Neuromodulation: What the neurointerventionalist needs to know

Abstract

Neuromodulation is the alteration of neural activity in the central, peripheral, or autonomic nervous systems. Consequently, this term lends itself to a variety of organ systems including but not limited to the cardiac, nervous, and even gastrointestinal systems. In this review, we provide a primer on neuromodulation, examining the various technological systems employed and neurological disorders targeted with this technology. Ultimately, we undergo a historical analysis of the field's development, pivotal discoveries and inventions gearing this review to neuro-adjacent subspecialties with a specific focus on neurointerventionalists.

Introduction

Neuromodulation is the alteration of neural activity in the central, peripheral, or autonomic nervous systems. ¹ Consequently, this term lends itself to various organ systems, including but not limited to the cardiac, nervous, and even gastrointestinal systems. Given its only expanding number of applications, the question arises: Who should care about neuromodulation and why? In this review, we provide a primer on neuromodulation for the neurointerventionalist, and, importantly, we examine why they have a stake in this ever-expanding field's future.

History of neuromodulation

There is value in a field's history. The earliest use of neuromodulation dates to the first century, circa 15 AD, when a freedman of Emperor Tiberius stepped on a torpedo fish. The ensuing shock taught him a valuable lesson, but an even greater one to his local physician, Scribonius Largus. He noted improvement in the man's chronic gout pain following the shock. Scribonius would then go on to adopt torpedo fish for the treatment of pain. ²

Several centuries later, foundational studies would then follow to establish the underlying electrical nature of neural transmission. In the 1800s, Giovanni Aldini applied galvanic current to human corpses to demonstrate muscular contraction, and successive application of current to the canine motor cortex by Fritsch and Hitzig elucidated the excitability of the cerebral cortex.^3–5 Fritsch and Hitzig are credited with the first widely accepted experimental evidence of what would later be termed the motor cortex. Such findings culminated in David Ferrier mapping motor cortex across species in his seminal book The Functions of the Brain in 1876. ⁶ This ultimately paved the way for Roberts Batholow to conduct direct cortical stimulation in the first human subject, Mary Rafferty. ⁷ However, the ultimate transition to intraoperative use of neuromodulation was championed by Sir Victor Horsley in 1884, at first diagnostically, then later to define epileptogenic foci for focal lesion resection in patients with focal epilepsy. ⁸

The conception of stereotaxy would form the lynchpin in what amounts to the modern era of functional neurosurgery. Along with contributions from several other leaders in the field, such as Fedor Krause, Charles Sherrington, and Wilder Penfield, Horsley's work formed the early basis for chronic stimulation studies and, ultimately, neuromodulation.^9–11 However, it was not until the publication of the stereotactic frame by Spiegel et al. in 1947 that stereotactic lesions could then be used to induce changes in electroencephalographic recordings during stimulation of human subcortical structures.^12,13 Uncannily, even at this early stage, Spiegel described stereotaxis for psychosurgery, pain, movement disorders, and other procedures. ¹⁴ Thus, with increasing traction for stereotactic surgery of subcortical structures and the coining of the “epileptogenic zone,” the modern era of functional neurosurgery was born. ¹⁵

Modern applications of neuromodulation are increasingly broad, but for this review, those that pertain to the central and peripheral nervous systems can be divided into three major categories: pain, movement disorders, and epilepsy. While all three uses emerged from fundamental studies already described, neuromodulation could only take a foothold as standard once it could be applied for extended periods. To this end, the first uses of long-term neuromodulation can be credited to J. Lawrence Pool, who was the first to implant a system in a human to stimulate the femoral nerve for a paraplegic patient experiencing spasms and an advanced Parkinson's patient suffering from depression from 1945 to 1948.^16,17 This was soon followed by Robert Heath stimulating other patients with psychiatric diseases such as schizophrenia. ¹⁸ From here, the evolution and current scope of each application diverge.

