A comprehensive regional neurochemical theory in depression: a protocol for the systematic review and meta-analysis of 1H-MRS studies in major depressive disorder.

BACKGROUND: Magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that investigates the presence and concentrations of brain metabolites. In the context of major depressive disorder (MDD), MRS has revealed regional biochemical changes in GABA, glutamate, and choline across different brain compartments. Technical and methodological advances in MRS data acquisition, in particular proton-based 1H-MRS, have resulted in a significant increase in the incidence of reports utilizing the technique for psychiatric disorder research and diagnosis. The most recent comprehensive meta-analysis reviewing MRS in MDD stems from 2006. Using contemporary systemic reviews and meta-analysis, the aim is to first test a neurochemical circuit-based theory of depression and then to determine if clinical scores relate to metabolite concentrations before and during treatment. METHODS: Region-specific metabolite changes in MDD will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Inclusion criteria will include participant age (18 to 65), English language studies, known regions of interest, and detailed documentation of 1H-MRS procedures. Reported brain regions will be standardized according neuroanatomical expertise allowing increased power of the meta-analysis. Regions of interest will initially include the hippocampus, thalamus, prefrontal cortex, anterior and posterior cingulate gyri, parietal lobe, and basal ganglia. Exclusion criteria will include comorbid psychiatric illness and drug use. Two independent reviewers will undertake all data extraction, while a third reviewer will check for reviewer discrepancies. Statistical analysis will be performed using STATA supplemented by Metan software and SPSS. DISCUSSION: This data will shed new light on the biochemical basis of depression in different brain regions, thereby highlighting the potential of MRS in identifying biomarkers and generating models of MDD and treatment response. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018091494.

Awakening Neuropsychiatric Research Into the Stria Medullaris: Development of a Diffusion-Weighted Imaging Tractography Protocol of This Key Limbic Structure.

The Stria medullaris (SM) Thalami is a discrete white matter tract that directly connects frontolimbic areas to the habenula, allowing the forebrain to influence midbrain monoaminergic output. Habenular dysfunction has been shown in various neuropsychiatric conditions. However, there exists a paucity of research into the habenula's principal afferent tract, the SM. Diffusion-weighted tractography may provide insights into the properties of the SM in vivo, opening up investigation of this tract in conditions of monoamine dysregulation such as depression, schizophrenia, addiction and pain. We present a reliable method for reconstructing the SM using diffusion-weighted imaging, and examine the effects of age and gender on tract diffusion metrics. We also investigate reproducibility of the method through inter-rater comparisons. In consultation with neuroanatomists, a Boolean logic gate protocol was developed for use in ExploreDTI to extract the SM from constrained spherical deconvolution based whole brain tractography. Particular emphasis was placed on the reproducibility of the tract, attention to crossing white matter tract proximity and anatomical consistency of anterior and posterior boundaries. The anterior commissure, pineal gland and mid point of the thalamus were defined as anatomical fixed points used for reconstruction. Fifty subjects were scanned using High Angular Resolution Diffusion Imaging (HARDI; 61 directions, b-value 1500 mm3). Following constrained spherical deconvolution whole brain tractography, two independent raters isolated the SM. Each output was checked, examined and cleaned for extraneous streamlines inconsistent with known anatomy of the tract by the rater and a neuroanatomist. A second neuroanatomist assessed tracts for face validity. The SM was reconstructed with excellent inter-rater reliability for dimensions and diffusion metrics. Gender had no effect on the dimensions or diffusion metrics, however radial diffusivity (RD) showed a positive correlation with age. Reliable identification and quantification of diffusion metrics of the SM invites further exploration of this key habenula linked structure in neuropsychiatric disorders such as depression, anxiety, chronic pain and addiction. The accurate anatomical localization of the SM may also aid preoperative stereotactic localization of the tract for deep brain stimulation (DBS) treatment.