A whole-brain neuromark resting-state fMRI analysis of first-episode and early psychosis: Evidence of aberrant cortical-subcortical-cerebellar functional circuitry

Abstract

Psychosis (including symptoms of delusions, hallucinations, and disorganized conduct/speech) is a main feature of schizophrenia and is frequently present in other major psychiatric illnesses. Studies in individuals with first-episode (FEP) and early psychosis (EP) have the potential to interpret aberrant connectivity associated with psychosis during a period with minimal influence from medication and other confounds. The current study uses a data-driven whole-brain approach to examine patterns of aberrant functional network connectivity (FNC) in a multi-site dataset comprising resting-state functional magnetic resonance images (rs-fMRI) from 117 individuals with FEP or EP and 130 individuals without a psychiatric disorder, as controls. Accounting for age, sex, race, head motion, and multiple imaging sites, differences in FNC were identified between psychosis and control participants in cortical (namely the inferior frontal gyrus, superior medial frontal gyrus, postcentral gyrus, supplementary motor area, posterior cingulate cortex, and superior and middle temporal gyri), subcortical (the caudate, thalamus, subthalamus, and hippocampus), and cerebellar regions. The prominent pattern of reduced cerebellar connectivity in psychosis is especially noteworthy, as most studies focus on cortical and subcortical regions, neglecting the cerebellum. The dysconnectivity reported here may indicate disruptions in cortical-subcortical-cerebellar circuitry involved in rudimentary cognitive functions which may serve as reliable correlates of psychosis.

Keywords: Early psychosis (EP); First-episode psychosis (FEP); Functional network connectivity (FNC); Independent component analysis (ICA); Resting-state fMRI; Schizophrenia.

Fig. 1

A composite view of spatial maps of z-transformed average static functional network connectivity (FNC) is shown above for each of our estimated 53 intrinsic connectivity networks (ICNs) from the Neuromark_fMRI_1.0 template. The ICNs have been grouped into seven domains: (a) subcortical (SC), (b) auditory (AU), (c) sensorimotor (SM), (d) visual (VI), (e) cognitive control (CC), (f) default mode (DM), and (g) cerebellar (CB).

Fig. 2

Mean functional network connectivity (FNC) for all participants is displayed in the matrix on the top left (a) with red indicating higher positive values and blue indicating lower negative values. The difference in mean FNC between diagnostic groups (psychosis - control) is displayed in the matrix on the top right (b). Results of the general linear model (GLM) for each combination of the 53 Neuromark intrinsic connectivity networks (ICNs) is displayed on the bottom (c). Significant (q < 0.05) case/control group associations with functional network connectivity (FNC) are marked with an asterisk in the matrix to the left. Sagittal slices of each ICN surround the connectogram to the right. ICNs are grouped by domain, consistent with the Neuromark_fMRI_1.0 template: subcortical (SC), auditory (AU), sensorimotor (SM), visual (VI), cognitive control (CC), default mode (DM), and cerebellar (CB). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

The percentage of significant aberrant functional network connectivity pairs (FNCs) within each domain block in the general linear model (GLM) results matrix in Fig. 2c (calculated as $\%sigFNCatthedomainlevel=\frac{\#FNCswithq<0.05fordomainblock}{\mathit{total}\#FNCsfordomainblock}$) are shown above. In the connectogram on the right, between domain relationships are represented with connecting lines, while within domain relationships are represented with an asterisk. Between and within domain relationships are not shown for domain blocks where less than 5 % of the FNCs are significant (q < 0.05). Domain labels are consistent with the Neuromark_fMRI_1.0 template: subcortical (SC), auditory (AU), sensorimotor (SM), visual (VI), cognitive control (CC), default mode (DM), and cerebellar (CB).

Fig. 4

Corresponding spatial maps for the most notable intrinsic connectivity networks (ICNs) are displayed with accompanying labels derived from Du et al. (2020). From the subcortical domain (SC): (a) ICN 1 – medial caudate, (b) ICN 2 – subthalamus/hypothalamus, (c) ICN 5 – thalamus. From the auditory domain (AU): (d) ICN 6 – superior temporal gyrus (STG), (e) ICN 7 – anterior middle temporal gyrus (A. MTG). From the Sensorimotor domain (SM): (f) ICN 8 – anterior postcentral gyrus (A. PoCG). From the cognitive control domain (CC): (g) ICN 19 – posterior middle temporal gyrus (P. MTG), (h) ICN 28 – superior medial frontal gyrus (SMFG), (i) ICN 29 – left inferior frontal gyrus (L. IFG), (j) ICN 34 - supplementary motor area (SMA), (k) ICN 37 – anterior hippocampus, (l) ICN 42 – posterior hippocampus. From the Default-mode domain (DM): (m) ICN 46 – ventral posterior cingulate cortex (V. PCC), (n) ICN 49 – dorsal posterior cingulate cortex (D. PCC). And from the cerebellar domain (CB): (o) ICN 50 – left cerebellum, (p) ICN 51 – posterior cerebellum, (q) ICN 52 – medial cerebellum, (r) ICN 53 – right cerebellum.

Fig. 5

Results of the general linear model (GLM) for each combination of the 53 Neuromark intrinsic connectivity networks (ICNs) in the reduced sample of psychosis within one year of their first clinical contact (N = 97) is displayed above. Significant (q < 0.05) case/control group associations with functional network connectivity (FNC) are marked with an asterisk. Note the similarity to Fig. 2c. ICNs are grouped by domain, consistent with the Neuromark_fMRI_1.0 template: subcortical (SC), auditory (AU), sensorimotor (SM), visual (VI), cognitive control (CC), default mode (DM), and cerebellar (CB).