Rapid variations in cortical state during wakefulness have a strong influence on neural and behavioural responses and are tightly coupled to changes in pupil size across species. However, the physiological processes linking cortical state and pupil variations are largely unknown. Here we demonstrate that these rapid variations, during both quiet waking and locomotion, are highly correlated with fluctuations in the activity of corticopetal noradrenergic and cholinergic projections. Rapid dilations of the pupil are tightly associated with phasic activity in noradrenergic axons, whereas longer-lasting dilations of the pupil, such as during locomotion, are accompanied by sustained activity in cholinergic axons. Thus, the pupil can be used to sensitively track the activity in multiple neuromodulatory transmitter systems as they control the state of the waking brain.

SUMMARY Pupil size is collectively controlled by the sympathetic dilator and parasympathetic sphincter muscles. Locus coeruleus (LC) activation has been shown to evoke pupil dilation, yet how the sympathetic and parasympathetic pathways contribute to this dilation remains unknown. We examined pupil dilation elicited by LC activation in lightly anesthetized rats. Unilateral LC activation evoked bilateral, yet lateralized pupil dilation, i.e, the ipsilateral dilation was significantly larger than the contralateral dilation. Surgically blocking the ipsilateral, but not contralateral, sympathetic pathway significantly reduced lateralization, suggesting lateralization is mainly due to sympathetic contribution. Moreover, we found that sympathetic, but not parasympathetic, contribution is correlated with LC activation frequency. Together, our results unveiled the frequency-dependent contributions of the sympathetic and parasympathetic pathways to LC-activation-evoked pupil dilation, and suggest that lateralization in task-evoked pupil dilations may be used as a biomarker for autonomic tone.

We investigated locus coeruleus (LC) modulation of thalamic feature selectivity through reverse correlation analysis of single-unit recordings from different stages of the rat vibrissa pathway. LC activation increased feature selectivity, drastically improving thalamic information transmission. We found this improvement was dependent on both local activation of α-adrenergic receptors and modulation of T-type calcium channels in the thalamus and was not due to LC modulation of trigeminothalamic feedforward or corticothalamic feedback inputs. Tonic spikes with LC stimulation carried 3-times the information than did tonic spikes without LC stimulation. Modelling confirmed norepinephrine (NE) regulation of intrathalamic circuit dynamics led to the improved information transmission. Behavioral data demonstrated that LC activation increased the perceptual performance of animals performing tactile discrimination tasks through LC-NE optimization of thalamic sensory processing. These results suggest a new sub-dimension within the tonic mode in which brain state can optimize thalamic sensory processing through modulation of intrathalamic circuit dynamics.

Objective. Vagus nerve stimulation (VNS) has been FDA-approved as a long-term, therapeutic treatment for multiple disorders, including pharmacoresistant epilepsy and depression. Here we elucidate the short-term effects of VNS on sensory processing. Approach. We employed an information theoretic approach to examine the effects of VNS on thalamocortical transmission of sensory-related information along the somatosensory pathway. Main results. We found that VNS enhanced the selectivity of the response of thalamic neurons to specific kinetic features in the stimuli, resulting in a significant increase in the efficiency and rate of stimulus-related information conveyed by thalamic spikes. VNS-induced improvements in thalamic sensory processing coincided with a decrease in thalamic burst firing. Importantly, we found VNS-induced enhancement of sensory processing had a rapid onset and offset, completely disappearing one minute after cessation of VNS. The timescales of these effects indicate against an underlying mechanism involving long-term neuroplasticity. We found several patterns of VNS (tonic, standard duty-cycle, and fast duty-cycle) all induced similar improvements in sensory processing. Under closer inspection we noticed that due to the fast timescale of VNS effects on sensory processing, standard duty-cycle VNS induced a fluctuating sensory processing state which may be sub-optimal for perceptual behavior. Fast duty-cycle VNS and continuous, tonic VNS induced quantitatively similar improvements in thalamic information transmission as standard duty-cycle VNS without inducing a fluctuating thalamic state. Further, we found the strength of VNS-induced improvements in sensory processing increased monotonically with amplitude and frequency of VNS. Significance. These results demonstrate, for the first time, the feasibility of utilizing specific patterns of VNS to rapidly improve sensory processing and confirm fast duty-cycle and tonic patterns as optimal for this purpose, while showing standard duty-cycle VNS causes non-optimal fluctuations in thalamic state.

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After sensory information is encoded into neural signals at the periphery, it is processed through multiple brain regions before perception occurs (i.e., sensory processing). Recent work has begun to tease apart how neuromodulatory systems influence sensory processing. Vagus nerve stimulation (VNS) is well-known as an effective and safe method of activating neuromodulatory systems. There is a growing body of studies confirming VNS has immediate effects on sensory processing across multiple sensory modalities. These immediate effects of VNS on sensory processing are distinct from the more well-documented method of inducing lasting neuroplastic changes to the sensory pathways through repeatedly delivering a brief VNS burst paired with a sensory stimulus. Immediate effects occur upon VNS onset, often disappear upon VNS offset, and the modulation is present for all sensory stimuli. Conversely, the neuroplastic effect of pairing sub-second bursts of VNS with a sensory stimulus alters sensory processing only after multiple pairing sessions, this alteration remains after cessation of pairing sessions, and the alteration selectively affects the response properties of neurons encoding the specific paired sensory stimulus. Here, we call attention to the immediate effects VNS has on sensory processing. This review discusses existing studies on this topic, provides an overview of the underlying neuromodulatory systems that likely play a role, and briefly explores the potential translational applications of using VNS to rapidly regulate sensory processing.

Background Accurate senses depend on high fidelity encoding by sensory receptors and error-free central processing in the brain. Progress has been made towards restoring damaged sensory receptors. However, methods for providing on demand treatment of impaired central sensory processing arising from factors including aging, neurological dysfunction, inattention, and fatigue are scarce. Recent studies have demonstrated that tonic vagus nerve stimulation in rodents can activate the locus coeruleus-norepinephrine system in the brain to improve sensory processing rapidly and continuously. Hypothesis We hypothesized that non-invasive neuromodulation via tonic transcutaneous vagus nerve stimulation (tVNS) improves sensory performance in humans. Methods Twenty-nine adults with no reported neurological dysfunction completed three sham-controlled experiments that measured effects of tVNS on sensory performance metrics (auditory gap detection, visual letter discrimination) and heart rate variability. Tonic tVNS was delivered continuously to cervical (neck) or auricular (ear) branches of the vagus nerve while participants performed psychophysics tasks or passively viewed a display without an accompanying task. Results Cervical tVNS improved auditory gap detection by 35% and visual letter discrimination by 20%, on average, relative to sham stimulation. Notably, participants with lower sensory performance during control conditions experienced larger tVNS-mediated improvements. Lastly, tVNS increased heart rate variability relative to sham stimulation during passive viewing, corroborating vagal engagement. Conclusion We demonstrate that non-invasive vagus nerve stimulation improves sensory processing in neurotypical human adults. These findings substantiate foundational studies in rodents and position tVNS as a neuromodulation method for targeted and on-demand interventions of impairments associated with central sensory processing dysfunction.

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