Peripheral nerve stimulation: A neuromodulation-based approach

Recent technological improvements have positioned us at the threshold of innovative discoveries that will assist in new perspectives and avenues of research. Increased attention has been directed towards peripheral nerve stimulation, particularly of the vagus, trigeminal, or greater occipital nerve, due to their unique pathway that engages neural circuits within networks involved in higher cognitive processes. Here, we question whether the effects of transcutaneous electrical stimulation are mediated by synergistic interactions of multiple neuro- modulatory networks, considering this pathway is shared by more than one neuromodulatory system. By spotlighting this attractive transcutaneous pathway, this opinion piece aims to acknowledge the contributions of four vital neuromodulators and prompt researchers to consider them in future investigations or explanations.


A shift from transcranial to transcutaneous
Over the past decade, investigations researching ways to boost synaptic plasticity have attracted attention from a broad array of professional fields, including neuroscience, engineering, and even the U.S. Department of Defensewhich in 2017 began funding research to exploit neuromodulation interventions to improve and accelerate training of military personnel via the activation of peripheral nerves to tune neural networks responsible for vital cognitive skills. However, the field's understanding of the underlying neurophysiological mechanism (s) of peripheral nerve stimulation remains limited and opposes the prevailing mechanistic explanation of non-invasive neuromodulation methods, namely transcranial electrical stimulation (tES), including direct and alternate current stimulation (see Box 1).
Lately, the debate concerning the transcranial versus transcutaneous mechanism has gained new prominence in light of recent investigations unveiling striking evidence that suggests a transcutaneous mechanism may be more suitable and plausible ( Fig. 1)  . Calculations on a realistic head model and validation studies in both animal and human experiments have indicated that only 25 (up to 50) percent of the applied current reaches the brain due to the high electrical resistance of the skull, while the remaining current is shunted through extracranial soft tissues Voroslakos et al., 2018). Additionally, tES delivered at peak 1 mA induced an electrical field of approximately 0.2 V/m when measured at the cortex, a level that contains an inadequate threshold to initiate an action potential in cortical neurons Voroslakos et al., 2018). It is important to note that the maximal electric field for 1 mA peak intensity amounts to <0.5 V/m in other independent studies with the use of intracranial electrodes (Huang et al., 2017;Opitz et al., 2016). Furthermore, human cadaver and in vivo rat experiments indicated that for brain networks to be adequately modified directly, an electric current of approximately 6 mA would need to be administered to the scalp . Regrettably, this requisite of 6 mA would considerably exceed the latest safety guidelines of <4 mA for tES application Thair et al., 2017). Alternatively, tES delivered at 1 mA results in an electrical field that surpasses 20 V/m in the scalp and engages peripheral nerves inside the scalp (Asamoah et al., 2019), initiating the action potentials needed to indirectly modify brain activity (So et al., 2004).
Recently, a perspective piece has endorsed the alternative, peripheral route, referencing the prior assumption of how the effects of tES transpire solely due to the weak, subthreshold electric field it generates in the cortex as being an oversimplification (van Boekholdt et al., 2021). The authors suggest that observed tES effects are instead triggered through peripheral stimulation of the ascending reticular activating system, which promotes the release of noradrenaline from the locus coeruleus (LC) throughout the brain (van Boekholdt et al., 2021). Building upon this alternative explanation, we provide evidence from several studies to extend this understanding and go beyond the noradrenergic system. We question whether the effects of tES and other forms of neuromodulation are mediated by additional neuromodulatory networks. In the following sections, we discuss an attractive transcutaneous pathway, followed by evidence highlighting the contributions of other vital neuromodulators that researchers might want to consider in future investigations or explanations.

