Christopher L. Averill

Ketamine Treatment and Global Brain Connectivity in Major Depression

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 ketamine. Medication-free patients with MDD and healthy control subjects (HC) completed baseline rs-fcMRI. MDD patients received a single infusion of ketamine and underwent repeated rs-fcMRI at 24 h posttreatment. Global brain connectivity with global signal regression (GBCr) values were computed as the average of correlations of each voxel with all other gray matter voxels in the brain. MDD group showed reduced GBCr in the prefrontal cortex (PFC) but increased GBCr in the posterior cingulate, precuneus, lingual gyrus, and cerebellum. Ketamine significantly increased GBCr in the PFC and reduced GBCr in the cerebellum. At baseline, 2174 voxels of altered GBCr were identified, but only 310 voxels significantly differed relative to controls following treatment (corrected α<0.05). Responders to ketamine showed increased GBCr in the lateral PFC, caudate, and insula. Follow-up seed-based analyses illustrated a pattern of dysconnectivity between the PFC/subcortex and the rest of the brain in MDD, which appeared to normalize postketamine. The extent of the functional dysconnectivity identified in MDD and the swift and robust normalization following treatment suggest that GBCr may serve as a treatment response biomarker for the development of rapid acting antidepressants. The data also identified unique prefrontal and striatal circuitry as a putative marker of successful treatment and a target for antidepressants’ development.

Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies

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. Accumulating evidence demonstrates aberrant glutamatergic function in mood, anxiety, and trauma-related disorders and dysfunction in glutamate neurotransmission is increasingly considered a cardinal feature of stress-related psychiatric disorders including PTSD. As part of a PTSD Special Issue, this mini-review provides a concise discussion of (1) evidence of glutamatergic abnormalities in PTSD, with emphasis on human subjects data; (2) glutamate-modulating agents as potential alternative pharmacologic treatments for PTSD; and (3) selected gaps in the literature and related future directions.

Anterior hippocampal dysconnectivity in posttraumatic stress disorder: a dimensional and multimodal approach

The anterior hippocampus (aHPC) has a central role in the regulation of anxiety-related behavior, stress response, emotional memory and fear. However, little is known about the presence and extent of aHPC abnormalities in posttraumatic stress disorder (PTSD). In this study, we used a multimodal approach, along with graph-based measures of global brain connectivity (GBC) termed functional GBC with global signal regression (f-GBCr) and diffusion GBC (d-GBC), in combat-exposed US Veterans with and without PTSD. Seed-based aHPC anatomical connectivity analyses were also performed. A whole-brain voxel-wise data-driven investigation revealed a significant association between elevated PTSD symptoms and reduced medial temporal f-GBCr, particularly in the aHPC. Similarly, aHPC d-GBC negatively correlated with PTSD severity. Both functional and anatomical aHPC dysconnectivity measures remained significant after controlling for hippocampal volume, age, gender, intelligence, education, combat severity, depression, anxiety, medication status, traumatic brain injury and alcohol/substance comorbidities. Depression-like PTSD dimensions were associated with reduced connectivity in the ventromedial and dorsolateral prefrontal cortex. In contrast, hyperarousal symptoms were positively correlated with ventromedial and dorsolateral prefrontal connectivity. We believe the findings provide first evidence of functional and anatomical dysconnectivity in the aHPC of veterans with high PTSD symptomatology. The data support the putative utility of aHPC connectivity as a measure of overall PTSD severity. Moreover, prefrontal global connectivity may be of clinical value as a brain biomarker to potentially distinguish between PTSD subgroups.

