Introduction
Facial pain, particularly chronic neuralgic conditions like trigeminal neuralgia (TN), presents a significant challenge in healthcare. Trigeminal neuralgia (TN) is a chronic neuralgic facial pain disorder that involves the territory of one or more branches of the trigeminal nerve and affects seniors and women more than men in a ratio of 3:1 with a prevalence of 0.03-0.3%. Traditional medical treatments, such as antiepileptic drugs (AEDs) and baclofen, often come with dose-related side effects and may lose efficacy over time due to age-related complications, intolerance, progression of pain severity, and the relapsing nature of TN. Consequently, there's a growing interest in non-medical interventions, especially neuromodulatory methods like transcranial direct current stimulation (tDCS), which have shown promise in managing pain. This article explores the research on tDCS as a therapeutic intervention for facial pain, focusing on its mechanisms, applications, and potential benefits.
Understanding Trigeminal Neuralgia
Trigeminal neuralgia (TN) is characterized by recurrent paroxysmal unilateral facial pain in the distribution(s) of one or more divisions of the 5th cranial nerve, without radiation beyond. The condition primarily affects seniors and women more than men in a ratio of 3:1 with a prevalence of 0.03-0.3%. Attacks of neuralgiform pain can be precipitated by innocuous stimuli within the affected territory of trigeminal division. Morphological changes of Trigeminal nerve are evident in MRI study. Added to the pain of the condition, patients with TN have an increased risk of anxiety and depression with significant life consequences. The processing of pain stimuli involves a complex arrangement of sites within the cerebral hemispheres that are accessible to neuromodulation.
The Role of Neuromodulation and tDCS
Neuromodulation techniques, including tDCS, offer a non-invasive approach to alter neural activity and mitigate pain. Nonmedical treatment has primarily involved minimally invasive surgical procedures while neuromodulatory methods have more recently become acknowledged as effective interventions. tDCS involves the application of a weak direct current to the scalp to modulate cortical excitability. Transcranial Direct Current Stimulation (tDCS) is a non-invasive neurostimulation method using low direct current (0.029-0.08 mA/cm2) applied to a cathode and anode, which directly stimulates the cranial surface. The applied current causes the most significant changes directly under the electrodes: the cathode reduces the excitability of cortical neurons, whereas the anode increases excitability. The effect of stimulation usually lasts a few hours up to a few days. Anodal stimulation generally enhances neuronal excitability, while cathodal stimulation reduces it. Repeated applications of anodal tDCS over the primary motor cortex (M1) have been shown to produce long-lasting relief of neuropathic pain. tDCS is a technique that can induce and modulate brain plasticity and thus be suitable for treating diverse chronic pain conditions, disorders associated with substantial reorganization of central nervous system activity.
Brain Circuits Involved in Pain Processing
Several brain regions and circuits are implicated in the processing of pain, making them potential targets for neuromodulation. Reciprocal connections exist both between motor (MC) and premotor (PM) cortices and between the PM and ventrolateral nucleus (VLN) of the thalamus. Both the PM and globus pallidus interna (GPi) project to the anterior VLN while both the MC and cerebellum project to the posterior VLN. The ventromedial nucleus (VMN) of the thalamus similarly receives input from the PM as well as the substantia nigra pars reticulata (SNpr). Striatal GABAergic spiny neurons exert an inhibitory effect upon nigrothalamic and pallidothalamic neurons resulting in a disinhibition of the VMN and its projection onto the MC. The ventroposterior nucleus pars medialis (VPM) of the thalamus similarly has reciprocal connections with the somatosensory cortex (SSC). It receives sensory information from the principal trigeminal nucleus. The posteromedial nucleus (POm) receives sensory information from the spinal trigeminal nucleus and from the SSC. The basal ganglia-thalamus-cerebral cortex circuit consists of fibers projecting from the supplementary motor area (SMA), PM, MC, and SSC to the putamen which projects to both external and internal segments of the globus pallidus The circuit is completed with efferents from the GPi to the VLN and back to the SMA. Two distinct pathways, direct and indirect, from the basal ganglia regulate the thalamic response with opposing effect. Activation of the striatum inhibits GPi neurons causing the direct pathway to release thalamic neurons from inhibition, and to excite the MC. The indirect pathway involves striatal inhibition of the external globus pallidus (GPe) which then disinhibits neurons of the subthalamic nucleus to bring about excitation of the GPi. Stimulation of the MC and caudate nucleus have both been shown to mitigate pain.
