Background: Transcranial direct current stimulation (tDCS) has emerged as a non-invasive brain stimulation technique. Most studies show that anodal tDCS increases cortical excitability. However, this effect has been found to be highly variable. Objective: To test the effect of anodal tDCS on cortical excitability and the interaction effect of two participant-specific factors that may explain individual differences in sensitivity to anodal tDCS: the Brain Derived Neurotrophic Factor Val66Met polymorphism (BDNF genotype) and the latency difference between anterior-posterior and lateromedial TMS pulses (APLM latency). Methods: In 62 healthy participants, cortical excitability over the left motor cortex was measured before and after anodal tDCS at 2 mA for 20 min in a pre-registered, double-blind, randomized, placebocontrolled trial with repeated measures. Results: We did not find a main effect of anodal tDCS, nor an interaction effect of the participant-specific predictors. Moreover, further analyses did not provide evidence for the existence of responders and nonresponders. Conclusion:This study indicates that anodal tDCS at 2 mA for 20 min may not reliably affect cortical excitability.

Background: Changes in transcranial magnetic stimulation motor map parameters can be used to quantify plasticity in the human motor cortex. The golden standard uses a counting analysis of motor evoked potentials (MEPs) acquired with a predefined grid. Recently, digital reconstruction methods have been proposed, allowing MEPs to be acquired with a faster pseudorandom procedure. However, the reliability of these reconstruction methods has never been compared to the golden standard. Objective: To compare the absolute reliability of the reconstruction methods with the golden standard. Methods: In 21 healthy subjects, both grid and pseudorandom acquisition were performed twice on the first day and once on the second day. The standard error of measurement was calculated for the counting analysis and the digital reconstructions. Results: The standard error of measurement was at least equal using digital reconstructions. Conclusion: Pseudorandom acquisition and digital reconstruction can be used in intervention studies without sacrificing reliability.

This work illustrates the use of normative models in a longitudinal neuroimaging study of children aged 6-17 years and demonstrates how such models can be used to make meaningful comparisons in longitudinal studies, even when individuals are scanned with different scanners across successive study waves. More specifically, we first estimated a large-scale reference normative model using hierarchical Bayesian regression from N=40,435 individuals across the lifespan and from dozens of sites. We then transfer these models to a longitudinal developmental cohort (N=5,985) with three measurement waves acquired on two different scanners that were unseen during estimation of the reference models. We show that the use of normative models provides individual deviation scores that are independent of scanner effects and efficiently accommodate inter-site variations. Moreover, we provide empirical evidence to guide the optimization of sample size for the transfer of prior knowledge about the distribution of regional cortical thicknesses. We show that a transfer set containing as few as 25 samples per site can lead to good performance metrics on the test set. Finally, we demonstrate the clinical utility of this approach by showing that deviation scores obtained from the transferred normative models are able to detect and chart morphological heterogeneity in individuals born pre-term.

The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.