Lynnette A Averill

• PhD
• Research Associate at Yale University

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that follows exposure to a traumatic stressor. Though previous in vivo proton (1H) MRS) research conducted at 4 T or lower has identified alterations in glutamate metabolism associated with PTSD predisposition and/or progression, no prior investigations have been conducted at h...

Reductions in default mode (DMN) connectivity strength have been reported in posttraumatic stress disorder (PTSD). However, the specificity of DMN connectivity deficits in PTSD compared to major depressive disorder (MDD), and the sensitivity of these alterations to acute stressors are not yet known. 52 participants with a primary diagnosis of PTSD...

Psychedelics have again become a subject of widespread interest, owing to the reinvigoration of research into their traditional uses, possible medical applications, and social implications. As evidence for psychedelics' clinical potential mounts, the field has increasingly focused on searching for mechanisms to explain the effects of psychedelics a...

Psychedelic therapy is, arguably, the next frontier in psychiatry. It offers a radical alternative to longstanding, mainstays of treatment, while exciting a paradigm shift in translational science and drug discovery. There is particular interest in 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)—a serotonergic psychedelic—as a novel, fast-acting thera...

Background: Research in psychedelic medicine has focused primarily on civilian populations. Further study is needed to understand whether these treatments are effective for Veteran populations.Objectives: Here, we examine the effectiveness of psychedelic-assisted therapy among trauma-exposed Special Operations Forces Veterans (SOFV) seeking treatme...

A Prior study demonstrated that psychedelic-assisted therapy was related to reductions in mental health symptoms and associated consequences among U.S. Special Operations Forces Veterans seeking treatment in Mexico. The present study extends this analysis to explore the prospective associations of baseline predictors on treatment outcomes and wheth...

Background: Early trauma predicts poor psychological and physical health. Glutamatergic synaptic processes offer one avenue for understanding this relationship, given glutamate’s abundance and involvement in reward and stress sensitivity, emotion, and learning. Trauma-induced glutamatergic excitotoxicity may alter neuroplasticity and approach/avoid...

Background: Research in psychedelic medicine has focused primarily on civilian populations. Further study is needed to understand whether these treatments are effective for Veteran populations. Objectives: Here we examine the effectiveness of psychedelic-assisted therapy among trauma-exposed Special Operations Forces Veterans (SOFV) seeking treatme...

Post-traumatic stress disorder is a mental disorder that may occur in the aftermath of severe psychological trauma. We examined 1,065,750 DNA methylation (DNAm) sites from 171 donors including neurotypicals, PTSD, and major depressive disorder cases across six areas implicated in the fear circuitry of the brain. We found significant differential me...

Ketamine is an effective intervention for treatment-resistant depression (TRD), including late-in-life (LL-TRD). The proposed mechanism of antidepressant effects of ketamine is a glutamatergic surge, which can be measured by electroencephalogram (EEG) gamma oscillations. Yet, non-linear EEG biomarkers of ketamine effects such as neural complexity a...

Posttraumatic stress disorder (PTSD) is a devastating condition, for which there are few pharmacological agents, often with a delayed onset of action and poor efficacy. Trauma-focused psychotherapies are further limited by few trained providers and low patient engagement. This frequently results in disease chronicity as well as psychiatric and medi...

Background A dissociative subtype of posttraumatic stress disorder, known as “D-PTSD”, has been included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. In addition to meeting criteria for PTSD, patients endorse prominent dissociative symptoms, namely depersonalization and derealization, or detachment from one's self an...

This study evaluated prospective associations of ibogaine and 5-MeO-DMT treatment for risky alcohol use and post-traumatic stress disorder (PTSD) symptoms among United States (US) Special Operations Forces Veterans (SOFV). Data were collected during standard clinical operations at pre-treatment and 1-month (1 m), 3-months (3 m), and 6-months (6 m)...

Background and Aims Ketamine and esketamine have garnered interest in both psychiatric research and clinical practice for treatment-resistant depression (TRD). In this review, we examined registered trials investigating the therapeutic use of ketamine or esketamine for TRD, with the aim of characterizing emerging trends and knowledge gaps. Methods...