Proposed transcutaneous pathway
Directly stimulating the trigeminal and the occipital nerve is an acknowledged and longstanding technique for neuropathic pain suppression and managing headache syndromes (Helm et al., 2021;Slavin, 2011;Zhou et al., 2021). Moreover, attention has been directed towards peripheral stimulation of these nerves due to their unique pathway that engages neural circuits within networks that are highly involved in higher cognitive processes (see Fig. 2). The trigeminal nerve begins in the brain and travels throughout the head to where the nerve endings span across the face and forehead (Rea, 2015). On the other hand, the greater occipital nerve arises from the C2 spinal nerve with several branches innervating the posterior occiput up to the scalp vertex (Weiner and Alo, 2018). These two nerves are interlinked (Busch et al., 2006) and presumably encompass many traditional anterior and posterior electrode montages of non-invasive stimulation utilized by current experimental studies (van Boekholdt et al., 2021)(see Box 3). Of particular importance, targeting either the trigeminal or greater occipital nerve via cutaneous electrodes establishes communication gateways from the periphery to the brain via the specific afferent fibers that project to the brainstem and synapse onto the nucleus tractus solitarius (NTS); various rodent studies have used anterograde neuronal tracers to demonstrate these connections (Adair et al., 2020;Caous et al., 2001;de Sousa Buck et al., 2001;Menetrey and Basbaum, 1987). From the NTS, the information is then integrated and relayed across the brainstem amongst networks within the complex reticular formation (Kawai, 2018), whereby sensory information is processed via the thalamocortical networks (Halassa and Sherman, 2019), and environmental or

Box 1
Traditional account of transcranial direct and alternate current stimulation.
One of the most significant current discussions regarding non-invasive stimulation techniques is whether much of the electrical current modulating the excitability of neurons is provided transcranially, directly and in a regionally constrained manner, or transcutaneously, where the current flow primarily affects neural circuits indirectly via peripheral nerves. The predominant understanding of transcranial direct current stimulation (tDCS) proposes that it employs a unidirectional, direct current at a low or weak intensity (1-2 mA) via two or more strategically placed electrodes (at least one anode and one cathode) in order to transmit the current from the device to the scalp in an effort to polarize the region (Nitsche and Paulus, 2000;Nitsche et al., 2005). In doing so, tDCS aims to modulate cortical excitability and spontaneous activity through subthreshold alterations on neuronal resting membrane potentials, thus increasing or decreasing the neuron's likelihood to fire an action potential (Nitsche and Paulus, 2000;Reed and Cohen Kadosh, 2018;Woods et al., 2016). Prior to the usage of tDCS, it is necessary to consider all components of the methodological design, such as the size and placement of the electrodes and selection of a tolerable stimulus protocol (i.e., current intensity) , given that they are key indicators of current density and the distribution of the electrical field (Jackson et al., 2016). Further attention is advised to the current intensity and stimulation duration, owing to their potential to substantially impact short-and long-term effects produced by tDCS (Nitsche and Paulus, 2000).
Effects generated by tDCS have been deemed similar to long-term potentiation and long-term depression (Kronberg et al., 2017). The ability to produce such outcomes has accelerated tDCS' usage as a treatment option for various neurocognitive disorders associated with plasticity deficits (Jahshan et al., 2017) and tDCS' capability to modify plasticity for memory stabilization (Zhao and Woodman, 2021). Moreover, a relatively recent model, known as activity-selectively, suggests that it is preferential to target neuronal populations that are simultaneously active when applying tDCS while also taking into account the state of the brain when stimulation is administered, thereby generating stimulus-specific brain state effects via tDCS (Boroda et al., 2020). It is of note that this has been emphasized in prior research, whereby it was suggested that tDCS be employed with the behavior it strives to modulate (Fritsch et al., 2010), therefore, gaining momentum as an explanation of cognitive enhancement when tasks are aided by t/DCS (Kronberg et al., 2020;Podda et al., 2016).
