Sub-millimeter variation in human locus coeruleus is associated with dimensional measures of psychopathology: An in vivoultra-high field 7-Tesla MRI study.

Laurel S. Morris,Thomas P. Naidich,Derek A. Smith,Kuang Han-Huang,Prantik Kundu,Aaron Tan,Dennis S. Charney,Priti Balchandani,Mora Grehl,James W. Murrough

doi:10.1016/j.nicl.2019.102148

Laurel S. Morris, Thomas P. Naidich + Show 8 more

Open Access

https://doi.org/10.1016/j.nicl.2019.102148

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Abstract

The locus coeruleus (LC) has a long-established role in the attentional and arousal response to threat, and in the emergence of pathological anxiety in pre-clinical models. However, human evidence of links between LC function and pathological anxiety has been restricted by limitations in discerning LC with current neuroimaging techniques. We combined ultra-high field 7-Tesla and 0.4×0.4×0.5mm quantitative MR imaging with a computational LC localization and segmentation algorithm to delineate the LC in 29 human subjects including subjects with and without an anxiety or stress-related disorder. Our automated, data-driven LC segmentation algorithm provided LC delineations that corresponded well with postmortem anatomic definitions of the LC. There was variation of LC size in healthy subjects (125.7 +/- 59.3mm3), which recapitulates histological reports. Patients with an anxiety or stress-related disorder had larger LC compared to controls (Cohen's d=1.08, p=0.024). Larger LC was additionally associated with poorer attentional and inhibitory control and higher anxious arousal (FDR-corrected p's<0.025), trans-diagnostically across the full sample. This study combined high-resolution and quantitative MR with a mixture of supervised and unsupervised computational techniques to provide robust, sub-millimeter measurements of the LC in vivo, which were additionally related to common psychopathology. This work has wide-reaching applications for a range of neurological and psychiatric disorders characterized by expected LC dysfunction.

Highlights

Pathological anxiety can be defined as an excessive, maladaptive fearlike state, which acts as a major risk factor for suicide (Rosen and Schulkin, 1998; Eysenck, 1992; Kessler et al, 2005)
Patients were recruited across clinical disorders characterized by pathological anxiety including posttraumatic stress disorder (PTSD), panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), as well as healthy control (HC) subjects
The following additional eligibility criteria are specific to study group: Posttraumatic Stress Disorder (PTSD): (a) meets diagnostic criteria for current PTSD according to the DSM-592, (b) Criteria A trauma of the civilian type, (c) index Criteria A trauma occurred after the age of 18, (d) duration of current PTSD >12 months; Panic Disorder (PD): (a) meets diagnostic criteria for current PD according to the DSM-5, (b) duration of current PD >12 months; Generalized Anxiety Disorder (GAD): (a) meets diagnostic criteria for current GAD according to the DSM-5, (b) duration of current GAD >12 months; HC: no lifetime history of a psychiatric or neurological disorder or criteria A trauma

Summary

Introduction

Pathological anxiety can be defined as an excessive, maladaptive fearlike state, which acts as a major risk factor for suicide (Rosen and Schulkin, 1998; Eysenck, 1992; Kessler et al, 2005). Pathological anxiety is a core feature of Anxiety Disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition (DSM-5), including Panic Disorder (PD), Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), as well as of Posttraumatic Stress Disorder (PTSD). The LC are small, paired, longitudinally oriented, highly pigmented nuclei that are situated in the upper pons to each side of the fourth ventricle. The LC contain norepinephrine (NE)elaborating neurons that project widely to cortical, subcortical and brainstem nuclei to rapidly and globally modulate arousal

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