The effects of tetrahydrobiopterin (BH4) treatement on nonverbal working memory-related brain activations and connectivity in individuals with phenylketonuria
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Previous research suggests that phenylketonuria (PKU) is associated with disruptions in structural and functional connectivity that may contribute to impairments in working memory. In many patients with PKU, tetrahydrobiopterin (BH4) treatment has been shown to reduce blood phe levels and, in some instances, to improve behavioral and cognitive symptoms associated with PKU. The present study sought to further examine the neurophysiological basis of nonverbal working memory impairment in PKU and the potential impact of BH4 treatment on working memory and its neural substrates. We utilized fMRI to examine activation and functional connectivity patterns in a sample of individuals with early-treated PKU and a sample of demographically-matched healthy individuals without PKU during performance of a nonverbal version of an n-back working memory task. Participants were assessed prior to treatment (baseline) and also after 4 weeks and 6 months of BH4 treatment. Results revealed PKU-related abnormalities in task-related activation (e.g., hyperactivation of PFC during working memory performance) as well as task-modulated functional connectivity (e.g., attenuated within-network yet elevated cross-network functional connectivity during working memory performance). Consistent with prior fMRI studies (Christ et al., 2012, 2013), the present results suggest that PKU-related disruptions in neurofunctional activation and connectivity are pervasive. However, these disruptions may be sensitive to BH4 treatment, as evidenced by normalized activation and connectivity patterns in several brain regions, including dorsolateral PFC and FFA.