Reductions in default mode (DMN) connectivity strength have been reported in posttraumatic stress disorder (PTSD). However, the specificity of DMN connectivity deficits in PTSD compared to major depressive disorder (MDD), and the sensitivity of these alterations to acute stressors are not yet known. 52 participants with primary diagnosis of PTSD (n...

There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine [MDMA]), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted B...

Background: The Rapid Acting Empathogen (RAE) 3,4-methylenedioxy-N-methylcathinone (methylone; also known as MDMC, βk-MDMA, and M1), is a phenethylamine compound with chemical and pharmacological similarities to 3,4-Methylenedioxymethamphetamine (MDMA). It has been used outside of medical settings to treat Posttraumatic Stress Disorder (PTSD) and d...

Post-traumatic stress disorder (PTSD) is an anxiety condition evidenced by wide-ranging emotional and cognitive dysfunction. While prefrontal glutamatergic excitotoxicity is thought to contribute to its presentation, no 1H-MRS studies of PTSD have yet been conducted at 7-Tesla field strength facilitating separation of glutamate from metabolic partn...

Background Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used E...

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the a...

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or stan...

Background & aims Special Operations Forces Veterans (SOFV) have unique treatment needs stemming from multiple repeated forms of combat exposure resulting in a complex sequela of problems including alcohol misuse and post-traumatic stress symptoms. Current approved pharmacologic treatments for alcohol misuse and PTSD are lacking in adherence and ef...

The STRONG STAR Consortium (South Texas Research Organizational Network Guiding Studies on Trauma and Resilience) and the Consortium to Alleviate PTSD are interdisciplinary and multi-institutional research consortia focused on the detection, diagnosis, prevention, and treatment of combat-related posttraumatic stress disorder (PTSD) and comorbid con...

A vast literature demonstrates that traumatic stress has deleterious effects on the brain; however, the precise mechanisms through which these neural alterations occur is not fully elucidated. Neurocircuitry and neuroplasticity have been identified as critical components in determining an individual's stress tolerance and response In this abridged...

Background: This study tested the efficacy of repeated intravenous ketamine doses to reduce antidepressant-resistant symptoms of posttraumatic stress disorder (PTSD). Methods: Veterans and service members with PTSD (n=158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n...

Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to inves...

Background Major depressive disorder (MDD) treatment is characterized by low remission rate and often involves weeks to months of treatment. Identification of pretreatment biomarkers of response may play a critical role in novel drug development, in enhanced prognostic predictions, and perhaps in providing more personalized medicine. Using a networ...

Over the past decade, various N-methyl-D-aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In th...

Background U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-...

A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term effica...

Early life stress (ELS) and glutamate neurotransmission have been implicated in the pathophysiology of major depressive disorder (MDD). In non-human primates, ELS was positively correlated with cortical Glx (i.e., glutamate + glutamine). However, the relationship between ELS and cortical glutamate in adult patients with MDD is not fully known. Usin...

Over the past decade, various N-Methyl-D-Aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In th...

Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients sufferi...

The serendipitous discovery of ketamine’s robust antidepressant effects has served as a major catalyst to usher in new era of drug development and a paradigm shift in our understanding of the neurobiology of chronic stress pathology (CSP). This review provides a selective synthesis of (1) the historical foundations of N-methyl-D-aspartate receptor...

More than six decades have passed since the discovery of monoaminergic antidepressants. Yet, it remains a mystery why these drugs take weeks to months to achieve therapeutic effects, although their monoaminergic actions are present rapidly after treatment. In an attempt to solve this mystery, rather than studying the acute neurochemical effects of...

Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential growth in the number of neuroimaging studies reporting structural and functional brain circuitr...

Background: Although the ε4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction. Methods: We analyzed data from European-American (EA) veterans who participated in the National Health a...