Distinguishing itself from tDCS, transcranial alternate current stimulation (tACS) omits the unidirectional voltage component and influences the polarization of neurons via sinusoidal fluctuations of the membrane potential (Tavakoli and Yun, 2017). tACS exerts a sine wave current between the anode and cathode electrodes in a half-cycle fashion to modify the spike-timing activity of individual neurons. Five mechanisms have been proposed for how tACS modifies brain activity, likely depending on the estimated field intensity being generated: stochastic resonance, rhythm resonance, temporal bias of spikes, network entrainment, and imposed pattern . Most conventionally, tACS is characterized to enhance brain oscillations via neural entrainment or synchronized firing of neurons through external stimuli (Reinhart and Nguyen, 2019;Tavakoli and Yun, 2017). To entrain endogenous oscillations, tACS delivers an exogenous oscillation at an equal or increased frequency to enhance the existing oscillation's power (i.e., amplitude), whereas transmitting a signal below the intrinsic frequency will reduce the intrinsic oscillation . Frequency, intensity, and phase are three parameters of tACS oscillations that each play a significant role in defining the direction and cyclical pattern of the delivered stimulation .
Cortical oscillations are fundamental processes underlying cognition and behavior (Buzsaki and Draguhn, 2004). Moreover, alterations in neuronal synchrony have been identified during the early stages of neurodegenerative disorders (Ahnaou et al., 2017), increasing studies utilizing tACS to intervene with and modulate synchrony to restore oscillatory activity. tACS may be applied across a wide array of frequency ranges, typically within conventional electroencephalography frequencies (0.01-80 Hz), and is generally considered to be brain-state dependent, such that the effect of tACS is influenced by the state the brain is in at the time of application. Accordingly, tACS requires a more concrete stimulation paradigm when preparing experimental study designs or intervention protocols, such that researchers need to predetermine the sought-after cognitive-behavioral processes to identify the underlying native oscillatory properties and frequencies of these processes to entrain the associated oscillations . Entraining oscillations at a fixed frequency in specific brain areas enables the researchers to extract causal inferences between brain modulation and obtained effects, such as improved communication leading to improved cognition and/or behavior (Herrmann et al., 2013). Although neural entrainment transpiring is yet to be unanimously supported (Beliaeva et al., 2021), the rationale that tACS' frequency may be applied at the exact frequency rhythm fundamental for optimal brain functioning results in favoring frequency-specific synchrony effect via tACS (Reinhart and Nguyen, 2019). arousal information, as well as other states of vigilance and novelty, will additionally activate LC noradrenergic projections from the brainstem throughout major cortical and subcortical regions (Berridge and Waterhouse, 2003). Therefore, this proposed transcutaneous pathway that emphasizes enhanced LC noradrenergic activation, thereby generating excitatory or inhibitory effects on neural activity (Salgado et al., 2016), has been described as the missing mechanistic link that may underpin the effects of non-invasive brain stimulation (van Boekholdt et al., 2021), and points to an attractive mediator of neuromodulation.

Activation of locus coeruleus noradrenaline pathway
Due to its vast connectedness and activation responses, we propose that the LC be considered a principal target for peripheral nerve stimulation. The LC noradrenaline system was previously thought to solely regulate arousal and autonomic functions (Berridge and Waterhouse, 2003); however, a greater understanding of organizational afferent projections to the LC has led to a widespread agreement that the LC noradrenaline system is one of the four principle neuromodulatory networks heavily engaged in physiological processes including being a significant contributor to signal transduction and synaptic plasticity required for the LC's dual involvement in behaviors and cognition (Avery and Krichmar, 2017;Poe et al., 2020;Samuels and Szabadi, 2008).