Systems for neuromodulation

Open-loop systems

Despite the large variety of techniques and neural substrates for modulation, delivery of neuromodulation can be synthesized into two major frameworks: open-loop and closed-loop systems. Open-loop systems involve preprogrammed stimulation paradigms that operate independently of the brain state. ¹⁹ Vagal nerve stimulation exemplifies the first use of open-loop stimulation for epilepsy. In open-loop stimulation, a current is continuously delivered without prior detection of epileptogenesis from the target tissue. While the efficacy of continuous stimulation was demonstrable, it had its drawbacks. Side effects such as hoarseness, coughing, nervous injury, and, importantly, limited battery life ushered the staged implementation of increasing degrees of responsive stimulation. That is, stimulation is delivered in response to ictogenesis rather than independently. ²⁰ Magnet activation arose from this need for intermittent stimulation and was successfully met. In 2001, Boon et al. demonstrated a reduction in seizure frequency of more than 50%, with 29% of patients no longer experiencing convulsive seizures. ²¹ However, even in the case of magnet activation, only a minority of patients could ever activate the system themselves—caregiver intervention was critical. Closed-loop systems address this issue.

Closed-loop systems

By providing temporal and spatial specificity over conventional open-loop paradigms, closed-loop systems obviate the need for third-party intervention. Such systems abate seizures by detecting epileptic states and inhibit seizures through stimulation. Based on a multicenter, double-blind, randomized controlled trial assessing the efficacy of responsive cortical stimulation for partial onset seizures in adults with drug-refractory epilepsy, responsive neurostimulation (RNS) gained U.S Food and Drug Administration (FDA) approval in 2013. ²² Recent studies continue to corroborate RNS efficacy for seizure prophylaxis demonstrating the tolerability and long-term benefit of RNS treatment. Specifically, Heck et al., demonstrated 53% reduction in seizures after 2 years with no adverse events inconsistent with well-documented risks of implanted medical devices, seizures, or other epilepsy treatments. ²³ Despite these results, compared to open-loop systems, there has not been a significant improvement in responder rates from those with a >50% reduction in seizures using these methods. ²⁴ This raises the question of how one can improve upon such systems. While other domains of epilepsy therapy can progress through empirical treatment, neuromodulation has only featured the application of neuromodulation to brain regions without fully incorporating network dynamics of the epileptogenic zone. Models which can better encapsulate network dynamics may improve upon seizure detection. Furthermore, it is the case that platforms on which to test neuromodulation remain to be established for more rational development of neuromodulation.

Neuromodulation in chronic pain

Spinal cord stimulation for chronic pain

In 1965, Melzack and Wall theorized that pain perception is gated based on the balance of firing from small and large neural fibers. Although the specific neuroanatomy details of this theory were shown to be incorrect, it still catapulted neuromodulation to the forefront of treatment for chronic pain by which stimulation of putative large neural fibers could induce focal analgesia and anesthesia. This was first demonstrated by Wall and Sweet in eight patients with cutaneous pain, then subsequently by Shealy et al., who implanted a radiofrequency-induced stimulator to relieve diffuse pain in a patient with inoperable bronchogenic carcinoma.^25,26 Shealy would then go on to iterate on versions of such stimulators for chronic pain patients in collaboration with Medtronic. ²

In the modern era, spinal cord stimulation (SCS) for pain is achieved through electrodes placed over spinal cords the dorsal columns, effecting a sensation of pleasant paresthesia in place of pain. SCS for pain management consists of two phases: trial and permanent phases. During the trial phase, the trial stimulator is implanted in the epidural space under fluoroscopic guidance and varied over hours to elicit analgesia in patients. Following a successful trial phase, permanent implantation is carried out with leads and battery implanted in a pocket in the patient, occasionally through laminectomy and suturing of leads to the dura. ²⁷ However, anatomic nuances are frequently taken into consideration. Notably, the level of implantation (cervical vs. thoracic vs. lumbar) for pain coverage and surgical history, which can impede lead placement in the case of prior surgery or any medical issue which predisposes to a smaller epidural space precluding placement of a stimulator such as spinal stenosis or ligamentum hypertrophy, are significant constraints.

Today, the major indications for SCS include neuropathic pain from failed back surgery syndrome, complex regional pain syndrome in the United States and coronary and peripheral ischemia of extremities in other countries.^28–32 This narrow range of indications can be attributed, in part, to the relatively inconsistent body of evidence on neuromodulation for chronic pain. In a systematic review by Taylor et al., the level of evidence for spinal cord stimulation in chronic back and leg pain/failed back surgery syndrome was found to be low to moderate. On the one hand, this could be related to the vast heterogeneity among treatment paradigms (stimulation parameters, transplant locations). Conversely, it could be due to the strong placebo effects that patients undergoing neuromodulation frequently experience.^33–36 Ultimately, following the availability of paresthesia/sensation-free spinal cord stimulation, most recent studies comparing traditional SCS to sham stimulation have only demonstrated mixed results. This has also been corroborated in a Cochrane review by O’Connell et al., where SCS yields low to very low-certainty evidence of clinically important benefits to pain intensity when added to conventional pain medical management or physical therapy. ³⁷ We forgo a discussion on the various stimulation frequencies available and evidence supporting them in this review but invite interested readership to examine a systematic review by Head et al., where they go into further detail on this topic.