Background: Better understanding of the neurobiology of posttraumatic stress disorder (PTSD) may be critical to developing novel, effective therapeutics. Here, we conducted a data-driven investigation using a well-established, graph-based topological measure of nodal strength to determine the extent of functional dysconnectivity in a cohort of act...

Background: In soldiers with posttraumatic stress disorder (PTSD), symptom provocation was found to induce increased connectivity within the salience network, as measured by functional magnetic resonance imaging (fMRI) and global brain connectivity with global signal regression (GBCr). However, it is unknown whether these GBCr disturbances would n...

Posttraumatic stress disorder (PTSD) is a debilitating disorder with limited medication treatment options. Recent reports have described the dearth of research on new drug development as a crisis in the pharmacotherapy of PTSD. There are only two PTSD medications approved by the U.S. Food and Drug Administration, and both are serotonergic antidepre...

BACKGROUND: In soldiers with posttraumatic stress disorder (PTSD), symptom provocation was found to induce increased connectivity within the salience network, as measured by functional magnetic resonance imaging (fMRI) and global brain connectivity with global signal regression (GBCr). However, it is unknown whether these GBCr disturbances would no...

BACKGROUND: Ketamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. METHODS: Twenty-three patients suffering a major depressive...

The societal burden of psychiatric disorders that result after exposure to psychological trauma is enormous. The study of trauma-related disorders using neurobiological and public health approaches is often disjointed. It is critical to emphasize the translational potential of neurobiological work and its relevance to the public health burden of ps...

BACKGROUND: Better understanding of the neurobiology of posttraumatic stress disorder (PTSD) may be critical to developing novel, effective therapeutics. Here, we conducted a data-driven investigation using a well-established, graph- based topological measure of nodal strength to determine the extent of functional dysconnectivity in a cohort of act...

Military sexual trauma (MST) is associated with a range of negative mental and physical health outcomes. Investigations of potential sex-based differences in outcomes in MST survivors have been inconsistent with little work evaluating psychosocial correlates of resilience (e.g., social support, humor, capacity to adapt to change). Data were analyze...

Background Identifying the neural correlates of ketamine treatment may facilitate and expedite the development of novel, robust, and safe rapid-acting antidepressants. Prefrontal cortex (PFC) global brain connectivity with global signal regression (GBCr) was recently identified as a putative biomarker of major depressive disorder. Accumulating evid...

New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-...

Here we present functional neuroimaging-based network data (focused on the default mode network) collected from a cohort of US Veterans with history of combat exposure, combined with clinical assessments for PTSD and other psychiatric comorbidities. The data has been processed and analyzed using several network construction methods (signed, thresho...

Purpose of the study: Prior studies showed posttraumatic stress disorder (PTSD)-related alterations in white matter integrity, but most of these studies have used region-based approaches. We address this limitation by investigating the relationship between PTSD severity and fractional anisotropy (FA) using a tract-based approach. Procedures: Str...

The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy (13C MRS) methods have shown ketamine and other N-me...

Manuscript Now Published at Molecular Neuropsychiatry. CITATION: Averill CL, Averill LA, Wrocklage KM, Scott JC, Akiki TJ, Schweinsburg B, Southwick SM, Krystal JH, Abdallah CG. Altered white matter diffusivity of the cingulum angular bundle in posttraumatic stress disorder. Mol Neuropsychiatry 2018;4:75–82. https://doi.org/10.1159/000490464

Disruption in the default mode network (DMN) has been implicated in numerous neuropsychiatric disorders, including posttraumatic stress disorder (PTSD). However, studies have largely been limited to seed-based methods and involved inconsistent definitions of the DMN. Recent advances in neuroimaging and graph theory now permit the systematic explora...

Purpose of review: This review focuses on the relationship between resilience and the ability to effectively modulate the stress response. Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes-manifesting psychopathology in one individual, but having minimal effect...

The Methodological Question: Can fMRI-derived restricted-network biomarkers serve as robust marker of PTSD symptomatology? Can these network-analyses identify abnormalities that can potentially be targeted using circuit-based therapeutics?