Recent research by our laboratory has endorsed peripheral nerve stimulation via non-invasive stimulation of the greater occipital nerve (NITESGON) to (1) upregulate the LC noradrenaline system, (2) confirm that the occipital nerve was sufficient to induce these changes, and (3) suggest an augmentation of memory performance (see Box 2) . The vagus nerve has also been proposed to activate the same transcutaneous pathway leading to the NTS and LC when stimulated (Yap et al., 2020). This pathway has led to vagus nerve stimulation (VNS) being investigated as an approach to modifying neuroplasticity (Farmer et al., 2020;Yap et al., 2020). Moreover, stimulation of the left cervical vagus nerve has received FDA approval for treating intractable epilepsy and depression (Farmer et al., 2020) and has been incorporated into rehabilitation programs for various neurological disorders, including ischemic stroke (Engineer et al., 2019;Hays, 2016). Like trigeminal and occipital nerve stimulation, the underlying mechanics of VNS are not yet fully comprehended; however, a proliferation of investigations into VNS have provided a greater understanding than trigeminal and occipital nerve stimulation. For example, Hulsey and colleagues (2017) assessed an extensive range of VNS parameters in rats to show that short bursts and low thresholds (starting at 0.1 mA) prompted phasic LC activity; greater intensities and pulse width increased the phasic activity while varying frequencies impacted timing but not the maximum activity of the LC (Hulsey et al., 2017). These findings demonstrate that VNS can activate the LC and modulate neural activity, suggesting that the LC could mediate the effect observed in VNS research (Hulsey et al., 2017). In a follow-up study, Hulsey and colleagues (2019) demonstrated that left-VNS paired with training resulted in over double the amount of motor cortex area dedicated to proximal forelimb movements detected when compared to the sham and the immunotoxin injected groups; this depletion of noradrenaline innervation to the motor cortex demonstrated the requirement of noradrenergic activity to be a mediator of VNS-directed plasticity (Hulsey et al., 2019).
Taken together, these studies have identified the LC noradrenergic system to be engaged by non-invasive stimulation of the greater occipital nerve and invasive stimulation of the vagus nerve, thus providing merit to its usage to enhance cortical plasticity and improve memory performance.

Activation of other neuromodulatory pathways
Considering how the vagus, trigeminal, and greater occipital nerve share a pathway leading to nuclei in the brainstem, particularly the NTS, we extracted parallels from preclinical studies employing VNS to highlight other ascending neuromodulatory systems, including the serotonergic, cholinergic, and dopaminergic systems (Brougher et al., 2021a;Hulsey et al., 2016;Hulsey et al., 2019), that have been suggestive of acting synergistically along with the noradrenergic system to contribute to plasticity to influence behaviors and cognition.
The researchers of the aforementioned preclinical studies carried out additional experiments to examine the significance of other neurotransmitters, such as acetylcholine, originating from the nucleus basalis, and serotonin, originating from the dorsal raphe nucleus, to the plasticity processes to identify whether neuromodulatory systems can substitute for other networks so that plasticity is not forfeited (Hulsey et al., 2016;Hulsey et al., 2019). Results obtained from intracortical microstimulation motor mapping again demonstrated that left-VNS during training resulted in more than double the percentage of proximal forelimb movements detected compared to the sham and

Box 3
The vagus, trigeminal and occipital nerve.
The trigeminal nerve (cranial nerve V) is a cranial nerve responsible for sensation in the face and motor functions such as biting and chewing; it is the most complex of the cranial nerves. Its name derives from each of the two nerves (one on each side of the pons) having three major branches: the ophthalmic nerve, the maxillary nerve, and the mandibular nerve. The ophthalmic and maxillary nerves are purely sensory, whereas the mandibular nerve supplies motor as well as functions. Adding to the complexity of this nerve is that autonomic nerve fibers as well as special sensory fibers (taste) are contained within it. The motor division of the trigeminal nerve derives from the basal plate of the embryonic pons, and the sensory division originates in the cranial neural crest. Sensory information from the face and body is processed by parallel pathways in the central nervous system. The greater occipital nerve is a nerve of the head. It is a spinal nerve, specifically the medial branch of the dorsal primary ramus of cervical spinal nerve 2. It arises from between the first and second cervical vertebrae, ascends, and then passes through the semispinalis muscle. It ascends further to supply the skin along the posterior part of the scalp to the vertex. It supplies sensation to the scalp at the top of the head, over the ear and over the parotid glands.

