Neocortical Localization and Thalamocortical Modulation of Neuronal Hyperexcitability in Fragile X Syndrome

Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key illness features. Translating these findings into patients may identify tractable treatment targets. Using a minimum norm estimate of resting state electroencephalography data, we report novel findings in FXS including: 1) increases in gamma activity across functional networks, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of these abnormalities based on female sex and genetic mosaicism, and 4) relationship of this physiology to intellectual disability and anxiety. Our observations extend findings in Fmr1-/- KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability, a mechanism that has received limited preclinical attention, but has significant implications for understanding fundamental disease mechanisms.

Parametrizing the Conditionally Gaussian Prior Model for Source Localization with Reference to the P20/N20 Component of Median Nerve SEP/SEF

In this article, we focused on developing the conditionally Gaussian hierarchical Bayesian model (CG-HBM), which forms a superclass of several inversion methods for source localization of brain activity using somatosensory evoked potential (SEP) and field (SEF) measurements. The goal of this proof-of-concept study was to improve the applicability of the CG-HBM as a superclass by proposing a robust approach for the parametrization of focal source scenarios. We aimed at a parametrization that is invariant with respect to altering the noise level and the source space size. The posterior difference between the gamma and inverse gamma hyperprior was minimized by optimizing the shape parameter, while a suitable range for the scale parameter can be obtained via the prior-over-measurement signal-to-noise ratio, which we introduce as a new concept in this study. In the source localization experiments, the primary generator of the P20/N20 component was detected in the Brodmann area 3b using the CG-HBM approach and a parameter range derived from the existing knowledge of the Tikhonov-regularized minimum norm estimate, i.e., the classical Gaussian prior model. Moreover, it seems that the detection of deep thalamic activity simultaneously with the P20/N20 component with the gamma hyperprior can be enhanced while using a close-to-optimal shape parameter value.

Combining Noninvasive Electromagnetic and Hemodynamic Measures of Human Brain Activity

Magnetoencephalography (MEG) is directly sensitive to postsynaptic neuronal activity with the millisecond temporal resolution. MEG is ideally to complement functional MRI (fMRI), which measures hemodynamic responses secondary to neuronal activity with the millimeter spatial resolution, for noninvasive imaging of human brain function. Here, using the Minimum-Norm Estimate as an example, we review how fMRI can be integrated with MEG (and electroencephalography, EEG) source modeling and summarize potential advantages and pitfalls of this data fusion technique. Neurovascular coupling as the physiological basis for MEG/EEG/fMRI integration is also discussed. Ultimately, we expect to develop multimodal MEG/EEG/fMRI neuroimaging methodology for characterizing spatiotemporal functional connectivity in large-scale neural networks of the human brain with high sensitivity and accuracy.