Gray Matter Atrophy in the Cortico-Striatal-Thalamic Network and Sensorimotor Network in Relapsing-Remitting and Primary Progressive Multiple Sclerosis.

Gray matter atrophy in multiple sclerosis (MS) is thought to be associated with disability and cognitive impairment, but previous studies have sometimes had discordant results, and the atrophy patterns of relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) remain to be clarified. We conducted a meta-analysis using anisotropic effect-size-based algorithms (AES-SDM) to identify consistent findings from whole-brain voxel-based morphometry (VBM) studies of gray matter volume (GMV) in 924 RRMS patients and 204 PPMS patients. This study is registered with PROSPERO (number CRD42019121319). Compared with healthy controls, RRMS and PPMS patients showed gray matter atrophy in the cortico-striatal-thalamic network, sensorimotor network, and bilateral insula. RRMS patients had a larger GMV in the left insula, cerebellum, right precentral gyrus, and bilateral putamen as well as a smaller GMV in the bilateral cingulate, caudate nucleus, right thalamus, superior temporal gyrus and left postcentral gyrus than PPMS patients. The disease duration, Expanded Disability Status Scale score, Paced Auditory Serial Addition Test z-score, and T2-weighted lesion load were associated with specific gray matter regions in RRMS or PPMS. Alterations in the cortico-striatal-thalamic networks, sensorimotor network, and insula may be involved in the common pathogenesis of RRMS and PPMS. The deficits in the cingulate gyrus and caudate nucleus are more apparent in RRMS than in PPMS. The more severe cerebellum atrophy in PPMS may be a brain feature associated with its neurological manifestations. These imaging biomarkers provide morphological evidence for the pathophysiology of MS and should be verified in future research.

Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations.

Absence seizures result from 3 to 5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens human seizures. Here, we show that blocking GABA transporters (GATs) in acute rat brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations into single-neuron and network-level computational models shows how a non-linear dependence of T-type calcium channel gating on GABAB receptor activity regulates network oscillations. Receptor activity that is either too brief or too protracted fails to sufficiently open T-type channels necessary for sustaining oscillations. Only within a narrow range does prolonging GABAB receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate inhibition kinetics.