Deep brain stimulation for chronic pain

If the Sixties saw the conception and implementation of spinal cord stimulation, the Seventies brought forth the revolution, deep brain stimulation (DBS). Surprisingly, DBS, as we know it today, was not first conceived as a treatment for movement disorders but rather as a solution to facial anesthesia dolorosa. In 1973, a few teams, including notably Mazars et al. in France and Hosobuchi et al. in the USA, theorized and then demonstrated that stimulation of the posterior ventralis medialis nucleus of the thalamus could confer pain relief for facial anesthesia dolorosa.^38,39 Hosobuchi noted successful analgesia in four of their five patients, submitting that they abated pain via the suppression of neuronal hyperactivity at the thalamic level. ³⁸ Further work throughout the 1970s documented the association of periventricular gray stimulation with endorphin release, lending further credibility to the use of this technique.^40–42 By 1975, Medtronic had established a neurological division and trademarked the term “DBS.” ⁴³

Based on the promising history of DBS for chronic pain, one would forecast its robust utilization in today's state of the art, but this has been far from the case. By the tail end of the 1970s, the FDA had entered the regulatory fray and required studies to demonstrate the benefit of DBS for motor disorders and pain management. ² Unfortunately, a single company demonstrated limited efficacy to the FDA. At the same time, the other two did not comply at all. As a result, DBS for chronic pain was not approval. A randomized controlled trial by Marchland et al. showed that thalamic stimulation produces a small but significant reduction in pain perception but that a significant placebo effect also exists. ⁴⁴ In two subsequent open-label studies by Medtronic, DBS failed to produce effective long-term pain relief. ⁴⁵ Therefore, the FDA could only assign DBS for chronic pain an “off-label” status, which remains off-label to this day. Despite this, several studies do demonstrate the efficacy of sensory thalamus stimulation.^44,46 Today, few neurosurgeons continue to offer DBS for pain; however, randomized controlled trials on DBS for chronic pain are forthcoming. Notwithstanding, DBS has been approved for chronic pain refractory to medical management in Europe and the United Kingdom. ⁴⁷

Targets for chronic pain are not limited to the thalamus. The motor cortex has also been shown to relieve pain in patients with intractable chronic pain. In 1991, Tsubokawa et al. demonstrated inhibition of burst hyperactivity of thalamic neurons by stimulating the motor cortex in seven cases of thalamic pain syndrome. ⁴⁸ Since this seminal work, several reports have confirmed the efficacy of motor cortex stimulation for various deafferentation pain syndromes.^49–52 Similarly, other areas have been targeted for stimulation, such as the pontomesencephalic parabrachial, Kölliker-Fuse nucleus, and the nucleus accumbens regions of the brain.^53–55

Neuromodulation in movement disorders

In 2022, the most emblematic use of neuromodulation is in treating movement disorders such as Parkinson's disease (PD) and essential tremor. However, as mentioned in the previous section, this did not occur until DBS had already been applied to chronic pain, and stereotactic surgery had already become cemented into the neurosurgical armamentarium. The earliest conception of DBS for movement disorders can likely be traced back to Spiegel and Wycis's reporting on stereotactic surgery to treat Huntington's, choreoathetosis, and PD.^12,14,56,57 At this early stage, electrical stimulation was used principally to ensure that an electrode was not in an eloquent structure and to assess clinical symptoms later. It soon developed to the point in which Alberts et al. noted that stimulation of the ventrolateral thalamus or internal segment of the globus pallidus could modulate tremors. ⁵⁸ This was only used for target localization for subsequent lesioning, as demonstrated by Sem-Jacobsen. ⁵⁹

