Todd Ogden

Elevated Serotonin 1A Binding in Remitted Major Depressive Disorder: Evidence for a Trait Biological Abnormality

Several biological abnormalities in major depressive disorder (MDD) persist during episode remission, including altered serotonin neurotransmission, and may reflect underlying pathophysiology. We previously described elevated brain serotonin 1A (5-HT1A) receptor binding in antidepressant-naive (AN) subjects with MDD within a major depressive episode (MDE) compared with that in healthy controls using positron emission tomography (PET). In this study, we measured 5-HT1A receptor binding in unmedicated subjects with MDD during sustained remission, hypothesizing higher binding compared with that in healthy controls, and binding comparable with currently depressed AN subjects, indicative of a biological trait. We compared 5-HT1A binding potential (BPF) assessed through PET scanning with [11C]WAY-100635 in 15 subjects with recurrent MDD in remission for ⩾12 months and off antidepressant medication for ⩾6 months, 51 healthy controls, and 13 AN MDD subjects in a current MDE. Metabolite-corrected arterial input functions were acquired for the estimation of BPF. Remitted depressed subjects had higher 5-HT1A BPF compared with healthy controls; this group difference did not vary significantly in magnitude across brain regions. 5-HT1A BPF was comparable in remitted and currently depressed subjects. Elevated 5-HT1A BPF level among subjects with remitted MDD appears to be a trait abnormality in MDD, which may underlie recurrent MDEs. Future studies should evaluate the role of genetic and environmental factors in producing elevated 5-HT1A BPF and MDD, and should examine whether 5-HT1A BPF is a vulnerability factor to MDEs that could have a role in screening high-risk populations for MDD.

Inference on variance components of autocorrelated sequences in the presence of drift

Many statistics techniques rely on the assumption that random variables measured over time have a common mean. In many situations, this assumption is violated, the mean of the observations drifting gradually over time. For a particular modeling situation, motivated by a psychological study of human rhythm and motor control, a testing procedure for the presence of drift is derived, along with consistent estimators for the variance components. These procedures are applied to a long-run sequence of tapping data.

A comparison of structural connectivity in anxious depression versus non-anxious depression

BACKGROUND Major depressive disorder (MDD) and anxiety disorders are highly co-morbid. Research has shown conflicting evidence for white matter alteration and amygdala volume reduction in mood and anxiety disorders. To date, no studies have examined differences in structural connectivity between anxious depressed and non-anxious depressed individuals. This study compared fractional anisotropy (FA) and density of selected white matter tracts and amygdala volume between anxious depressed and non-anxious depressed individuals. METHODS 64- direction DTI and T1 scans were collected from 110 unmedicated subjects with MDD, 39 of whom had a co-morbid anxiety disorder diagnosis. Region of interest (ROI) and tractography methods were performed to calculate amygdala volume and FA in the uncinate fasciculus, respectively. Diffusion connectometry was performed to identify whole brain group differences in white matter health. Correlations were computed between biological and clinical measures. RESULTS Tractography and ROI analyses showed no significant differences between bilateral FA values or bilateral amygdala volumes when comparing the anxious depressed and non-anxious depressed groups. The diffusion connectometry analysis showed no significant differences in anisotropy between the groups. Furthermore, there were no significant relationships between MRI-based and clinical measures. CONCLUSION The lack of group differences could indicate that structural connectivity and amygdalae volumes of those with anxious-depression are not significantly altered by a co-morbid anxiety disorder. Improving understanding of anxiety co-morbid with MDD would facilitate development of treatments that more accurately target the underlying networks.

Cortical thickness is not associated with current depression in a clinical treatment study

Reduced cortical thickness is a candidate biological marker of depression, although findings are inconsistent. This could reflect analytic heterogeneity, such as use of region‐wise cortical thickness based on the Freesurfer Desikan–Killiany (DK) atlas or surface‐based morphometry (SBM). The Freesurfer Destrieux (DS) atlas (more, smaller regions) has not been utilized in depression studies. This could also reflect differential gender and age effects.

Accuracy and reliability of [11C]PBR28 specific binding estimated without the use of a reference region

[11C]PBR28 is a positron emission tomography radioligand used to estimate the expression of 18kDa translocator protein (TSPO). TSPO is expressed on glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding (VND). Therefore, estimates of specific binding, such as binding potentials (e.g., BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these measures are obtainable for [11C]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of VND, which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [11C]PB28, and suggest that VS can be used in preference to, or as a complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.