Non-invasive neurostimulation encompasses methodologies that apply stimulatory modalities to the nervous system without breaching the integument. These modalities, including electrical, magnetic or alternative forms of stimuli, facilitate the modulation of neural tissue excitability and the overarching neural networks implicated (Boes et al, 2018). Despite the demonstrated efficacy and safety of non-invasive neurostimulation for certain neurological pathologies in the human population (Terranova et al, 2019), a notable challenge persists as a result of the considerable interindividual variability in response to these interventions. This variability may be attributed to factors such as the absence of uniform stimulation protocols across research endeavours, inherent biological diversity and the specific neurophysiological state of the targeted neural regions (Terranova et al, 2019).
The execution of research in the domain of non-invasive neurostimulation is characterised by its time-intensive nature and the necessity for meticulous planning. Nevertheless, these investigations are imperative for the development of more effective therapeutic protocols, the determination of optimal stimulation parameters and the augmentation of neurostimulation outcomes for the amelioration of diverse neurological conditions. Among the array of non-invasive neurostimulation techniques explored (Terranova et al, 2019) – such as transcutaneous vagal nerve stimulation, transcutaneous electrical nerve stimulation across various nerves, single or repetitive transcranial magnetic stimulation and transcranial direct current stimulation – repetitive transcranial magnetic stimulation has emerged as the pre-eminent modality within both human and, to a lesser extent, veterinary medical research, attracting significant scientific scrutiny for its application across a spectrum of neurological disorders.
Transcranial magnetic stimulation
Mechanism of action
Transcranial magnetic stimulation represents a non-invasive neuromodulatory technique predicated on the electromagnetic induction principle to generate an electric field within the cerebral milieu. This method involves positioning a magnetic coil adjacent to the scalp, using the coil's ability to project a magnetic field through both soft and osseous cranial tissues. This field acts as a conduit for transmitting the coil's electrical current into the brain, culminating in the induction of a brief, intense current pulse within neural tissue. Such currents are capable of activating cortical neurons to depths ranging from approximately 1.5–3.0 cm, although the extent of penetration is influenced by variables including the intensity of the coil's stimulus, coil design and the intervening soft and osseous tissue thickness (Bestmann et al, 2004).
The application of transcranial magnetic stimulation can be stratified into several modalities: single-pulse transcranial magnetic stimulation, which is used to evaluate cortical excitability; pairedpulse transcranial magnetic stimulation, used in the examination of cortico-cortical connectivity and the dynamics of intracortical inhibitory and excitatory mechanisms; and repetitive transcranial magnetic stimulation, which is used for therapeutic interventions because of its capacity to induce persistent changes in cerebral activity beyond the stimulation timeframe. The neuromodulatory outcomes of repetitive transcranial magnetic stimulation can manifest as either excitatory or inhibitory, contingent upon the stimulation frequency deployed (Wagner et al, 2004; Hallett, 2007).
Furthermore, repetitive transcranial magnetic stimulation is capable of modulating neuronal excitability, metabolic processes and cerebral blood flow not solely within the directly targeted cortical region, but also within distal areas that are anatomically and functionally interconnected with the stimulation locus (Bestmann et al, 2004; Hoogendam et al, 2010; Nasios et al, 2018). In the context of epilepsy management, repetitive transcranial magnetic stimulation is strategically used to modulate activity within either focal epileptogenic zones or more widespread epileptogenic networks (Badawy et al, 2012). In canine models, the precise delineation of epileptogenic zones remains underdeveloped, leading to a predominant focus on modulating broader network activities through repetitive transcranial magnetic stimulation. The primary influence of transcranial magnetic stimulation is observed in cortical regions, attributed to the rapid attenuation of the magnetic field's efficacy with increasing distance from the coil, a phenomenon not observed in invasive neurostimulation approaches such as deep brain stimulation in human or canine medicine, which can directly target subcortical structures.