Perhaps the earliest application of neuromodulation (in the form of chronic electrical stimulation) to movement disorders (for that sole purpose) occurred in Russia with Bekhtevera et al.^60–63 In 1963, she reported the use of multiple electrodes implanted in subcortical structures to treat hyperkinetic disorders. Unfortunately, much of her work was written in Russian and poorly disseminated. ⁶² Regardless, by the late 1970s, several groups had taken to trialing neuromodulation for various movement disorders. In 1976, Dooley et al. documented an improvement in spasticity in multiple sclerosis patients receiving SCS for pain. They had placed electrodes in the spinal epidural space of 48 patients with various disorders, including mostly multiple sclerosis, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, and Friedreich's ataxia.^64,65 Interestingly, they also observed that almost all their patients who received electrostimulation of the spinal cord reported their lower extremities feeling warmer during stimulation, providing further evidence and basis for neuromodulation to treat peripheral vascular disease.^64–66 Indeed, in 1986, SCS became utilized for peripheral vascular disease in Europe and much later in the USA, as discussed in a subsequent section of this review. ⁶⁷

Following such promising work, implementing an implantable SCS device geared toward motor disorders took only a short time. At first, this came as cerebellar stimulation for spastic cerebral palsy by Davis et al.^68–70 Of note, further work by Davis and others would then go on to develop DBS for epilepsy, which we discuss in the next section. Similarly, by 1978, the American neurosurgeon Irving S. Cooper reported in a review of clinical results from 200 patients and neurophysiological results from 42 patients that chronic cerebellar stimulation could improve cerebral palsy and reduce intractable seizures. ⁷¹

By 1987, much of the groundwork for DBS had been laid. The first use of DBS for movement disorders in patients without pain occurred in 1980 with Brice and McLellan. They stimulated the contralateral midbrain and basal ganglia and suppressed severe intention tremor in three women with multiple sclerosis. ⁷² Subsequently, Siegfried et al. observed improvement in dyskinesia in a patient with a stimulator for Dejerine-Roussy syndrome. ⁷³ Finally, using ventralis intermediate nucleus (VIM) thalamotomy as the basis for their work, Benabid et al. were able to report on unilateral VIM thalamotomy and contralateral continuous, high-frequency VIM stimulation in patients with PD.^74–76 They demonstrated a complete abatement of tremors due to thalamotomy and strong relief without full suppression from stimulation. DBS was later shown to be safer than thalamotomy, leading to the gradual departure from lesional techniques. Soon, Laitinen et al. demonstrated successful treatment of bradykinesia and dyskinesia in PD by ventral posterior pallidotomy.^77,78 Shortly thereafter, the subthalamic nucleus (STN) was found to be a new target capable of improving bradykinesia, tremor, and rigidity. ⁷⁹ Today, the VIM stimulation for essential tremor is the only FDA-approved target in the USA, but there is a growing body of evidence to support other targets.

VIM, STN, and GPi

The body of literature supporting this DBS for movement disorders is only growing. In a double-blind crossover study of patients with high-frequency stimulation of the subthalamic nucleus (STN) or globus pallidus Interna (GPi), a significant improvement in motor function was demonstrated in patients whose condition cannot be further improved with medical therapy. ⁸⁰ Similarly, in a randomized-pairs trial, 156 patients with advanced PD receiving neurostimulation of the subthalamic nucleus was shown to be was shown to be more effective than medical management alone. ⁸¹ Interestingly, no significant differences have been found in improvement between these two targets, although STN stimulation has been associated with increased incidence of depression and cognitive impairment and faster medication reduction following surgery. ⁸²

The zona incerta/prelemniscal radiation

While the STN is a frequent target, several groups have identified the region of pallidofugal fibers and zona incerta nucleus (cZI) as an optimal target.^83,84 Plaha et al. demonstrated greater improvement in tremor during stimulation of the cZI compared to stimulation of the STN. Similarly, Blomstedt and Kitagawa et al. report safe and effective stimulation of the cZI for patients with severe Parkinsonian tremor, with reliable therapeutic benefits being demonstrated in the long term.^85,86 Further work is needed to qualify the extent and mechanism of benefit conferred through this target.