Box 2
Non-invasive stimulation of the greater occipital nerve.
The effects of NITESGON on the LC noradrenaline activity were measured via three common proxy measures: pupillometry, salivary α-amylase, and neurophysiology [event-related potentials (ERPs)]. This enabled us to track changes (significant increases) from baseline measurements; however, caution should be applied considering these proxy measures possess limitations such as being substantially variable and the potential of other brain regions and monoamine neurotransmitters associated with changes Joshi, 2021;Joshi and Gold, 2020). Nevertheless, significant intercorrelations were found amongst the three proxy measures, suggesting that NITESGON can induce changes in LC activity, thus promoting noradrenaline release.
The second set of experiments, including a direct and indirect route of occipital nerve stimulation, were designed to substantiate the transcutaneous mechanism that drives the memory-effect of NITESGON . A more invasive technique directly stimulated the greater occipital nerve in rats to improve memory performance during inhibitory avoidance and object recognition tasks. Additionally, a group of participants received a topical skin anesthetic (lidocaine/prilocaine) cream during initial learning with stimulation to block the activation of peripheral nerves (Kumar et al., 2015). Seven days later, participants with no anesthesia cream demonstrated enhanced memory recollection, indicating effects are driven by peripheral nerve stimulation. Together, these studies suggest that invasive and non-invasive occipital nerve stimulation directly affects memory . These memory improvements have since been replicated in younger and older adult populations and by utilizing transcranial alternating current stimulation (tACS) with salivary α-amylase concentration levels used to substantiate noradrenergic activation (Luckey et al., 2022;Luckey et al., 2020). These replications divert from proposed limitations associated with age and endorse that other neuromodulation devices are capable of activating transcutaneous pathways.
immunotoxin groups, demonstrating the requirement of serotonergic and cholinergic activity each to be facilitators of VNS-directed plasticity (Hulsey et al., 2016;Hulsey et al., 2019). Multiple neuromodulatory systems being necessary aligns with previous research that exhibited various neuromodulators could cooperatively govern plasticity and how the absence of any of these specific neuromodulators could not be replaced by other neuromodulatory networks also being activated by VNS.
In light of the evidence exhibiting cortical plasticity's dependency on multiple neuromodulators, a second group of researchers sought to determine if cortical dopamine, a neuromodulator originating from the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc), was required for VNS-induced plasticity in the motor cortex. Unexpectedly, the depletion of cortical dopamine did not affect cortical plasticity (Brougher et al., 2021b). However, recent findings of the right nodose ganglion projecting to the NTS and activating dopamine via the VTA and the left nodose ganglion having no such effect (Han et al., 2018) prompted the researchers to compare how stimulation to the right cervical vagus nerve and the traditional left cervical vagus nerve affected behavior and dopaminergic activity from the midbrain when employing matching VNS parameters (Brougher et al., 2021a). Results indicated that right-VNS enhanced activation of the midbrain dopaminergic system and resulted in a more significant number of forelimb movements compared to the left-VNS group (Brougher et al., 2021a). These findings suggest that the preclinical and clinical protocol of traditional left-VNS is unsuitable for driving dopaminergic activity or enhancing behavior. However, right-VNS may be exploited to preferentially promote plasticity via the midbrain dopaminergic systems (Brougher et al., 2021a).
Taken together, the evidence from these studies suggests that lesions in three neuromodulatory networks prevented VNS-movement pairing from generating cortical plasticity, specifically the dorsal raphe nucleus serotonergic and nucleus basalis cholinergic networks. Moreover, the additional findings evoke the potential of right-VNS being an effective intervention to promote dopamine-dependent plasticity. Collectively, the observed results insinuate that cortical serotonin, acetylcholine, and dopamine are each essential to plasticity and can be driven by peripheral nerve stimulation.