Consequently, subcortical epileptogenic networks, including those within basal ganglia or thalamic regions, are less amenable to direct repetitive transcranial magnetic stimulation interventions unless the coil's output is sufficiently robust or the intervening cranial tissues are minimally obstructive, thus permitting deeper magnetic field penetration (Wagner al, 2004). In certain cases, involving small- to medium-sized dogs, the use of larger coils designed for human application may facilitate simultaneous cortical and subcortical region stimulation. Despite the potential, there is a paucity of advanced neuroimaging research to precisely map the effects of repetitive transcranial magnetic stimulation across different canine breeds within veterinary medicine.
It is noteworthy that repetitive transcranial magnetic stimulation has been demonstrated to influence subcortical regions indirectly through mechanisms such as trans-synaptic signalling and the induction of long-term neuroplasticity (Bestmann et al, 2004; Hoogendam et al, 2010; Nasios et al, 2018). The enduring effects of repetitive transcranial magnetic stimulation are largely attributed to its capacity to modulate synaptic functionality, particularly by adjusting the equilibrium between long-term potentiation and long-term depression within neuronal circuits. Such alterations can profoundly impact various neural networks, influencing a spectrum of pathological and physiological processes, including but not limited to cognitive functions like memory formation, learning and behavioural regulation (Nasios et al, 2018).
The optimisation of stimulation parameters is critical in the administration of repetitive transcranial magnetic stimulation because of its significant impact on neuronal network modulation. These parameters encompass stimulation frequency, coil intensity, the total number of stimulation trains and individual pulses within each train, intervals between trains and the overall duration of the stimulation session. Among these, coil intensity and stimulation frequency are paramount, directly influencing the therapeutic outcome. A lower frequency of repetitive transcranial magnetic stimulation (≤1 Hz) results in a reduction of corticospinal tract excitability, whereas frequencies above 1 Hz enhance it (Sun et al, 2012). The selection of stimulation frequency is contingent upon the neurological condition being addressed; for example, lower frequencies are preferred in the treatment of epilepsy because of their depressant effects on neural excitability. Moreover, evidence suggests that higher coil intensities, ranging between 70% and 90% of the maximum device output, are associated with superior therapeutic outcomes, including a notable reduction in seizure occurrences in epileptic patients (Charalambous et al, 2020; Sun et al, 2012). This is attributed to the hypothesis that increased coil intensity allows for a more profound stimulation of a larger volume of brain tissue.
Before the establishment of specific stimulation parameters, such as coil output for a tailored repetitive transcranial magnetic stimulation treatment regimen, it is imperative to evaluate the motor threshold. The motor threshold is the minimal intensity of the transcranial magnetic stimulation coil required to elicit compound motor action potentials in a contralateral limb muscle – in humans, this is typically an arm muscle, and in dogs, a muscle of the thoracic limb – during at least 50% of single-pulse stimulations (Rossini et al, 1994). This threshold exhibits significant interindividual variability but remains relatively stable within an individual (Cicinelli et al, 1997). The determination of the motor threshold is foundational in the development of a repetitive transcranial magnetic stimulation protocol, providing a basis for clinicians and researchers to ascertain the necessary coil output intensity to effectively stimulate the brain of an individual, thereby defining appropriate dosage and establishing safety margins. Insufficient stimulation may reduce the likelihood of achieving desirable clinical results (Mosimann et al, 2002). Conversely, excessive stimulation may engage a broader area of the brain (Roth et al, 1991) and facilitate indirect trans-synaptic activation of subcortical structures (Paus et al, 1997). This process may offer particular benefits for dogs with epilepsy, reducing seizures. However, the propensity for overstimulation to enlarge the stimulated brain volume carries an increased risk of adverse effects (Wassermann, 1998).