Ultimately, DBS has become a popular technique for treating movement disorders, but has drawbacks. The cost of implantation is high, and it is certainly vulnerable to hardware-related complications such as disconnection and migration or surgical-related complications, such as infection and intracranial hemorrhage.^87–90

Neuromodulation in epilepsy

Vagal nerve stimulation

The earliest FDA approval for neuromodulation began with external nerve stimulation due to easier access and evaluation. The first commercial VNS device arose from a canine model of epilepsy induced by strychnine and PTZ. By the late nineties, it had been established that inhibition of motor activity was possible through the activation of visceral vagal afferents. This pathway was harnessed to abolish seizures arising from strychnine and pentylenetetrazol induction. Uniquely, it was consistently noted that chronic vagal stimulation elicited inhibitory effects that persisted after stimulation. ⁹¹ Our understanding of VNS modulation of the central nervous system (CNS) is forthcoming. However, it is surmised to arise from vagal afferent projections that integrate within the nucleus tractus solitarius before being relayed to other regions of the CNS. ⁹² Such convincing data was then corroborated in other animal models of epilepsy, ushering in the implementation of an implantable, multiprogrammable pulse generator to serve as a vagus nerve stimulator in human patients.^93–95 VNS for epilepsy ultimately gained FDA approval in 1997.^92,96

Trigeminal nerve stimulation

As the locus ceruleus and nucleus solitarius also project to the trigeminal nucleus, trigeminal nerve stimulation (TNS) may also recruit similar inhibitory pathways to vagal nerve stimulation. TNS is theorized to activate the midbrain reticular formation, resulting in cortical and thalamic desynchronization and concomitant reduction in seizure activity.^97–99 In 2000, Fanselow et al. demonstrated the anticonvulsive capabilities of TNS in a PTZ rat model of epilepsy. TNS was delivered externally at a low cost, offering another noninvasive neurostimulation method with the added advantage of bypassing visceral fibers implicated in vagus nerve innervation. In their studies, Fanselow et al. showed a 78% reduction in seizure activity in rats through unilateral TN stimulation and even more efficacy during bilateral stimulation.^97,100,101 Furthermore, they demonstrated an early iteration of responsive stimulation, in which stimulation was only applied during seizure activity, unlike in VNS. ⁹⁷ Similar to VNS and TNS, DBS arose from the neuromodulation of epilepsy networks in animal models of epilepsy.

The CNS involves the most extensive range of neural substrates for stimulation. Neuromodulation is a promising avenue for chronic therapy for patients unamenable to surgical resection. While vagus nerve stimulation has been well-established, increasing research suggests that intervening in neocortical and deep brain structures is both feasible and sustainable in the long term. While cortical stimulation had been observed to perturb seizure activity, the first use of chronic stimulation arose from psychosurgery for suicidal ideation in the depressed elderly and chronic intractable pain. ¹⁶ Subsequently, the first reported arrest of focal seizures from stimulation of the cerebellar cortex followed. ¹⁰²

The cerebellum

While the regulatory influence of the cerebellum on motor centers was clear, the mechanism by which it influenced distal seizure-like activity through cerebellar projections required robust investigation. The 1950s saw sequential clarifications on this relationship by establishing the influence of cerebral activity on the electrocerebellogram and vice versa. Moreover, shedding light on cortico-olivo-cerebellar and cortico-fugal pathways through animal models, such as the strychnine model of epilepsy in cats, enabled better investigation of cerebellar modulation of seizure discharges.^102–105 Following these studies, Cooper et al. were the first to apply chronic stimulation to the cerebellum to treat epilepsy. They showed that 10 of 15 patients subjected to chronic stimulation could abate their previously drug-resistant epilepsy for up to 3 years. They corroborated these findings in a longer-term study of 32 patients.^106,107 This paved the way for more robust clinical trials of chronic cerebellar stimulation of the cerebellum over longer periods, ultimately suggesting the viability of cerebellar neuromodulation for both focal and generalized epilepsy.^108–111

The anterior nucleus of the thalamus

Cooper's contributions also extended to the use of DBS in the anterior nucleus of the thalamus.^112,113 Complemented by the successful use of DBS for movement disorders and chronic pain, the Stimulation of the Anterior Nuclei of the Thalamus for Epilepsy (SANTE) trial became the first and only complete large, randomized controlled trial regarding DBS for thalamic nuclei in epilepsy. However, even within this domain, animal models of epilepsy have consistently played a pivotal role in developing DBS. By this point in time, the involvement of the anterior nucleus of the thalamus (ANT) in the propagation of seizures had been established, and bilateral lesions to ANT tracts had been shown to render immunity to PTZ-induced seizure activity. ¹¹⁴ Furthermore, these models allowed us to refine our mechanistic understanding of the role of stimulation parameters. For example, it became clear that high-frequency stimulation increased the seizure threshold in PTZ rat models of epilepsy, while low-frequency DBS proved proconvulsant. Similarly, bilateral ANT-DBS was shown to prolong seizure latency in a pilocarpine model.^115,116 However, chronic stimulation worsened seizure frequency in a kainate-treated rat model. ¹¹⁷ Thereby setting aside the controversy surrounding its efficacy and devoting further attention to the mechanistic interaction between neuromodulation and seizure propagation. ANT-DBS was then hypothesized to activate inhibitory corticothalamic projections. ¹¹⁵

