Acute electrical neuromodulation paradigms restore firing behavior and inhibition in secondary brain injury: A computational study

Abstract Secondary Brain Injury (SBI) occurs after the initial physical insult caused due to traumatic brain injuries and strokes. SBI leads to a massive loss of brain functionalities if timely intervention is not administered. This work analyses the delineated effects of three acute SBI processes in two-neuron motifs and shows that the right stimulation paradigm during specific key SBI events help restore firing rate trends in neurons. The Hodgkin-Huxley neuron is extended to theoretically model two categories of two-neuron motifs: a feedforward excitatory motif (Motif 1: Two pyramidal neurons with glutamatergic synapses) and a feedforward inhibitory motif (Motif 2: One pyramidal neuron and one interneuron with GABAergic synapses). Three important SBI processes in the motifs were modeled: glutamate excitotoxicity, increased extracellular potassium ion concentration, and cellular energy deficit. Firing rate trend analysis is performed for increasing severity of SBI processes, and interesting points (key events) are identified. A wide range of ACS and DBS stimulation parameters are applied to the motifs during these key events to assess the firing rate response during stimulation. Increasing SBI severity caused an overall increase in excitation, synchronizing neuronal activities in Motif 1 and reducing inhibition in Motif 2. Alternate current stimulation paradigms were found to desynchronize and regulate neuronal firing in Motif 1. Deep brain stimulation parameters were found to increase inhibition in Motif 2, thereby helping to maintain the excitation-inhibition balance. The right stimulation paradigm administered at appropriate key events helps regulate neuronal firing, thereby reducing the metabolic burden on the neurons during acute SBI. Author Summary Traumatic Brain Injuries (TBIs) and strokes affect millions causing issues such as motor and speech disorders, memory and cognitive decline adding to high global economic burden. Secondary Brain Injury (SBI) is the aftermath of TBIs and strokes, which causes loss of brain functionalities, leading to disabilities. Early intervention reduces disabilities and improves quality of survivor’s life. Therapeutic electrical brain stimulation has gained prominence to help restore brain functionalities post brain injuries. It is usually administered chronically post injury, when disabilities have set. Here, we investigate if electrical brain stimulation during acute SBI leads to prevention of neurodegeneration, thereby retention of brain functionalities using biophysics. We model fundamental two neuron motifs exhibiting feedforward excitatory and feedforward inhibitory behavior (form the backbone of neuronal networks) and add SBI pathways and brain stimulation models to this scenario. On analyzing neuronal firing during various stimulation strategies at key SBI events, we found that specific Alternate Current Stimulation parameters can desynchronize and regulate firing, and Deep Brain Stimulation parameters could restore inhibition when the underlying neuronal properties are known and leveraged. Hence, we show that acute electrical stimulation regulates neuronal firing with appropriate stimulation parameters and SBI conditions, thereby suggesting possible effective early intervention strategies. Competing Interest Statement Behnaam Aazhang and Ananya Muguli report financial support and article publishing charges were provided by Houston Methodist Academic Institute. Behnaam Aazhang and Ananya Muguli report a relationship with Houston Methodist Academic Institute that includes funding grants. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.