Theta burst stimulation, a novel paradigm within repetitive transcranial magnetic stimulation, is posited to modulate synaptic plasticity more efficiently than conventional repetitive transcranial magnetic stimulation methods (Chung et al, 2017). Characterised by its delivery of high-frequency bursts at submotor threshold intensity, typically around 80% of the motor threshold, theta burst stimulation can be administered in either an intermittent or continuous mode. Intermittent theta burst stimulation is believed to augment cortical excitability, paralleling the effects observed with traditional high-frequency repetitive transcranial magnetic stimulation, while continuous theta burst stimulation exerts a dampening effect, akin to that of low-frequency repetitive transcranial magnetic stimulation applications (Chung et al, 2016; 2017). Notably, both theta burst stimulation and select high-frequency repetitive transcranial stimulation protocols have received endorsement from the US Food and Drug Administration for managing treatment-resistant depression in the human population (Blumberger et al, 2018).
Clinical use in human medicine
The capability of repetitive transcranial magnetic stimulation to modulate neural circuits and functions non-invasively, with negligible to absent adverse effects, renders this modality a promising therapeutic intervention for a spectrum of neurological conditions. Over 15 years of research substantiates the antidepressant properties of repetitive transcranial magnetic stimulation, consolidating its role in the management of psychiatric ailments, notably treatment-resistant depression, alongside certain forms of migraine headaches in humans (Blumberger et al, 2018; Lefaucheur et al, 2020). Evidence from numerous studies and ongoing research suggests repetitive transcranial magnetic stimulation holds potential efficacy and safety in the treatment of movement and neurodegenerative disorders (Pateraki et al, 2022). However, a more comprehensive body of evidence is required for formal endorsement and integration of repetitive transcranial magnetic stimulation into clinical protocols for these conditions (Boes et al, 2018; Pateraki et al, 2022).
Interictal repetitive transcranial magnetic stimulation represents an emerging, effective and safe modality for the management of individuals with epilepsy resistant to pharmacological treatment (Lin and Wang, 2017; Boon et al, 2018). Cumulative evidence from three meta-analyses underscores a notable decrease in seizure frequency, predominantly among patients diagnosed with cortical dysplasia and neocortical epilepsy forms, following the administration of low-frequency repetitive transcranial magnetic stimulation targeted at the epileptogenic zones (Hsu et al, 2011; Cooper et al, 2017; Mishra et al, 2020). Nevertheless, the therapeutic efficacy of repetitive transcranial magnetic stimulation in the context of drug-resistant epilepsy is variable (Lin and Wang, 2017; Boon et al, 2018). Such differing outcomes may be attributable to factors including the selection criteria of patient cohorts, potential biases related to study blinding and the use of suboptimal stimulation protocols (Lin and Wang, 2017). Furthermore, exploratory investigations have shown the advantageous impacts of low-frequency ictal repetitive transcranial magnetic stimulation application in cases of (intractable) status epilepticus, thereby extending its potential therapeutic use (Rossini et al, 1994; Lin and Wang, 2017; Boon et al, 2018).
Clinical use in veterinary medicine
Currently, research on repetitive transcranial magnetic stimulation within the field of veterinary medicine is limited. A conference abstract disclosed an exploratory study on a minimal cohort of canines with epilepsy (n=3), demonstrating a post-stimulation extension in the interval between seizures relative to baseline measures; nonetheless, the abstract did not provide extensive results (Poma et al, 2006). Subsequently, a rigorous, double-blind, placebo-controlled clinical trial was conducted, which revealed a marked decrease in both monthly seizure occurrences and the frequency of days with seizures among dogs receiving active repetitive transcranial magnetic stimulation in comparison to those subjected to a placebo procedure (Charalambous et al, 2020). A subsequent analysis involved administering active repetitive transcranial magnetic stimulation to the cohort initially given the placebo treatment, using identical stimulation parameters and noted substantial enhancements. The antiepileptic effect persisted for a median duration of 4 months, ranging from 2–10 months, without observing any adverse effects linked to the treatment (Charalambous et al, 2020).