The SANTE trial was the first and only completed randomized controlled clinical trial for DBS in epilepsy. It was a multicenter, randomized, double-blind, parallel group study of 110 patients with localization-related epilepsy. The stimulation group showed a relatively greater estimated reduction of seizure frequency than the nonstimulated group, with a difference of 29%. Long-term follow up at 5 years showed an increase in mean seizure reduction to 69%. ¹¹⁸ Further reports on its efficacy and safety arose in the years following the publication of the trial, ranging from the added benefit of an insertional effect to even cognitive improvement after long-term electrical stimulation.^119–121

Centromedian nucleus of the thalamus

Similarly, the centromedian nucleus of the thalamus (CMT) has also been explored as a target for DBS in epilepsy. As part of the ascending subcortical system with projections to the cortex, it plays a role in alertness and cortical excitability. Initial studies in PTZ rat models established that midline and intralaminar thamalic stimulation could incite electrographic desynchronization and concomitant seizure suppression. ¹²²

Velasco et al. were the first to explore CM-DBS in human patients. In a preliminary report, they recruited five patients. They established clinically significant reductions in seizures by electrical stimulation and improved psychological performance beyond that expected from seizure reduction. ¹²³ However, in contrast to the experience with ANT-DBS, consistent efficacy was not seen in further studies. Several factors could explain these contradictory results, ranging from different seizure types to the appropriate confirmation of synchronous discharges. Ultimately, the best candidates for CM-DBS were found to be patients with Lennox-Gastaut syndrome.^124–126 However, even for these patients—two meeting criteria for Lennox-Gastaut syndrome, Fisher et al. observed no statistically significant effect of CM stimulation. ¹²⁷

Subthalamic nucleus

The subthalamic nucleus is well-known as a target for DBS in PD. ¹²⁸ However, animal studies, including the kinding, flurothyl seizure, and maximal electroshock test, implicate the role of the substantia nigra in inhibiting the propagation of generalized convulsions. This suggests that these seizures may be intervenable through the subthalamic nucleus through the involvement of subthalamo-nigral projection in the modulation and propagation of seizures.^129–131 Charbardès et al. were the first to demonstrate a mean seizure frequency reduction of 64.2%. Following these findings, other smaller studies corroborated evidence of STN-DBS benefit for partial seizures.^{130,132–136}

Mesio-temporal lobe

One of the most common forms of medically intractable epilepsy is mesial temporal lobe epilepsy. The ability of resective surgery to render patients seizure-free in mesial temporal lobe epilepsy (MTLE) is around 60%; although significant, this still renders a sizable amount of patients’ refractory to surgical intervention. Several in vitro studies, including high-potassium hippocampal slice models, low-calcium slice models, high-potassium, and penicillin-treated slices support hippocampal stimulation as a feasible neuromodulatory intervention on MTLE. Specifically, they corroborate the suppression of spontaneous epileptiform discharges through electrical stimulation.^137–147 While hippocampal stimulation appears to be an exciting avenue for therapy, at the moment, there is no robust evidence for its use. All randomized controlled trials to date have yielded nonsignificant results, been underpowered, or been halted prematurely due to low recruitment.

Neuromodulation in vascular disorders

The age-old aphorism “history does not repeat itself, but it often rhymes,” often credited to Mark Twain, is a constant reminder not to repeat past errors. However, history and errors are the currency of science. For the past century, neuromodulation has followed a repetitive developmental pattern: a putative pathophysiology is identified, and a target to intervene on is sought. The technological means of intervening on such targets continue to be the lynchpin of functional neurosurgery. Whether this is a craniotomy or some other form of surgical implantation, there is always an expected risk of hemorrhage, infection, and pain.^87–90 Endovascular intervention is a natural solution to this major drawback. The neurointerventionalist should have a major stake in neuromodulation. Frankly, the idea that neuromodulation has not already entered the neurovascular arena is a misconception.

