Electrical stimulation of cranial nerves in cognition and disease.

The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.

Closed-Loop Acoustic Stimulation Enhances Sleep Oscillations But Not Memory Performance.

Slow oscillations and spindle activity during non-rapid eye movement sleep have been implicated in memory consolidation. Closed-loop acoustic stimulation has previously been shown to enhance slow oscillations and spindle activity during sleep and improve verbal associative memory. We assessed the effect of closed-loop acoustic stimulation during a daytime nap on a virtual reality spatial navigation task in 12 healthy human subjects in a randomized within-subject crossover design. We show robust enhancement of slow oscillation and spindle activity during sleep. However, no effects on behavioral performance were observed when comparing real versus sham stimulation. To explore whether memory enhancement effects were task specific and dependent on nocturnal sleep, in a second experiment with 19 healthy subjects, we aimed to replicate a previous study that used closed-loop acoustic stimulation to enhance memory for word pairs. The methods used were as close as possible to those used in the original study, except that we used a double-blind protocol, in which both subject and experimenter were unaware of the test condition. Again, we successfully enhanced slow oscillation and spindle power, but again did not strengthen associative memory performance with stimulation. We conclude that enhancement of sleep oscillations may be insufficient to enhance memory performance in spatial navigation or verbal association tasks, and provide possible explanations for lack of behavioral replication.