Although these findings offer encouraging evidence for the application of repetitive transcranial magnetic stimulation in managing canine drug-resistant epilepsy, definitive assertions await corroboration from larger, comprehensive studies. Other clinical trials to evaluate a repetitive transcranial magnetic stimulation protocol in epilepsy are ongoing. Preliminary data suggest that canines with drug-resistant epilepsy exhibit favourable responses to active low-frequency repetitive transcranial magnetic stimulation compared to placebo interventions. High-frequency repetitive transcranial magnetic stimulation has also been explored as a therapeutic option for behavioural issues in dogs, such as anxiety and aggression, with positive preliminary outcomes. Further research is imperative to substantiate these initial findings.
Future directions
An increasing number of scientific investigations worldwide are exploring non-invasive neurostimulation techniques, notably repetitive transcranial magnetic stimulation, for their potential in treating various neurological disorders in humans and elucidating their pathophysiological underpinnings. However, it is imperative to recognise the current standing and limitations within the scientific domain to streamline future research efforts. Presently, the application of repetitive transcranial magnetic stimulation is clinically approved for a limited array of neurological conditions in humans, with additional robust evidence required to substantiate its efficacy and safety for a wider spectrum of disorders, including epilepsy, movement disorders and neurodegenerative diseases. The preponderance of neuromodulation clinical trials has been conducted on patients resistant to pharmacotherapy, thus limiting the extrapolation of findings regarding the efficacy and applicability of non-invasive neurostimulation to the broader patient population beyond those most severely affected. Given the non-invasive nature and favourable safety profile of repetitive transcranial magnetic stimulation, there is a compelling rationale for conducting research on drug-responsive individuals in both human and canine populations. Such studies could remove the need for multi-drug regimens and mitigate the risk of significant pharmacological side effects.
The preponderance of research in both human and veterinary medicine predominantly concentrates on evaluating the clinical effects, specifically the reduction in seizure frequency and intensity. While these outcomes are of paramount importance, an imperative next step involves a comprehensive exploration into the anti-epileptogenic capabilities of non-invasive neurostimulation across various cerebral regions and its impact on the pathophysiological underpinnings of disorders. The alterations induced by neurostimulation in cerebral functionality and their correlation with clinical indices can be quantitatively analysed through the use of sophisticated neuroimaging methodologies. Such investigative pursuits would enhance the understanding of the mechanistic principles of repetitive transcranial magnetic stimulation, facilitate the formulation of more effective personalised treatment regimens, ascertain optimal stimulatory parameters tailored to the specific pathology and potentially delineate likely responders from non-responders. In the realm of veterinary science, the accessibility to advanced neuroimaging modalities lags behind that of human medicine. Initiating exploratory investigations into the ramifications of non-invasive neurostimulation using neuroimaging techniques remains crucial for the advancement and validation of novel and existing therapeutic interventions.
Previous investigations into neurostimulation and deep brain electroencephalography in canines have posited that dogs may serve as a viable translational model for human neuromodulation research (Charalambous et al, 2020). A consensus among a cross-disciplinary panel of human and veterinary neurologists and neuroscientists, founded on current evidence and expert assessments, supports the proposition that dogs offer a promising avenue for the exploration of neurostimulation techniques in both healthy and diseased brains (Charalambous et al, 2023). Nevertheless, several significant challenges hinder the widespread adoption and evaluation of non-invasive neurostimulation methodologies within veterinary practice. These include the necessity for sedation during procedures, pronounced breed-specific cranial and neurological variances, a general paucity of neurostimulation knowledge among veterinary practitioners and the high costs associated with neurostimulation equipment.
Conclusions
Neurostimulation leads to changes in brain circuits through mechanisms such as neuroplasticity. These effects are not limited to the stimulation site but extend across the brain because of the interconnected nature of brain networks. The outcomes of neurostimulation vary among individuals, and depend mainly on the anatomical differences among species or breeds, the specific disorder being treated and the stimulation parameters used. Various non-invasive neurostimulation devices are being studied in human medicine and, to a lesser extent, in veterinary applications, offering a promising therapeutic approach for numerous neurological disorders. Although research in veterinary neurostimulation is currently less advanced than in human medicine, these applications hold significant promise for enhancing the quality of life and therapeutic outcomes for animals with various neurological disorders.