Recall work from Dooley et al. (see Neuromodulation for Chronic Pain), where they document an improvement in spasticity in multiple sclerosis patients receiving SCS for pain but also note a sensation of warmth in their distal extremities upon turning their stimulators on. ⁶⁵ Even at this early stage, they could already parse the autonomic effects of spinal cord stimulation on peripheral blood flow, lending credibility to its use for peripheral vascular disease. Although the mechanism by which this occurs is unclear, it is unlikely to occur through a peripheral pathway. In work by Patel et al., the resection of the superior cervical ganglion bore no effect on SCS-induced cerebral blood flow (CBF) augmentation, suggesting the role of a central pathway—a reversible functional sympathectomy after a fashion. ¹⁴⁸ At this point, cervical spinal cord stimulation has been shown to reduce mortality in stroke, ischemic spastic hemiparesis, and extremity ischemia.^148–154

In unilateral stroke, neuromodulation has been shown to enhance spontaneous recovery through ipsilesional corticomotor excitability and angiogenesis.^155–157 Granted that this involved noninvasive repetitive transcranial magnetic stimulation (rTMS) and is outside the scope of this review, this still suggests the possibility for more invasive and profound effects on rehabilitation, whether through DBS or SCS. This functional recovery has been demonstrated in DBS for post-stroke pain and chronic deep cerebellar stimulation in rodent models of cortical infarcts.^{156,158–160} Moreover, a recent randomized controlled trial of VNS for upper-limb rehabilitation after ischemic stroke demonstrated a significant improvement in Fugl-Meyer Assessment-Upper Extremity scores with VNS compared to rehabilitation alone. ¹⁶¹

Importantly, we have reached a new frontier in not just the application of neuromodulation but also the delivery of neuromodulatory devices. Interestingly, since the earliest neurostimulation conceptions the concept of recording neural activity from within vasculature has been proposed. Penn et al. recorded electroencephalography intravascularly in baboons and a human patient with an arteriovenous malformation in 1973. ¹⁶² Zeitlhofer, Nakase, Stoeter, and others have further described recording neural activity from electrodes placed in larger vessels such as the middle cerebral, callosomarginal, and basilar arteries.^163–165 Frankly, by 2014, the groundwork for an endovascular electrode had been laid in abundance, and the feasibility of this approach had been mapped out in theory. ¹⁶⁶ In 2016, Oxley et al. reported the feasibility of chronically recording and stimulating brain activity from a permanently implanted stent-electrode recording array in the superior sagittal sinus. ¹⁶⁷ They dubbed it the Stentrode.

In August 2020, Synchron received break-through device designation from the FDA for Stentrode. In addition to their SWITCH trial, already underway in Melbourne, Australia, this will be the first human early feasibility study of the Stentrode^TM. The stentrode is instantly reminiscent of the first implantable spinal cord stimulator, and it appears that we are again at the cusp of a new paradigm in neuromodulation. However, practical questions now arise: Are there spinal etiologies amenable to Stentrodes? Can we intervene in peripheral vascular disease with the bi-pronged approach of concurrent angioplasty and neuromodulation? While much can be gleaned from our well-documented venous sinus stenting experience, we have yet to examine the prevalence of associated venous thrombosis, device-related infection, and lead failure. Regardless, the fact remains that this is a promising conduit for neuromodulation, and the superior sagittal sinus will not be the only vessel explored for this purpose.

Importantly, this begs the question of where else this can be applied. For any subcortical structure requiring modulation, there are likely associated vessels from which we may target them. Teplitzky et al. support this notion by outlining 17 potential DBS targets using neurovascular modeling. ¹⁶⁰ Perhaps a future in which the anterior nucleus of the thalamus is targeted from the internal cerebral vein or the nucleus accumbens from the A­₁­ segment of the ACA is not so far-fetched. Even now, pigs have demonstrated feasibility for vagus nerve stimulation through the internal jugular vein. ¹⁶⁸

Conclusion

Neuromodulation has followed a stereotyped development pattern: After a target from which seizures, tremors, or pain arise is identified, the application of stimulation to an animal model is studied and then extended to human subjects. Historically, this has been a sound method for translating therapy to patients. Rational development of neuromodulation will continue to rely on models that can recapitulate the vast mechanisms surrounding epileptogenesis, tremor, neuropsychiatry, and network dynamics that it seeks to abate. While history serves as a strong reference for how we have advanced within the field, it should also recruit continued effort into modeling this devastating disease—thereby improving neuromodulation as a therapy.