A Network-Based Neurobiological Model of PTSD: Evidence From Structural and Functional Neuroimaging Studies

Purpose of ReviewAlthough a fine-grained understanding of the neurobiology of posttraumatic stress disorder (PTSD) is yet to be elucidated, the last two decades have seen a rapid growth in the study of PTSD using neuroimaging techniques. The current review summarizes important findings from functional and structural neuroimaging studies of PTSD, by primarily focusing on their relevance towards an emerging network-based neurobiological model of the disorder.Recent FindingsPTSD may be characterized by a weakly connected and hypoactive default mode network (DMN) and central executive network (CEN) that are putatively destabilized by an overactive and hyperconnected salience network (SN), which appears to have a low threshold for perceived saliency, and inefficient DMN-CEN modulation.SummaryThere is considerable evidence for large-scale functional and structural network dysfunction in PTSD. Nevertheless, several limitations and gaps in the literature need to be addressed in future research.

Cortical thickness reduction in combat exposed U.S. veterans with and without PTSD

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 Veterans completed high-resolution magnetic resonance imaging (MRI) scans to estimate cortical thickness. The Clinician Administered PTSD Scale (CAPS) and Combat Exposure Scale (CES) assessments were completed to measure current PTSD and historical combat severity, respectively. PTSD symptom dimensions (numbing, avoidance, reexperiencing, anxious arousal, and dysphoric arousal) were studied. Vertex-wise whole cerebrum analyses were conducted. We found widespread negative correlations between CAPS severity and cortical thickness, particularly within the prefrontal cortex. This prefrontal correlation remained significant after controlling for depression severity, medication status, and other potential confounds. PTSD dimensions, except anxious arousal, negatively correlated with cortical thickness in various unique brain regions. CES negatively correlated with cortical thickness in the left lateral prefrontal, regardless of PTSD diagnosis. A significant interaction between CES and PTSD diagnosis was found, such that CES negatively correlated with cortical thickness in the non-PTSD, but not in the PTSD, participants. The results underscore the severity of cortical thinning in U.S. Veterans suffering from high level of PTSD symptoms, as well as in Veterans with no PTSD diagnosis but severe combat exposure. The latter finding raises considerable concerns about a concealed injury potentially related to combat exposure in the post-9/11 era.

The Association of PTSD Symptom Severity With Localized Hippocampus and Amygdala Abnormalities

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 made it possible to identify specific locations of subtle morphometric changes within a structure of interest. Methods In this cross-sectional study, we used high-resolution magnetic resonance imaging to examine the relationship between PTSD symptomatology, as measured using the Clinician Administered PTSD Scale for the DSM-IV, and structural shape of the hippocampus and amygdala using vertex-wise shape analyses in a group of combat-exposed U.S. Veterans (N = 69). Results Following correction for multiple comparisons and controlling for age and cranial volume, we found that participants with more severe PTSD symptoms showed an indentation in the anterior half of the right hippocampus and an indentation in the dorsal region of the right amygdala (corresponding to the centromedial amygdala). Post hoc analysis using stepwise regression suggest that among PTSD symptom clusters, arousal symptoms explain most of the variance in the hippocampal abnormality, whereas reexperiencing symptoms explain most of the variance in the amygdala abnormality. Conclusion The results provide evidence of localized abnormalities in the anterior hippocampus and centromedial amygdala in combat-exposed U.S. Veterans suffering from PTSD symptoms. This novel finding provides a more fine-grained analysis of structural abnormalities in PTSD and may be informative for understanding the neurobiology of the disorder.

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

BACKGROUND Prefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression, and was associated with ketamines 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 challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr. METHODS In study A, we used functional magnetic resonance imaging (fMRI) to compare GBCr between 22 TRD and 29 healthy control. Then, we examined the effects of ketamine and midazolam on GBCr in TRD patients 24h post-treatment. In study B, we acquired repeated fMRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction. RESULTS In study A, TRD patients showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared to healthy control. In TRD patients, GBCr in the altered clusters significantly increased 24h following ketamine (effect size = 1.0 [0.3 1.8]), but not midazolam (effect size = 0.5 [-0.6 1.3]). In study B, oral lamotrigine reduced GBCr 2h post-administration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects. CONCLUSIONS This study provides first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission.

