On-chip brain slice stimulation: precise control of electric fields and tissue orientation

Abstract

Non-invasive brain stimulation modalities, including transcranial direct current stimulation (tDCS), are widely used in neuroscience and clinical practice to modulate brain function and treat neuropsychiatric diseases. DC stimulation of ex vivo brain tissue slices has been a method used to understand mechanisms imparted by tDCS. However, delivering spatiotemporally uniform direct current electric fields (dcEFs) that have precisely engineered magnitudes and are also exempt from toxic electrochemical by-products are both significant limitations in conventional experimental setups. As a consequence, bioelectronic dose-response interrelations, the role of EF orientation, and the biomechanisms of prolonged or repeated stimulation over several days all remain not well understood. Here we developed a platform with fluidic, electrochemical, and magnetically-induced spatial control. Fluidically, the chamber geometrically confines precise dcEF delivery to the enclosed brain slice and allows for tissue recovery in order to monitor post-stimulation effects. Electrochemically, conducting hydrogel electrodes mitigate stimulation-induced faradaic reactions typical of commonly-used metal electrodes. Magnetically, we applied ferromagnetic substrates beneath the tissue and used an external permanent magnet to enable in situ rotational control in relation to the dcEF. By combining the microfluidic chamber with live-cell calcium imaging and electrophysiological recordings, we showcased the potential to study the acute and lasting effects of dcEFs with the potential of providing multi-session stimulation. This on-chip bioelectronic platform presents a modernized yet simple solution to electrically stimulate explanted tissue by offering more environmental control to users, which unlocks new opportunities to conduct thorough brain stimulation mechanistic investigations. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/536696v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@10bac4dorg.highwire.dtl.DTLVardef@15d1dd3org.highwire.dtl.DTLVardef@5119c8org.highwire.dtl.DTLVardef@73b554_HPS_FORMAT_FIGEXP M_FIG C_FIG