Critical implications for transcutaneous stimulation
Empirical findings within this opinion piece provide an initial understanding of various neuromodulators that can be activated via peripheral nerve stimulation. Taken together, these findings suggest a role for peripheral nerve stimulation in improving or restoring neuroplasticity. For instance, a recent investigation sought to determine if lesions in the nucleus basalis blocking VNS-induced plasticity would consequently affect the efficacy of VNS when paired with motor rehabilitation (Meyers et al., 2019), given that VNS has previously been used to improve recovery after injury Meyers et al., 2018). Results indicated that VNS during rehabilitation showed repaired motor map representations and improved volitional forelimb function compared to groups that rehabilitated without VNS or received delayed VNS. To address a more causal role, a second set of experiments blocked acetylcholine to further investigate VNS's effect on plasticity and recovery. Results demonstrated that VNS during rehabilitation reversed maladaptive plasticity and helped improve recovery, whereas blocking acetylcholine prevented recovery even when receiving VNS during rehabilitation, thus highlighting cortical acetylcholine's critical function in restoring brain circuits (Meyers et al., 2019).
As demonstrated by the preclinical studies, peripheral nerve stimulation activates these four main neuromodulators (Brougher et al., 2021a;Hulsey et al., 2016;Hulsey et al., 2019), and evidence suggests these neuromodulators are essential for neuroplasticity and, therefore, underlie the effectiveness of peripheral nerve stimulation (Meyers et al., 2019). Through interactions with other brain regions and within the neuromodulatory systems, neuromodulators are responsible for signalling risk and reward, uncertainty and novelty, and thus directly influence higher-order cognitive functions, including attention, decision-making, goal-directed behavior, and emotion (Avery and Krichmar, 2017). Accordingly, utilizing peripheral nerve stimulation as a therapeutic intervention to upregulate these neuromodulators or as an adjunctive treatment to enhance neuroplasticity may be a suitable approach, considering that a range of neurocognitive and psychiatric disorders are associated with downregulated neuromodulatory systems or plasticity deficits (Avery and Krichmar, 2017;Briand et al., 2007). For example, mood disorders and depression have been linked to impairments in the connections between the serotonergic pathway and the prefrontal cortex (Liu et al., 2019). Moreover, associations regarding malfunction in the cholinergic pathway and disorders of memory, attention deficit hyperactivity disorder, and schizophrenia have been acknowledged (Scarr et al., 2013), whereas abnormal noradrenergic and dopaminergic activity, respectively, have been associated with neurological and psychiatric disorders, most notably Alzheimer's and Parkinson's disease (Beardmore et al., 2021;Latif et al., 2021). Given that previous evidence has spotlighted these neuromodulators' significant role, utilizing peripheral nerve stimulation represents a potential therapeutic strategy.

Concluding remarks and future perspectives
Research to date has not yet determined the mechanism(s) of noninvasive neuromodulation methods. The significance of this issue has grown in light of recent evidence suggesting that standard electrode montages applied directly to the scalp result in peripheral nerves sustaining electric fields significantly greater in strength than those measured in the cortex (Asamoah et al., 2019). These findings have begun to shift researchers' position away from the prevailing transcranial mechanism toward favoring a transcutaneous approach. The advantage of these novel non-invasive methods of stimulation is that they are easy to apply at a relatively low cost that are easy to be used in a home setting.
This opinion piece aimed to provide greater insight into a bottom-up transcutaneous pathway shared by four neuromodulatory systems (Fig. 3). This proposed concept lays the groundwork for future investigations into peripheral nerve stimulation being an optimal strategy to modulate neuroplasticity in key brain regions that contribute to relevant cognitive processes or brain regions impacted by neurological disease and psychiatric disorders.