Study on Navigated tDCS for Treatment-Refractory TN
A study evaluated different applications of navigated tDCS in six patients with treatment-refractory TN, specifically the locations of anode and cathode, were evaluated to determine response to treatment. Magnetic resonance imaging was undertaken to identify coincident structural and functional changes underlying the effect of the stimulation. Six otherwise healthy patients with unilateral primary TN (five left, one right) refractory to maximal medical therapy (including Carbamazepine, Pregabalin, and Clonidine) were enrolled in the study following informed consent. Inclusion eligibility was drawn from the criteria established by the Headache Classification Committee for TN [International Headache Society (HIS)]; specifically, recurrent paroxysmal unilateral facial pain in the distribution(s) of one or more divisions of the 5th cranial nerve, without radiation beyond. Exclusion criteria included: (1) Presence of any severe systemic comorbidity, (2) History of arrhythmia or seizure, and (3) Any contraindication for magnetic resonance imaging (MRI). Both SSC and MC were determined using standard neuronavigation technique. Functional MRI-based navigation was used to identify sites within the SSC and MC corresponding to the region of facial pain. The precise locations of tDCS electrodes were determined using a transcranial magnetic stimulation (TMS)-based navigator. A high spatial resolution T1-MPRAGE MRI with voxel size 1 mm3, 3D brain segmentation and registration tools confirmed the stimulation target sites for subsequent imaging and therapeutic sessions. A conductive paste (Ten20) was manually applied as a conductor between the electrodes and skin, with the resultant impedance checked for the subject’s safety. MR-compatible tDCS equipment (NeuroConn DC-stimulator) was used to apply 2 mA direct current concurrently with fMRI paradigm. A pair of MR-compatible rectangular rubber electrodes with dimensions of 35 cm2 (7 × 5) were used with rubber band fixation to keep the electrodes in place during imaging.
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fMRI and dMRI Study Protocol
The pretreatment session with fMRI consisted of the standard three stages in the block-design imaging analysis approach: (1) “tDCS” stimulation task targeting optimal regions in the block design; (2) Pain stimulation task with pain triggered in the block design; (3) “Pain + tDCS” stimulation task with pain triggered instantaneously with tDCS in the block design between rest phases. During activation blocks in the “Pain” task, the patients were instructed to bite their ipsilateral interior cheek next to the second upper molar tooth in order to reproduce their neuralgiform pain in the territory of trigeminal nerve. The same scenario was applied for the “Pain + tDCS” task, while an electrical stimulus was directed to the motor (anodic/excitatory stimulation) or sensory (cathodic/inhibitory stimulation) cortex. For the “tDCS” task, only the electrical current was applied during activation blocks with the patients instructed to do nothing during the task. A diffusion MRI (dMRI) study was also performed in the pretreatment phase. The patients then underwent five sessions of tDCS treatment with either cathodic stimulation delivered onto the contralateral SSC or anodic stimulation upon the contralateral MC. Again, a direct current of 2mA was applied by the same tDCS for a 20-min duration with 30s fade in/out. A saturated sponge with normal saline (0.9%) was used as a conductor between the electrode and skin with impedance checking for the subject’s safety. A one-day interval was provided between sessions and the posttreatment study was performed two days after the last treatment session. Both fMRI and DTI were performed with the same tasks and imaging parameters as in the initial study. The Numeric Rating Scale (NRS) and the Headache Disability Index (HDI) were used to score the subjective efficacy of treatment.
Imaging Parameters and Data Processing
All subjects underwent high-resolution structural MRI and fMRI block-design stimulation tasks, along with a single-shell dMRI acquisition using a 64-channel phased array head coil and a 3-Tesla scanner (Siemens Prisma, Erlangen, Germany) using the software version “Syngo MR E11.” A structural MRI was acquired using a standardized protocol as follows: transverse T1-weighted images using the MPRAGE protocol with imaging parameters, TR = 1840 ms, TI = 900 ms, TE = 2.43ms, flip angle = 8°, matrix = 224 × 224, in-plane resolution = 1.0 × 1.0 mm2, slice thickness = 1.0 mm, pixel bandwidth = 250 Hz/pixel. The volumes of the task-related fMRI (120 measurements) covering the whole brain were acquired in the transverse plane using an echo planar imaging (EPI) sequence (TR = 3,000 ms, TE = 30 ms, flip angle = 90, matrix = 640 × 640, slice thickness = 2.4 mm). In the “Pain” stimulation task, sic blocks of activation were applied, each followed by a rest period. The duration of each fMRI task block was 6 min. Single shell dMRI (b-value of 1,000 s/mm2 involved 64 diffusion gradient directions acquired using EPI with the same unit in an anteroposterior phase direction with the following imaging parameters: TR = 9,600 ms, TE = 92 ms, flip angle = 90, matrix = 110 110, in-plane resolution = 2.0 × 2.0 mm2, slice thickness = 2.0 mm, pixel bandwidth = 1,420 Hz/pixel. Preprocessing steps included motion correction and eddy current correction, followed by a two-step registration protocol. First, each dMRI or fMRI volume was registered to its own T1 space. A transformation of dMRI or fMRI was then undertaken to register the individual subject’s T1 space to standard MNI space. After preprocessing, FEAT in FSL tools (Linux) was used to extract the activation areas for each of the three tasks. To determine the effectiveness of tDCS upon network activation, particular sites such as the caudate, SSC, globus pallidus GP, putamen, thalamus, and cingulate gyrus, believed to be influenced by TN, were extracted using FEAT in FSL. Both MD and FA were determined at the trigeminal root entry zone (REZ). The number of sensory fibers, speculated to be involved in the pain propagation of TN, were extracted using ExploreDTI and manual ROI insertion.
