Cognitive and behavioral correlates of caudate subregion shape variation in fragile X syndrome

Individuals with fragile X syndrome (FXS) exhibit frontal lobe-associated cognitive and behavioral deficits, including impaired general cognitive abilities, perseverative behaviors, and social difficulties. Neural signals related to these functions are communicated through frontostriatal circuits, which connect with distinct regions of the caudate nucleus (CN). Enlargement of the CN is the most robust and reproduced neuroanatomical abnormality in FXS, but very little is known on how this affects behavioral/cognitive outcomes in this condition. Here, we investigated topography within focal regions of the CN associated with prefrontal circuitry and its link with aberrant behavior and intellect in FXS. Imaging data were acquired from 48 individuals with FXS, 28 IQ-matched controls without FXS (IQ-CTL), and 36 typically developing controls (TD-CTL). Of the total participant count, cognitive and behavioral assessment data were obtained from 44 individuals with FXS and 27 participants in the IQ-CTL group. CN volume and topography were compared between groups. Correlations were performed between CN topography and cognitive as well as behavioral measures within FXS and IQ-CTL groups. As expected, the FXS group had larger CN compared with both IQ-CTL and TD-CTL groups. Correlations between focal CN topography and frontal lobe-associated cognitive and behavioral deficits in the FXS group supported the hypothesis that CN enlargement is related to abnormal orbitofrontal-caudate and dorsolateral-caudate circuitry in FXS. These findings deepen our understanding of neuroanatomical mechanisms underlying cognitive-behavioral problems in FXS and hold promise for informing future behavioral and psychopharmacological interventions targeting specific neural pathways.