An unexpected target of spinal direct current stimulation: Interhemispheric connectivity in humans.

BACKGROUND: Transcutaneous spinal Direct Current Stimulation (tsDCS) is a noninvasive technique based on the application of weak electrical currents over spinal cord. NEW METHOD: We studied the effects of tsDCS on interhemispheric motor connectivity and visual processing by evaluating changes in ipsilateral Silent Period (iSP), Transcallosal Conduction Time (TCT) and hemifield Visual Evoked Potentials (hVEPs), before (T0) and at a different intervals following sham, anodal and cathodal tsDCS (T9-T11 level, 2.0 mA, 20'). Motor Evoked Potentials (MEPs) were recorded from abductor pollicis brevis (APB), abductor hallucis (AH) and deltoid muscles. hVEPs were recorded bilaterally by reversal of a horizontal square wave grating with the display positioned in the right hemifield. RESULTS: Anodal tsDCS increased TCT (p < 0.001) and the interhemispheric delay for both the main VEP components (N1: p = 0.0003; P1: p < 0.0001), dampening at the same time iSP duration (APB: p < 0.0001; AH: p = 0.0005; deltoid: p < 0.0001), while cathodal stimulation elicited opposite effects (p < 0.0001). DISCUSSION: tsDCS modulates interhemispheric processing in a polarity-specific manner, with anodal stimulation leading to a functional disconnection between hemispheres. tsDCS would be a new promising therapeutic tool in managing a number of human diseases characterized by an impaired interhemispheric balance, or an early rehabilitation strategy in patients with acute brain lesions, when other non-invasive brain stimulation techniques (NIBS) are not indicated due to safety concerns.

Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs.

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.

Antiepileptic effects of botulinum neurotoxin E.

Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/E-injected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.