Deep Brain Stimulation Synchronizes Neuron Firing to Rewire the Brain

Deep brain stimulation (DBS) is a neurological treatment that involves inserting an electrode into the brain and using electric pulses to stimulate therapeutic effects. So far, researchers have used DBS to treat Parkinson’s disease and are currently exploring using it to treat psychiatric disorders as well.¹ Despite the success of this therapy, scientists do not fully understand how it alters neurons to exert its effects.

Recently, a team of researchers from the University of California, Los Angeles (UCLA) and the University of Texas Southwestern Medical Center used ex vivo and in vivo human brain tissue to explore how electric stimulation changes brain cell activity. In a study published in Nature, the team showed how the electric pulses synchronized neuronal firing and activated gene expression in neurons, in particular excitatory cells.² These findings could help better inform how to dial in DBS therapy and complement it with pharmacological treatments.

Previous studies indicated that electrical stimulation changed the strength of neuronal connections and how cells fired in neuron assemblies, groups of neurons that synchronize to encode information.³ While researchers have observed these assemblies in people, how DBS alters their activity or gene expression had not been explored.⁴

To address this gap, the researchers collected living brain tissue from the cortices of 12 individuals who were undergoing neurosurgery. When they stimulated the samples with a microelectrode ex vivo, they saw that all of the cells increased their firing rate, suggesting more cellular activation. But, when they clustered the cells based on the pattern of their electrical response, the team found that excitatory neurons responded more strongly to stimulation than interneurons predominantly responsible for communicating between different cell types.

Exploring this increased activation further, the researchers showed that neurons that worked in an assembly had more synchronized activation after stimulation and that the electrical pulses strengthened their connections. This suggested that electrical stimulation increased neuronal activity, in particular among excitatory neurons and those working together.

To assess the effects of stimulation on gene expression, the researchers completed single cell sequencing to study the active transcripts and accessible DNA, respectively. After clustering the cells based on their expression patterns, the team found hundreds of differentially expressed genes, though the number of these impacted genes varied depending on where in the cortex the cells came from. Affected genes included those related in rapid and delayed responses as well as those involved in regulating cellular activity.

Comparing these findings with their DNA accessibility data, the researchers observed that DNA was more accessible in activity-dependent transcription factors in excitatory cells following stimulation. These transcription factors included those for rapid response genes and genes involved in responding to stimuli and growth factors, organizing synapses, and promoting the formation of new neurons.

These findings indicated that electrical stimulation activated expression of genes that are important for promoting neuronal activity, leading to increased cellular activity, especially within assemblies of cells.

To compare these ex vivo findings to more realistic conditions, the researchers collected brain tissue from patients undergoing stimulation, taking samples from near the stimulated site and adjacent to it. Similar to their ex vivo studies, the researchers found activated genes in excitatory cells throughout the cortex involved in rapid response and activity regulation.

“Not only was it a privilege and challenge to work with donated living human brain tissue, but to see it reveal the genes and cell types underlying human brain plasticity as new targets for future therapies makes the work feel even more meaningful,” said Genevieve Konopka, a study coauthor and neurobiologist at UCLA in a press statement. “By understanding exactly which genes turn on in which cells during stimulation, we can start to design more precise approaches to deep brain stimulation and potentially augment this clinical strategy with pharmacological therapies to help slow cognitive decline.”