On temporal scale-free non-periodic stimulation and its mechanisms as an infinite improbability drive of the brain’s functional connectogram

Abstract

Rationalized development of electrical stimulation (ES) therapy is of paramount importance. Not only it will foster new techniques and technologies with increased levels of safety, efficacy, and efficiency, but it will also facilitate the translation from basic research to clinical practice. For such endeavor, design of new technologies must dialogue with state-of-the-art neuroscientific knowledge. By its turn, neuroscience is transitioning—a movement started a couple of decades earlier—into adopting a new conceptual framework for brain architecture, in which time and thus temporal patterns plays a central role in the neuronal representation of sampled data from the world. This article discusses how neuroscience has evolved to understand the importance of brain rhythms in the overall functional architecture of the nervous system and, consequently, that neuromodulation research should embrace this new conceptual framework. Based on such support, we revisit the literature on standard (fixed-frequency pulsatile stimuli) and mostly non-standard patterns of ES to put forward our own rationale on how temporally complex stimulation schemes may impact neuromodulation strategies. We then proceed to present a low frequency, on average (thus low energy), scale-free temporally randomized ES pattern for the treatment of experimental epilepsy, devised by our group and termed NPS (Non-periodic Stimulation). The approach has been shown to have robust anticonvulsant effects in different animal models of acute and chronic seizures (displaying dysfunctional hyperexcitable tissue), while also preserving neural function. In our understanding, accumulated mechanistic evidence suggests such a beneficial mechanism of action may be due to the natural-like characteristic of a scale-free temporal pattern that may robustly compete with aberrant epileptiform activity for the recruitment of neural circuits. Delivering temporally patterned or random stimuli within specific phases of the underlying oscillations (i.e., those involved in the communication within and across brain regions) could both potentiate and disrupt the formation of neuronal assemblies with random probability. The usage of infinite improbability drive here is obviously a reference to the “The Hitchhiker’s Guide to the Galaxy” comedy science fiction classic, written by Douglas Adams. The parallel is that dynamically driving brain functional connectogram, through neuromodulation, in a manner that would not favor any specific neuronal assembly and/or circuit, could re-stabilize a system that is transitioning to fall under the control of a single attractor. We conclude by discussing future avenues of investigation and their potentially disruptive impact on neurotechnology, with a particular interest in NPS implications in neural plasticity, motor rehabilitation, and its potential for clinical translation.

Personalized strategies of neurostimulation: from static biomarkers to dynamic closed-loop assessment of neural function

“…Along several decades of development, neurostimulation has benefited extensively from scientific progress and technological breakthroughs, such as a better understanding of the neurophysical basis of the interaction between electromagnetic fields and brain tissue ( Nunez and Harth, 2005 ; Buzsáki and Vöröslakos, 2023 ), paradigm-shifting neuroscientific discoveries related to the processing of neural information ( Varela et al, 2001 ; Buzsáki and Watson, 2012 ), innovative neural interfaces ( Panuccio et al, 2018 ), and powerful signal processing methods, including the usage of artificial intelligence/machine learning tools ( Fellous et al, 2019 ; Chandrabhatla et al, 2023 ), and neuromorphic strategies ( Chiappalone et al, 2022 ; Christensen et al, 2022 ). By its turn, these allowed for the exploration of a series of novel stimulation paradigms, including temporally spatial complex stimulus patterns ( Cota et al, 2023 ), and closed-loop modes of operation ( Panuccio et al, 2016 ; Iturrate et al, 2018 ; Sellers et al, 2024 ). Collectively, these advancements are spurring a new era of disruptive neurostimulation, referred to as electroceuticals ( Famm et al, 2013 ; Reardon, 2014 , 2017 ), which can target specific nerves or neural pathways, addressing various chronic diseases and conditions, not limited to neuronal disorders.…”