A recent perspective piece proposed that the effects of non-invasive brain stimulation may be attributable to the activation of a peripheral pathway that promotes LC noradrenergic activity, especially considering that a myriad of tDCS studies utilize anterior and posterior electrode montages, many of which engage with the trigeminal and the occipital nerve (van Boekholdt et al., 2021). Per this peripheral route, information is transmitted from the trigeminal and occipital nerve to a common hub, the brainstem. Within the brainstem, information is integrated, relayed, and projected from the NTS throughout widespread regions of the central nervous system. However, despite identifying this promising transcutaneous pathway, many factors of peripheral nerve stimulation remain unclear and require further investigation (see Outstanding Questions). Although limited research regarding stimulation of the trigeminal and greater occipital nerve exists, this pathway sharing a central hub with the vagus nerve suggests that stimulation of these nerves can have similar effects to VNS. Therefore, assimilating evidence from VNS literature has helped to detail other neuromodulatory systems, including the serotonergic, cholinergic, and dopaminergic systems, that may be activated when the trigeminal and greater occipital nerves are stimulated.
Although both trigeminal and greater occipital nerve stimulation share a common neural pathway, it does not exclude that both types of nerve stimulation also activate additional pathways that do not overlap.
It is also difficult to compare trigeminal and greater occipital nerve stimulation as well as the outcome of different labs. At this point there is no consistency in the application of different parameters for trigeminal and greater occipital nerve stimulation including for example amplitude (mA), current (direct versus alternating), specific site of stimulation.
Per this evidence, it is suggested that cortical noradrenaline, serotonin, acetylcholine, and dopamine are each imperative to plasticity (Brougher et al., 2021a;Hulsey et al., 2016;Hulsey et al., 2019). Furthermore, it can be speculated that these neuromodulators underlie the effectiveness of peripheral nerve stimulation (Meyers et al., 2019); however, whether, and if so, how, these multiple neurotransmitter systems work synergistically to modulate certain behaviors and cognition when activated by transcutaneous stimulation of either of these peripheral nerves needs further investigation.
Outstanding Questions.
• Seeing that variables such as charge density have shown to alter the effects of non-invasive brain stimulation, it is necessary to discern what the optimal stimulation parameters and variables of stimulating the vagus, trigeminal, and greater occipital nerve are for optimal efficacy, including length of stimulation, number of sessions, and more. Additionally, how do optimal stimulation parameters change based on the peripheral nerve and the neuromodulatory system being targeted? • Previous research has highlighted that the timing of stimulation may need to vary based upon the desired stimulation effect. Taking this into consideration, it is critical to determine when peripheral nerve stimulation should occur (i.e., online or offline) to produce its desired outcome. Also, does peripheral nerve stimulation need to be paired with a task to activate a specific pathway to see the desired effect? • Is there an interaction between multiple neuromodulators to optimize peripheral nerve stimulation? If so, how much interaction is required, and how would the multiple neuromodulators interactions be affected by various pharmacological blockades? Would this then affect the stimulation's efficacy? • Although modelling calculations support that minimal amounts of direct current reach the cortex, and when they do, the electrical field is inadequate to cause significant effects, it is still unknown how much, if any, direct current contributes to the effect of non-invasive stimulation. Do the minimal amounts of direct current stimulation that reach the cortex contribute to the effects of peripheral nerve stimulation? • Prior research has identified beneficial effects of alternative neuromodulatory techniques such as TMS and tACS. Considering these effects are similar to those seen from tDCS, could these effects be attributed to these techniques stimulating peripheral nerves? • What are the effects on behaviour and cognition? How specific are these effects?

Data Availability
No data was used for the research described in the article.

Fig. 3.
A transcutaneous pathway shared by four neuromodulatory systems. In this proposed transcutaneous mechanism, tES electrodes may be placed amongst cites that stimulate either the trigeminal or greater occipital nerve − likewise, stimulating the cervical vagus nerve via a handheld device applied to the neck or stimulating the auricular vagus nerve via electrodes within ear regions (for VNS recommendations see (Farmer et al., 2020)). Activation of these nerves will send ascending projections to the brainstem, particularly the NTS. From here, there is potential to activate four core neuromodulatory systems, including the far-reaching LC noradrenergic, nucleus basalis cholinergic, raphe nucleus serotonergic, and the SNc and VTA dopaminergic neurotransmitter networks.