Localized Increased Permeability of Blood-Brain Barrier for Antibody Conjugates in the Cuprizone Model of Demyelination.

The development of new neurotherapeutics depends on appropriate animal models being chosen in preclinical studies. The cuprizone model is an effective tool for studying demyelination and remyelination processes in the brain, but blood-brain barrier (BBB) integrity in the cuprizone model is still a topic for debate. Several publications claim that the BBB remains intact during cuprizone-induced demyelination; others demonstrate results that could explain the increased BBB permeability. In this study, we aim to analyze the permeability of the BBB for different macromolecules, particularly antibody conjugates, in a cuprizone-induced model of demyelination. We compared the traditional approach using Evans blue injection with subsequent dye extraction and detection of antibody conjugates using magnetic resonance imaging (MRI) and confocal microscopy to analyze BBB permeability in the cuprizone model. First, we validated our model of demyelination by performing T2-weighted MRI, diffusion tensor imaging, quantitative rt-PCR to detect changes in mRNA expression of myelin basic protein and proteolipid protein, and Luxol fast blue histological staining of myelin. Intraperitoneal injection of Evans blue did not result in any differences between the fluorescent signal in the brain of healthy and cuprizone-treated mice (IVIS analysis with subsequent dye extraction). In contrast, intravenous injection of antibody conjugates (anti-GFAP or non-specific IgG) after 4 weeks of a cuprizone diet demonstrated accumulation in the corpus callosum of cuprizone-treated mice both by contrast-enhanced MRI (for gadolinium-labeled antibodies) and by fluorescence microscopy (for Alexa488-labeled antibodies). Our results suggest that the methods with better sensitivity could detect the accumulation of macromolecules (such as fluorescent-labeled or gadolinium-labeled antibody conjugates) in the brain, suggesting a local BBB disruption in the demyelinating area. These findings support previous investigations that questioned BBB integrity in the cuprizone model and demonstrate the possibility of delivering antibody conjugates to the corpus callosum of cuprizone-treated mice.

Author Correction: State-Dependent Effects of Transcranial Oscillatory Currents on the Motor System during Action Observation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

State-Dependent Effects of Transcranial Oscillatory Currents on the Motor System during Action Observation.

We applied transcranial alternating current stimulation (tACS) to the primary motor cortex (M1) at different frequencies during an index-thumb pinch-grip observation task. To estimate changes in the corticospinal output, we used the size of motor evoked potentials (MEPs) obtained by transcranial magnetic stimulation (TMS) of M1 using an online MRI-guided simultaneous TMS-tACS approach. The results of the beta-tACS confirm a non-selective increase in corticospinal excitability in subjects at rest; an increase was observed for both of the tested hand muscles, the first dorsal interosseous (FDI) and the abductor digiti minimi (ADM). However, during action observation of the pinch-grip movement, the increase of corticospinal excitability was only observed for the prime mover FDI muscle and took place during alpha-tACS, while gamma-tACS affected both the FDI and control muscle (ADM) responses. These phenomena likely reflect the hypothesis that the mu and gamma rhythms specifically index the downstream modulation of primary sensorimotor areas by engaging mirror neuron activity. The current neuromodulation approach confirms that tACS can be used to induce neurophysiologically detectable state-dependent enhancement effects, even in complex motor-cognitive tasks.