Study Findings: Brain Activation and Sensory Fiber Changes
We assessed the effect of unilateral pain application upon ipsilateral vs. contralateral brain structures with the “Pain” stimulation task alone. This was followed by assessing the sites of activation generated by application of the “Pain + tDCS” task expected to bring about a dynamic suppression of pain induced. Repeated measurement analysis showed no differences between groups with cathodic and anodic stimulations for HDI (F test = 0.237, P = 0.6) and NPRS (F test = 0.14, P = 0.7). A significantly greater activation was found with anodic tDCS, after Bonferroni adjustment, of the caudate and SSC within the ipsilateral pain zone compared to that of the contralateral side as determined in the pretreatment session. Concurrent application of tDCS stimulation during the “Pain task” (“tDCS + Pain”) in the pretreatment session significantly reduced activation in both ipsilateral and contralateral caudate and ipsilateral SSC in cases of anodic tDCS treatment. The same occurred in both ipsilateral and contralateral thalamus in cases treated by cathodic tDCS treatment. There was no significant difference between “Pain” and “Pain + tDCS” stimulation tasks for these structures during the posttreatment session. A significant increase in activation was found within the caudate and putamen bilaterally with anodic stimulation. Following a course of five tDCS treatments, regardless of stimulation methodology, we observed a significant decrease in activation of the ipsilateral caudate, SSC, GP, and thalamus, and in the contralateral GP during the posttreatment session compared to that of pretreatment.
With anodic stimulation, the observed significant decrease from pre- to posttreatment occurred only in the ipsilateral caudate and SSC. On the other hand, cathodic stimulation brought about increased activation in the ipsilateral thalamus. The decrease within the ipsilateral and contralateral GP occurred with both anodic and cathodic applications. These observations prompted investigation of anodic and cathodic cases separately. For cases of anodic stimulation, a significant decrease in activation occurred in the ipsilateral caudate, SSC and GP, and the contralateral GP. The dMRI analysis showed a substantial increase (>50%) in the number of contralateral sensory fibers in the spinothalamocortical sensory tract (STCT) following the complete course of tDCS stimulation in three of the six patients. A significant reduction in fractional anisotropy (FA) (>40%) was observed in the ipsilateral trigeminal REZ, after Bonferroni adjustment, in the posttreatment phase compared to pretreatment in five of the six patients. Three patients showed a substantial increase (>32%) while a single case was found to have a relatively minor decrease (13%) in FA within the contralateral REZ in the posttreatment phase.
Implications of Anodic and Cathodic tDCS
The concurrent application of anodic tDCS and a relevant pain stimulus significantly attenuates activation in both the ipsilateral and contralateral caudate and the ipsilateral SSC. Likewise, following a course of anodic tDCS, the ipsilateral caudate, GP and SSC and the contralateral GP showed a significantly attenuated activation as assessed by the “Pain” stimulation task. Stimulation rendered within the TN pain zone revealed an area of activation within the ipsilateral caudate and SSC that was significantly greater when compared to the contralateral side. This difference disappeared following a course of anodic tDCS treatment. Concurrent application of cathodic tDCS and pain stimulation significantly reduced activation in both ipsilateral and contralateral thalamus. Findings in the current study are consistent with prior formulations of a pain neuromatrix. The remarkable feature here, however, was the significant success achieved with both cathodic and anodic tDCS in relieving pain.
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Broader Applications and Future Directions
Non-invasive neuromodulation techniques such as transcranial direct current stimulation (tDCS) enable researchers and health care professionals to gain unique insight into brain functions and to treat a number of neurological and psychiatric conditions. A recent review analyzed the therapeutic effect of repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on different types of chronic headache. Cases of mild-moderate grade headache have responded with a reduced frequency of events using anodic tDCS applied to either the left MC or the dorsolateral prefrontal cortex (DLPFC) with the cathode overlying the contralateral fp2 site of the 10-20 EEG system. The number of published basic research and clinical papers in this field is increasing exponentially, but the number of studies that include patients with facial pain is still limited, and there are no "gold standards" with regard to how to treat the various kinds of pain disorders.
tDCS as an Affordable and Accessible Technique
tDCS is a non-invasive stimulation technique that is affordable and can be easily administered, especially when compared to other neurostimulation techniques. Pharmacoresistant facial pain is a substantial burden for the patient as manifested by its interference with daily functioning and reduced health status associated with pain severity. Without doubt, further trials are needed to optimize stimulation parameters and find effective protocols for this disorder. In addition, evaluation of the clinical effects of tDCS shows that low-intensity electrical stimulation techniques are exceptionally suitable for gaining further insight into the functional role of a given brain region.
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tags: #transcranial #direct #current #stimulation #facial #pain