Neurostimulation in Theory and Practice

**3**

**Chapter 1**

*Denis Larrivee*

impairments.

that they be reconstructed.

their utility to therapeutic design uncertain.

Introductory Chapter:

Neurostimulation and the

**1. Introduction: neurostimulation and global organization**

Structural Basis of Brain Activity

Despite its remarkable clinical efficacy and several decades of use, neurostimulation remains a therapy whose neurophysiological basis is yet undetermined [1]. This lack of basic scientific understanding has imposed a conceptual barrier that has broader implications for therapeutic efficacy. Nonetheless, an improved understanding of the mechanisms of brain activity, observations on the etiological basis of neurological diseases, and insights from diverse therapeutic applications offer hope for understanding how the therapy physiologically impacts neural

Because the form of neurostimulation is rhythmic, it has been suggested that neural mechanisms responding to stimulation are similarly rhythmic [2]. Rhythmic activity is notably ubiquitous in brain operation, and has been observed in single neurons that display patterned spiking, as well as at network levels, where variable inhibitory and excitatory feedback configure repetitive activity [3]. Increasingly, these are proposed to be oscillatory [4]. Significantly, oscillators are prone to pairing and can combine in an indefinite number of permutations to recreate encoded feature representations. The therapeutic role played by neurostimulation thus plausibly entails oscillatory interactions, where neurostimulation could modify dysfunctional oscillations, presumably by altering their intrinsic features, like patterning, synchronization, and desynchronization. Recent studies show in fact that brain activity is globally structured through oscillatory interactions, with key elements distributed throughout the brain. Such elements would be expected to be similarly perturbed in various impairments; hence, restoring normal function would require

Consistent with this proposal, it is known that global brain activity is coordinated by slow frequency oscillations that resonate between subcortical and cortical regions [4]. These activity structures mediate organismal functions, which are cohesively ordered to the good of the individual; hence, their investigation can be expected to provide a basis for understanding the higher order organization that underlies brain dynamics at global scales. Indeed, without such understanding, the effects induced by neuromodulation and neurostimulation remain anecdotal and

How then is global brain activity affected by neurostimulation? Some insight into this question can be expected from the study of diseases known to disrupt global brain events. One candidate is epilepsy, which has been treated by neurostimulation for several decades. Significantly, a characteristic feature of epilepsy is the occurrence of epileptogenesis outside initial seizure foci. The processes associated with this distribution are not known, but current evidence implicates
