Effects of central nervous system electrical stimulation on non-neuronal cells

Abstract

Over the past few decades, much progress has been made in the clinical use of electrical stimulation of the central nervous system (CNS) to treat an ever-growing number of conditions from Parkinson's disease (PD) to epilepsy as well as for sensory restoration and many other applications. However, little is known about the effects of microstimulation at the cellular level. Most of the existing research focuses on the effects of electrical stimulation on neurons. Other cells of the CNS such as microglia, astrocytes, oligodendrocytes, and vascular endothelial cells have been understudied in terms of their response to stimulation. The varied and critical functions of these cell types are now beginning to be better understood, and their vital roles in brain function in both health and disease are becoming better appreciated. To shed light on the importance of the way electrical stimulation as distinct from device implantation impacts non-neuronal cell types, this review will first summarize common stimulation modalities from the perspective of device design and stimulation parameters and how these different parameters have an impact on the physiological response. Following this, what is known about the responses of different cell types to different stimulation modalities will be summarized, drawing on findings from both clinical studies as well as clinically relevant animal models and in vitro systems.

Keywords: astrocytes; blood brain barrier (BBB); electrical stimulation; endothelial cells; microglia; neuroinflammation; non-neuronal cell types; oligodendrocytes.

FIGURE 1

Electrical and cellular effects of deep brain stimulation (DBS): High frequency DBS causes axonal action potentials and depolarization of inhibitory and excitatory fibers projecting to target neurons (a) and induces release of neurotransmitters (b). In response to stimulation, activated astrocytes release calcium (c), gliotransmitters and trophic factors (e). Increased calcium from activated astrocytes also triggers neurotransmitter and gliotransmitter release (d) which can modulate synaptic transmission. DBS causes subsequent release of the inhibitory transmitter γ-aminobutyric acid (GABA), and a depolarization block which causes reduced activity in neuronal cell bodies (f). Stimulation can also generate synaptic plasticity changes, which can lead to long term potentiation (g). DBS induces an activated ameboid morphology in microglia and an upregulation of cytokines is observed (h). Boxed panels indicate effects on non-neuronal cell types (Hamani and Temel, 2012; Jakobs et al., 2019; Lozano et al., 2019).

FIGURE 2

The type of stimulation determines the modulatory effect of transcranial direct current stimulation (tDCS). Anodal stimulation depolarizes the neuronal membrane and enhances neuronal excitability. Cathodal stimulation hyperpolarizes the neuronal membrane and reduces neuronal excitability. Anodal tDCS exacerbates bleeding and damage to the blood-brain barrier following ischemic injury. (a) tDCS activates noradrenergic fibers that release noradrenaline, increasing (b) astrocytic Ca²⁺ levels and release of gliotransmitters (c). Decreased GABA release by both anodal and cathodal tDCS results in decreased inhibition (d). Activated microglia release cytokines that cause inflammation and result in axonal degeneration (e). Anodal tDCS is involved in increasing dendritic spine density (f). tDCS also leads to change in neuronal neurotransmitter release. Boxed panels indicate effects on non-neuronal cell types.