Focal targeting of the prefrontal cortex via electrical temporal interference

Abstract

How many people do you meet on your regular working day? If you commute by public transport this number can easily be as high as 100. In 2021 World Health Organization (WHO) estimated the prevalence of depression at the level of 5% worldwide, meaning that almost every day you meet several people who suffer from a serious mental health condition. Moreover, 75% of people in low and middle-income countries receive no treatment for depression. Despite heterogeneous manifestations depression may be identified by a presence of a characteristic behavioral trait – anhedonia. Anhedonia can be summarized as a consistent loss of interest in reward-based activity. Importantly, in addition to depression, anhedonia is also detected in schizophrenia, substance abuse, obsessive-compulsive disorder, and post-traumatic stress disorder. Therefore, not surprisingly anhedonia is at the hotspot of both human and animal-based research. Neuroscientific studies on humans and animal models suggest that the ventral portion of the medial prefrontal cortex (vmPFC) is an important brain structure supporting sensory integration, the processing of motivational and reward-related information, and the implementation of reward-related strategies and actions. Functional magnetic resonance imaging (fMRI) studies detected an elevated metabolic activity in the vmPFC in patients with severe anhedonic symptoms and depression. When depressed patients are resistant to currently available medical and psychotherapies (on average 30%), they may undergo surgical procedures for the implantation of electrodes in specific regions of the brain (e.g. vmPFC) to modulate neural activity and to alleviate depression – Deep Brain Stimulation (DBS). However, according to WHO, in addition to requiring an extensive surgical intervention DBS technology is currently not available to at least 75% of people with depression in low and middle-income countries.Based on the discussed findings, we sought to perform the following steps to contribute to the development of a non-invasive, safe, and convenient method to target brain areas regulating anhedonic behavior. At first, we emphasized benefits of selecting target brain regions utilizing their integration in the functional connectome of an entire brain as opposed to using only anatomical references. We suggested an analytical pipeline to identify discrete and reproducible functional clusters within mouse Prefrontal Cortex (PFC) that can potentially be used as targets for a prospective intervention. Secondly, as the intervention method, we suggested a recently published non-invasive brain stimulation technique, named Temporal Interference (TI). Original TI design is based on using two pairs of electrodes (e.g. dipole) to produce two distinct waveforms with the frequencies in a kHz range that have a shift in a Hz range. As the waves travel in the brain, they overlap and interfere in a desired region in which the destructive and additive interferences of the stimuli create an envelope frequency in the Hz range. Despite being a promising candidate for non-invasive DBS, recent animal-based studies showed that, along with the target intervention, TI also produces off-target stimulations leading to detrimental side effects. To circumvent this limitation, we proposed a novel TI design using an additional phase-shifted electrical field that allowed us to improve the previously limited spatial focality by cancelling the off-target TI stimulations via destructive interference. Finally, we conducted an extensive state-of-the-art literature review on how electrical stimulations can be used to study causative roles of neural oscillations and argued that the modified version of TI can be used in this direction alongside with other existing electrical stimulation protocols.