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. 2021 Aug 27:412:113428.
doi: 10.1016/j.bbr.2021.113428. Epub 2021 Jun 26.

BNST and amygdala connectivity are altered during threat anticipation in schizophrenia

Brandee Feola  1 , Maureen McHugo  2 , Kristan Armstrong  2 , Madison P Noall  2 , Elizabeth A Flook  2 , Neil D Woodward  2 , Stephan Heckers  2 , Jennifer Urbano Blackford  3
Affiliations

BNST and amygdala connectivity are altered during threat anticipation in schizophrenia

Brandee Feola et al. Behav Brain Res. .

Abstract

In schizophrenia, impairments in affect are prominent and anxiety disorders are prevalent. Neuroimaging studies of fear and anxiety in schizophrenia have focused on the amygdala and show alterations in connectivity. Emerging evidence suggests that the bed nucleus of the stria terminalis (BNST) also plays a critical role in anxiety, especially during anticipation of an unpredictable threat; however, previous studies have not examined the BNST in schizophrenia. In the present study, we examined BNST function and connectivity in people with schizophrenia (n = 31; n = 15 with comorbid anxiety) and controls (n = 15) during anticipation of unpredictable and predictable threat. A secondary analysis tested for differences in activation and connectivity of the central nucleus of the amygdala (CeA), which has also been implicated in threat anticipation. Analyses tested for group differences in both activation and connectivity during anticipation of unpredictable threat and predictable threat (p < .05). Relative to controls, individuals with schizophrenia showed stronger BNST-middle temporal gyrus (MTG) connectivity during unpredictable threat anticipation and stronger BNST-MTG and BNST-dorsolateral prefrontal connectivity during predictable threat anticipation. Comparing subgroups of individuals with schizophrenia and a comorbid anxiety disorder (SZ+ANX) to those without an anxiety disorder (SZ-ANX) revealed broader patterns of altered connectivity. During unpredictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions of the salience network (insula, dorsal anterior cingulate cortex). During predictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions associated with fear processing (insula, extended amygdala, prefrontal cortex). A secondary CeA analysis revealed a different pattern; the SZ+ANX group had weaker CeA connectivity across multiple brain regions during threat anticipation compared to the SZ-ANX group. These findings provide novel evidence for altered functional connectivity during threat anticipation in schizophrenia, especially in individuals with comorbid anxiety.

Keywords: Anxiety; Extended amygdala; Fear; Unpredictable threat.

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Figures

Figure 1:
Figure 1:
Threat anticipation task. Participants were trained to associate three different cues (colored shapes) with three different events: (1) the predictable neutral cue (purple diamond) is always followed by a neutral image; (2) the predictable threat cue (blue square) is always followed by an fear face image; (3) the unpredictable threat cue (yellow circle) may be followed by either an fear face or neutral image.
Figure 2:
Figure 2:
BNST connectivity during anticipation of unpredictable threat. a) Regions that showed significantly increased BNST connectivity during unpredictable threat anticipation in individuals with schizophrenia with anxiety relative to individuals without anxiety. b) Bar graphs with violin plot overlays illustrate connectivity values for each region by group. Connectivity values for healthy controls are displayed to provide a reference for interpreting the schizophrenia group findings. Error bars represent ±1 standard deviation from the mean. STG, superior temporal gyrus; dACC, dorsal anterior cingulate cortex; MTG, medial temporal gyrus.
Figure 3:
Figure 3:
BNST connectivity during anticipation of predictable threat. a) Regions that showed significantly increased BNST connectivity during predictable threat anticipation in individuals with schizophrenia with anxiety relative to individuals without anxiety. b) Bar graphs with overlays of violin plots of the connectivity values for each region by group; connectivity values for healthy controls are displayed to provide a reference. Error bars represent ±1 standard deviation from the mean. dlPFC, dorsolateral prefrontal cortex; SLEA, sublenticular extended amygdala; IPC, inferior parietal cortex.
Figure 4:
Figure 4:
Ce amygdala connectivity during threat anticipation. a) Regions that showed significantly decreased amygdala connectivity during unpredictable threat anticipation in individuals with schizophrenia with anxiety relative to individuals without anxiety. b) Regions that showed significantly decreased amygdala connectivity during predictable threat anticipation in individuals with schizophrenia with anxiety relative to individuals without anxiety. c) Bar graphs with violin plot overlays show connectivity values for the significant clusters by group for unpredictable threat anticipation; connectivity values for healthy controls are displayed to provide a reference. d) Bar graphs with violin plot overlays show connectivity values for the significant clusters by group for predictable threat anticipation; connectivity values for healthy controls are displayed to provide a reference. MTG, middle temporal gyrus.
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