion dysregulation was significantly associated with higher CRP (p < 0.001) independent of body mass index, trauma exposure, and MDD diagnosis. These findings suggest that emotion dysregulation may be an important risk factor for chronic inflammation beyond already known risk factors among women with T2DM, though a causal relationship cannot be determined from this study.Publication Neural correlates and structural markers of emotion dysregulation in traumatized civilians(Oxford University Press, 2017) Powers, Abigail; Stevens, Jennifer S.; van Rooij, Sanne J.H.; Ely, Timothy D.; Fani, Negar; Jovanovic, Tanja; Ressler, Kerry; Bradley, BekhAbstract Emotion dysregulation (ED) reflects deficits in understanding and managing negative emotions and may serve as a transdiagnostic mechanism of risk for trauma-related psychiatric disorders. Therefore, understanding neurobiological substrates of ED in traumatized individuals is critical. The present study examined associations between ED and baseline structural differences and patterns of functional activity during an emotional task in a sample of African American women (n = 136) recruited from an urban hospital. Participants engaged in a structural magnetic resonance imaging (MRI) session. A subsample (n = 92) also viewed emotional face stimuli during functional MRI. ED was related to greater dorsal anterior cingulate cortex (dACC) surface area (Pcorr < 0.05) and increased dorsomedial prefrontal cortex (dmPFC) and ventromedial PFC activation to fearful stimuli (Pcorr < 0.05), independent of the trauma and psychiatric symptoms. DMPFC activation was also associated with posttraumatic stress disorder and depression symptoms. Mediation analyses showed a significant mediation effect of ED on the relation between dmPFC activation and psychiatric symptoms. These findings are important since dACC and dmPFC play central roles in fear expression and attention to emotional stimuli. Future longitudinal research is needed to help solidify a model of risk for how such neural substrates may be impacted by traumatic experiences to create ED.Publication Exposure to Childhood Abuse and Later Substance Use: Indirect Effects of Emotion Dysregulation and Exposure to Trauma(John Wiley and Sons Inc., 2016) Mandavia, Amar; Robinson, Gabriella G. N.; Bradley, Bekh; Ressler, Kerry; Powers, AbigailLittle is known about how emotion dysregulation (ED) and trauma exposure differentially affect the relationship between abuse in childhood and adult substance use. We examined associations between child abuse, trauma exposure, ED, and current substance use in an already existing dataset. Participants (N = 2,014 adults, 90% African American) had been recruited from an urban hospital for a parent study. Analyses showed that drug and alcohol use was significantly positively correlated with child abuse (emotional, physical, and sexual), later trauma exposure, and ED (all ps < .001). Linear regression showed that exposure to abuse when older than a child was significantly associated with drug and alcohol use independent of child abuse and demographic variables (R 2Δ = .08, p < .001; R 2Δ = .04, p < .001). ED was significantly associated with drug and alcohol use independently of child abuse, nonabuse trauma, and demographic variables (R 2Δ = .02, p < .001; R 2Δ = .04, p < .001). Multiple mediation analyses showed that ED and later trauma exposure accounted for variance in the association between emotional abuse and substance use (p < .001). A better understanding of vulnerabilities to additional traumatization and emotion‐regulation deficits in individuals who have been exposed to child abuse and in addition have comorbid substance use problems may inform treatments that lead to improved outcomes.