Regional Limbic and Somatosensory Cortical Thinning in Adults with Major Depressive Disorder Matthew Crawshaw

Theories of MDD Hypothalamic-pituitary-adrenal (HPA) axis dyfunction Hippocampus over-production of glucocorticoids, a response to stress, disruptng memory and learningand promoting dendritic atrophy in limbic areas. Limbic-cortico dysregulation theory failures in the coordinated interactions of limbic-frontal cortical pathways (Mayberg 1997) Frontal failure to inhibit limbic activity because of abnormal activity in two pathways: Dorsal: prefrontal cortex and anterior cingulate gyrus Ventral: the orbitofrontal cortex and lower limbic structures

Fraught Cortical Volume and VBM evidence Generally support both theories, but few studies measuring volumetric changes indicate support of all the predictions of the theories Hippocampal, Parahippocampal, Amygdala, Entorhinal, Frontal and Orbitofrontal cortex volume shrinkage Left lateralised, sometimes Sometimes Amygdala is larger Perhaps other kinds of measurements may sheld light on other structural changes in MDD.

Cortical Thickness Analysis Tu et al., 2012 MDD patients had large areas of cortical thinning in the bilateral superior frontal gyrus, rostral and caudal middle frontal gyrus and right orbitofrontal gyrus Lesser extent, cortical thinning was present in the left entorhinal cortex, and parietal, temporal and occipital lobes, postcentral gyrus. Present study will similarly adopt a whole-surface analysis, and also specifically analyse cortical thickness in the main regions of interest identified by Tu and colleagues (2012).

Hypotheses Analysis 1 considers thickness measurements of the whole cortical surface. H1: MDD patients will have significant cortical thinning in regions of the frontal lobe and limbic cortex, compared with healthy controls. Analysis 2 adopts a regions-of-interest approach, analysing the mean thickness measurements in nine frontal lobe regions based on the main findings of Tu et al. (2012) H2: MDD patients will have significant cortical thinning in the bilateral superior frontal gyrus, rostral and caudal middle frontal gyrus, precentral gyrus, and right lateral orbitofrontal gyrus, compared with healthy controls.

Participants

Methods Scanning and BrainVoyager Analysis Cortex-based Alignment

Methods Cortical Thickness Measurement (a) segmentation and smoothed intensities of GM, WM and CSF; (b) thickness measurement results in mm; (c) projection of thickness data onto subject’s surface mesh.

Statistical analysis Analysis 1: Multiple subject cortical thickness measurements compared using t-tests in BVQX. Cortical thickness differences were tested throughout all vertices. Analysis 2: a priori regions of interest (ROIs) were defined on the average surface mesh. Average cortical thicknesses for the ROIs were found and these were compared between healthy and MDD groups using t-tests within BrainVoyager. ANCOVA also performed in SPSS 19 controlling age and verbal IQ.

Results: Analysis 1 Area of significantly thinner grey matter for MDD patients in the right entorhinal cortex.

Results: Analysis 1 Area of significantly thinner grey matter for MDD patients in the left postcentral gyrus. Lowered threshold for cluster size estimation.

Analysis 2: ROIs SFG = Superior Frontal Gyrus; rMFG = Rostral middle frontal gyrus; cMFG = Caudal middle frontal gyrus; preCG = Precentral gyrus; latOFG = Lateral orbitofrontal gyrus

Analysis 2: Results BVQX ROI mean thickness between-group t-tests No significant differences SPSS 19 ANCOVA controlling for Age and Hamilton Score No significant differences in mean ROI thicknesses between groups

Discussion Main finding: MDD patients showed cortical thinning in the right entorhinal cortex and left postcentral gyrus, but not in the frontal lobe Support HPA axis theory, partial support of Fronto- cortical dysregulation theory Entorhinal cortex key limbic pathway into hippocampus Changes in sometosensory (post-central) gyrus observed before but not explained. Lack of frontal thinning may be due to MDD not severe enough in this sample

Limitations Although subjects were age and gender matched, there was a gender imbalance within groups, which was not controlled for in the analysis No control for the effects of medication, which is known to affect brain structure and is therefore cited as a possible reason for the often-conflicting results in the literature CTA and CBA still a nascent method in MDD studies Captures multiple cytoarchitectural changes in the cortex under one measure, and requires cellular studies to reveal details of what they are.