HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch-Nyhan disease.

In Lesch-Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that LND is associated with dysfunction of midbrain dopamine neurons, without overt structural brain abnormalities. Emerging post mortem and in vitro evidence supports the hypothesis that the dopaminergic dysfunction in LND is of developmental origin, but specific pathogenic mechanisms have not been revealed. In the current study, HGprt deficiency causes specific neurodevelopmental abnormalities in mice during embryogenesis, particularly affecting proliferation and migration of developing midbrain dopamine (mDA) neurons. In mutant embryos at E14.5, proliferation was increased, accompanied by a decrease in cell cycle exit and the distribution and orientation of dividing cells suggested a premature deviation from their migratory route. An abnormally structured radial glia-like scaffold supporting this mDA neuronal migration might lie at the basis of these abnormalities. Consequently, these abnormalities were associated with an increase in area occupied by TH+ cells and an abnormal mDA subpopulation organization at E18.5. Finally, dopaminergic innervation was disorganized in prefrontal and decreased in HGprt deficient primary motor and somatosensory cortices. These data provide direct in vivo evidence for a neurodevelopmental nature of the brain disorder in LND. Future studies should not only focus the specific molecular mechanisms underlying the reported neurodevelopmental abnormalities, but also on optimal timing of therapeutic interventions to rescue the DA neuron defects, which may also be relevant for other neurodevelopmental disorders.

A test-retest reliability analysis of diffusion measures of white matter tracts relevant for cognitive control.

Recent efforts to replicate structural brain-behavior correlations have called into question the replicability of structural brain measures used in cognitive neuroscience. Here, we report an evaluation of test-retest reliability of diffusion tensor imaging (DTI) measures, including fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, in several white matter tracts previously shown to be involved in cognitive control. In a data set consisting of 34 healthy participants scanned twice on a single day, we observe overall stability of DTI measures. This stability remained in a subset of participants who were also scanned a third time on the same day as well as in a 2-week follow-up session. We conclude that DTI measures in these tracts show relative stability, and that alternative explanations for the recent failures of replication must be considered.

Toward a model-based cognitive neuroscience of mind wandering.

People often "mind wander" during everyday tasks, temporarily losing track of time, place, or current task goals. In laboratory-based tasks, mind wandering is often associated with performance decrements in behavioral variables and changes in neural recordings. Such empirical associations provide descriptive accounts of mind wandering - how it affects ongoing task performance - but fail to provide true explanatory accounts - why it affects task performance. In this perspectives paper, we consider mind wandering as a neural state or process that affects the parameters of quantitative cognitive process models, which in turn affect observed behavioral performance. Our approach thus uses cognitive process models to bridge the explanatory divide between neural and behavioral data. We provide an overview of two general frameworks for developing a model-based cognitive neuroscience of mind wandering. The first approach uses neural data to segment observed performance into a discrete mixture of latent task-related and task-unrelated states, and the second regresses single-trial measures of neural activity onto structured trial-by-trial variation in the parameters of cognitive process models. We discuss the relative merits of the two approaches, and the research questions they can answer, and highlight that both approaches allow neural data to provide additional constraint on the parameters of cognitive models, which will lead to a more precise account of the effect of mind wandering on brain and behavior. We conclude by summarizing prospects for mind wandering as conceived within a model-based cognitive neuroscience framework, highlighting the opportunities for its continued study and the benefits that arise from using well-developed quantitative techniques to study abstract theoretical constructs.