# Resting‐state connectivity and tobacco smoking in clinical high‐risk for psychosis (NAPLS‐3)

## TL;DR

This study found no link between smoking and brain network changes in people at high risk for psychosis, suggesting that such effects may emerge later or with heavier smoking.

## Contribution

The study is the first to examine longitudinal resting-state connectivity in clinical high-risk individuals and its relation to smoking.

## Key findings

- Smoking was not associated with altered functional connectivity in key brain networks at baseline.
- No significant longitudinal changes in connectivity were observed over 8 months in smokers versus non-smokers.
- The absence of differences may be due to early illness stage and limited nicotine exposure.

## Abstract

Smoking is highly prevalent among people at clinical high‐risk for psychosis (CHR‐P) and is associated with poorer clinical outcomes. Large‐scale brain networks have been linked to both psychosis and tobacco smoking. However, their relationship in CHR‐P individuals remains unexplored, which may provide valuable insights into the potential neurobiological background of the co‐occurrence.

The current study aimed to examine whether smoking is associated with altered resting‐state network connectivity over time in CHR‐P individuals.

Resting‐state functional magnetic resonance imaging scans from the North American Prodrome Longitudinal Study 3 were used. At baseline, 486 CHR‐P non‐smokers and 101 CHR‐P smokers were included, with 1128 scans across 2‐, 4‐, 6‐ and 8‐month follow‐up. Independent component analysis was used to extract functional connectivity for the default mode network (DMN), salience network (SN) and left and right frontoparietal networks (FPN). Differences in within‐ and between‐network strength of the networks of interest were assessed between smoking CHR‐P and non‐smoking CHR‐P at baseline. Linear mixed‐effects models were used to examine associations between longitudinal connectivity changes and smoking.

Results showed that smoking participants were generally light smokers. Smoking was not significantly associated with within‐ or between‐network functional connectivity of the DMN, SN or FPN at baseline or over an 8‐month period in CHR‐P participants.

In this large, longitudinal CHR‐P sample, smoking was not linked to large‐scale functional network connectivity alterations. The early illness stage and limited nicotine exposure may explain the absence of differences, contrasting with findings of reduced network connectivity in schizophrenia and chronic smokers. Future studies could examine connectivity changes over longer periods to determine whether connectivity alterations emerge with increased smoking, illness progression or both.

WHAT IS ALREADY KNOWN ON THIS TOPIC
Smoking is pervasive in individuals at clinical high‐risk for psychosis (CHR‐P) and is linked to worse clinical outcomes. Although both smoking and psychosis have been linked to large‐scale brain network alterations, their relationship in CHR‐P individuals remains unexplored.

Smoking is pervasive in individuals at clinical high‐risk for psychosis (CHR‐P) and is linked to worse clinical outcomes. Although both smoking and psychosis have been linked to large‐scale brain network alterations, their relationship in CHR‐P individuals remains unexplored.

WHAT THIS STUDY ADDS
Smoking is not associated with large‐scale network changes at this early stage of illness.

Smoking is not associated with large‐scale network changes at this early stage of illness.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study provides initial evidence that smoking is not associated with functional connectivity vulnerabilities or changes in large‐scale functional brain networks before the onset of psychosis. However, longitudinal studies with greater smoking exposure and extended follow‐up are needed to determine whether network alterations emerge with heavier use, longer duration or illness progression.

This study provides initial evidence that smoking is not associated with functional connectivity vulnerabilities or changes in large‐scale functional brain networks before the onset of psychosis. However, longitudinal studies with greater smoking exposure and extended follow‐up are needed to determine whether network alterations emerge with heavier use, longer duration or illness progression.