Default mode network abnormalities in posttraumatic stress disorder: A novel network-restricted topology approach

ABSTRACT 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 exploration of intrinsic brain networks. In this study, we used resting‐state functional magnetic resonance imaging (fMRI), diffusion MRI, and graph theoretical analyses to systematically examine the DMN connectivity and its relationship with PTSD symptom severity in a cohort of 65 combat‐exposed US Veterans. We employed metrics that index overall connectivity strength, network integration (global efficiency), and network segregation (clustering coefficient). Then, we conducted a modularity and network‐based statistical analysis to identify DMN regions of particular importance in PTSD. Finally, structural connectivity analyses were used to probe whether white matter abnormalities are associated with the identified functional DMN changes. We found decreased DMN functional connectivity strength to be associated with increased PTSD symptom severity. Further topological characterization suggests decreased functional integration and increased segregation in subjects with severe PTSD. Modularity analyses suggest a spared connectivity in the posterior DMN community (posterior cingulate, precuneus, angular gyrus) despite overall DMN weakened connections with increasing PTSD severity. Edge‐wise network‐based statistical analyses revealed a prefrontal dysconnectivity. Analysis of the diffusion networks revealed no alterations in overall strength or prefrontal structural connectivity. DMN abnormalities in patients with severe PTSD symptoms are characterized by decreased overall interconnections. On a finer scale, we found a pattern of prefrontal dysconnectivity, but increased cohesiveness in the posterior DMN community and relative sparing of connectivity in this region. The DMN measures established in this study may serve as a biomarker of disease severity and could have potential utility in developing circuit‐based therapeutics. HIGHLIGHTSA network‐restricted topology method was implemented to study the relationship between the DMN and PTSD in combat Veterans.Veterans suffering from severe PTSD symptoms were found to have decreased within‐DMN functional connectivity strength.A pattern of prefrontal dysconnectivity but sparing of the posterior DMN was associated with increasing PTSD symptomatology.Further topological characterization suggested decreased functional integration and increased segregation in severe PTSD.DMN functional dysconnectivity in PTSD appears not to be mediated by white matter anatomical network dysconnectivity.

Combat Exposure Severity Is Associated With Reduced Cortical Thickness in Combat Veterans: A Preliminary Report:

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 evidence suggests structural alterations in posttraumatic stress disorder (PTSD) and more recent studies have explored cortical thinning specifically. This preliminary study investigates the impact of combat exposure on cortical thickness, controlling for history of early life stress and age. Methods Twenty-one combat-exposed Veterans with PTSD and 20 non-PTSD combat-exposed controls (mean age 32.7) completed the Combat Exposure Scale, Childhood Trauma Questionnaire, and structural magnetic resonance imaging in a Siemens 3T TIM trio system. General linear model was used to examine the effect of combat exposure on cortical thickness, controlling for early life trauma exposure and age using cluster-wise correction (p < 0.05). Results This preliminary study found a negative correlation between combat exposure severity (CES) and cortical thickness in the left superior temporal and left rostral middle frontal regions, as well as an interaction between PTSD diagnosis status and CES, in the superior temporal/insular region showing a stronger negative correlation between CES and cortical thickness in the non-PTSD group. Conclusions Though caution should be taken with interpretation given the preliminary nature of the findings, the results indicate combat exposure may affect cortical structure beyond possible alterations due to early life stress exposure or PTSD psychopathology. Though replication in larger samples is required, these results provide useful information regarding possible neural biomarkers and treatment targets for combat-related psychopathology as well as highlighting the pathogenic effects of combat.

Development and preliminary validation of the Opioid Abuse Risk Screener

Prescription opioid drug abuse has reached epidemic proportions. Individuals with chronic pain represent a large population at considerable risk of abusing opioids. The Opioid Abuse Risk Screener was developed as a comprehensive self-administered measure of potential risk that includes a wide range of critical elements noted in the literature to be relevant to opioid risk. The creation, refinement, and preliminary modeling of the item pool, establishment of preliminary concurrent validity, and the determination of the factor structure are presented. The initial development and validation of the Opioid Abuse Risk Screener shows promise for effective risk stratification.