# Exploring subthreshold functional network alterations in women with phenylketonuria by higher criticism

## TL;DR

This study explores brain network differences in women with PKU using functional MRI, finding subtle changes in attention and default mode networks.

## Contribution

The study applies higher criticism statistics to identify subthreshold functional network alterations in PKU patients.

## Key findings

- Functional connectivity changes were observed in attention and default mode networks in PKU patients.
- No significant differences were found in fronto-parietal networks or between-network connectivity.
- Results align with previous findings on PKU-related cognitive profiles despite small sample size.

## Abstract

Phenylketonuria (PKU) is an inherited disorder of amino acid metabolism. Despite early dietary treatment, cognitive functioning of patients has been reported as being inferior to healthy controls. Objective of this study was to assess functional connectivity (FC) alterations in PKU in cognition-related brain networks by resting-state functional magnetic resonance imaging. We followed a hierarchical analysis approach partially based on higher criticism (HC) statistics as previously applied in a larger sister-project in fetal alcohol syndrome.

After exclusions for excessive head movement, 11 female young adults with early-treated PKU (age: 27.2 ± 3.7 years) and 11 age-matched female healthy controls (age: 25.9 ± 3.8 years) were included in the analysis. We observed effects within attention networks and the default mode network, but not in fronto-parietal networks, at the HC-based intermediate analysis level. No between-network FC differences were found. In the most detailed analysis level, we could not identify single affected functional connections. Despite statistical power limitations in this small sample, these preliminary findings are in line with previously reported FC alterations in PKU and the cognitive profile in young adults with PKU, particularly the still uncertain notion that cognitive control deficits might become less pronounced when PKU patients reach adulthood.

The online version contains supplementary material available at 10.1186/s13104-026-07745-2.