Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk

Abstract

Background Individuals at clinical high-risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with those without symptomatic progression and with healthy controls. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. Methods In this multisite study, 274 CHR cases, including 35 who converted to psychosis, and 135 healthy comparison subjects were scanned with MRI at baseline, 12-month follow-up, and/or the point of conversion for those who developed fully psychotic symptoms. Results In a traveling subjects sub-study, we observed excellent reliability for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR converters showed a steeper rate of gray matter loss in right superior frontal, middle frontal, and medial orbitofrontal cortical regions, as well as a greater rate of expansion of the third ventricle, compared with CHR non-converters and healthy controls. Differential tissue loss was present among cases who had not received antipsychotic medications during the inter-scan interval and was predicted by baseline levels of an aggregate measure of pro-inflammatory cytokines in plasma. Conclusions These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs, but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced among cases with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study

“…Although the observation of an increase in resting hippocampal perfusion in HS is consistent with the majority of previous studies in CHR and schizophrenia with a specific focus on the hippocampus, as discussed above, the cross‐sectional nature of the present study prevents investigating whether this finding is prospectively linked to a subsequent emergence of mental health disorders in schizotypy (Cannon et al, 2015). Furthermore, although the significant effect on our sample was restricted to the right hippocampus, consistent with a recent study in CHR individuals compared to healthy controls (Allen et al, 2017), this observation is only partly consistent with other studies in CHR subjects in which hyperperfusion involved both hippocampi (Allen et al, 2016; Schobel et al, 2013).…”

Preserved, deteriorated, and premorbidly impaired patterns of intellectual ability in schizophrenia.

“…In fact, one of the principal pathological findings in the brains of those affected with schizophrenia involves abnormal cortical thinning (Cannon et al, 2015). Reduced cortical thickness has also been demonstrated in the unaffected siblings of patients with the disorder (Goldman et al, 2009;Goghari, Rehm, Carter, & MacDonald, 2007;Gogtay et al, 2007), suggesting a possible relationship of these cortical changes to the genetic liability for developing the illness.…”

Motion‐related artifacts in structural brain images revealed with independent estimates of in‐scanner head motion

“…Structural magnetic resonance imaging (MRI) can provide high‐resolution measurements of gray and white matter anatomy that are often the focus of within‐ and between‐participant comparisons of aging [see Dickerson et al, 2009; Fjell et al, 2009; Fotenos et al, 2005], development [e.g., Tamnes et al, 2010], clinical disorders [e.g., Cannon et al, 2015; Dickerson et al, 2009; Kempton et al, 2011], and therapeutic intervention [e.g., Bearden et al, 2008; Dazzan et al, 2005]. In practice, structural MRI scans are readily analyzed with convenient, automated image segmentation tools that derive measurements from an individual's regional neuroanatomy (e.g., thickness, surface area, volume), often implemented with freely available software packages [e.g., FreeSurfer [FS], VBM8, FSL‐VBM; Ashburner and Friston, 2000; Dale et al, 1999; Fischl et al, 1999a; Smith et al, 2004] that have been externally validated with manual tracing and post‐mortem analyses [Cardinale et al, 2014; Kennedy et al, 2009; Kuperberg et al, 2003; Rosas et al, 2002; Salat et al, 2004; Sanchez‐Benavides et al, 2010].…”