The Opioid Abuse Risk Screener was developed to support well-informed decision-making in opioid analgesic prescribing by extending the breadth of psychiatric risk factors evaluated relative to other non–clinician-administered measures. We examined the preliminary predictive validity of the Opioid Abuse Risk Screener relative to the widely used Scre...

This manuscript (https://goo.gl/ea9UU9) includes an animated 3D video that was created (in Blender) using meshes from one of the combat control (non-PTSD) participants described in the manuscript. It demonstrates the gray matter subfields of the hippocampus, walking through each one to better visualize the more hidden areas. This video is an excell...

Background Two decades of human neuroimaging research have associated volume reductions in the hippocampus with posttraumatic stress disorder. However, little is known about the distribution of volume loss across hippocampal subfields. Recent advances in neuroimaging methods have made it possible to accurately delineate 10 gray matter hippocampal s...

Background: The discovery of the rapid acting antidepressant effects of ketamine have generated considerable interest in academia and industry about the prospect of targeting NMDA receptors (NMDAR) in the treatment of refractory depression. However, the results from clinical trials failing to reach primary outcomes, combined with recent preclinical...

Abstract Background The hippocampus and amygdala have been repeatedly implicated in the psychopathology of posttraumatic stress disorder (PTSD). While numerous structural neuroimaging studies examined these two structures in PTSD, these analyses have largely been limited to volumetric measures. Recent advances in vertex-based neuroimaging methods h...

Abstract Background: Two decades of human neuroimaging research have associated volume reductions in the hippocampus with posttraumatic stress disorder. However, little is known about the distribution of volume loss across hippocampal subfields. Recent advances in neuroimaging methods have made it possible to accurately delineate 10 gray matter hip...

Purpose of review: Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the...

Background: Chronic stress and related physiological responses are known to have deleterious effects on neural integrity. Combat exposure is a notoriously pathogenic stressor and with over 2 million U.S. troops deployed to active combat zones since 2001, there is an urgent need to advance our understanding of its potential neural impact. Previous...

Background: The hippocampus and amygdala have been repeatedly implicated in the psychopathology of posttraumatic stress disorder (PTSD). While numerous structural neuroimaging studies examined these two structures in PTSD, these analyses have largely been limited to volumetric measures. Recent advances in vertex-based neuroimaging methods have mad...

Covering both natural and man-made scenarios including war and terrorism, the Textbook of Disaster Psychiatry is a vital international reference for medical professionals, community leaders and disaster responders a decade after its initial publication. Spanning a decade of advances in disaster psychiatry, this new and updated second edition brings...

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Background: Prefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression, and was associated with ketamine’s mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological...

We investigated the extent of cortical thinning in U.S. Veterans exposed to combat who varied in the severity of their posttraumatic stress disorder (PTSD) symptoms. In addition, we explored the neural correlates of PTSD symptom dimensions and the interactive effects of combat exposure and PTSD upon cortical thickness. Sixty-nine combat exposed Vet...

We are excited to announce the launch of a new journal, Chronic Stress. The detrimental effects of chronic stress are increasingly evident in preclinical and clinical research. The journal will publish original and review articles related to stress across psychiatric disorders. The journal will be peer-reviewed and open-access. It will publish orig...

Posttraumatic stress disorder (PTSD) is a chronic and debilitating psychiatric disorder afflicting millions of individuals across the world. While the availability of robust pharmacologic interventions is quite lacking, our understanding of the putative neurobiological underpinnings of PTSD has significantly increased over the past two decades. Acc...

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The discovery of antidepressant medications more than 50 years ago was one of the major breakthroughs in medical science. Today, the field of antidepressant drug development is experiencing a paradigm shift. Changing perceptions regarding the neurobiology of depression and the serendipitous discovery of ketamine’s rapid antidepressant effects have...

Capitalizing on recent advances in resting state functional connectivity magnetic resonance imaging (rs-fcMRI) and the distinctive paradigm of rapid mood normalization following ketamine treatment, the current study investigated intrinsic brain networks in major depressive disorder (MDD) during a depressive episode and following treatment with keta...