NIBS techniques have significant potentials in the study and treatment of various psychiatric and neurological disorders including pain [
58]. However, it must be stressed that the underlying mechanisms are complex and the clinical effects depend on various factors leading to high degree of variability [
59]. Therefore, the best clinical practice for the use NIBS techniques in pain management should be derived from standardized guidelines [
60,
61]. The two main studied NIBS techniques are TMS and tDCS. The principle of TMS is the non-invasive application of magnetic field pulses, which carry a current through the skull and excite superficial layers of the cortex. The two main cortical region to which TMS is applied are the primary motor (M1) cortex and the dorsolateral prefrontal cortex (DLPFC), both of which are associated with chronic pain and affect various aspects of pain processing [
62,
63]. The repetitive application of TMS (rTMS) produces long-lasting, stimulation frequency-dependent excitability effects [
64,
65] and leads to widespread activity changes in connected cortical and subcortical regions, yet the alterations of functional connectivity remain network-specific [
66,
67]. The rTMS-induced excitability changes are believed to be mediated through neural plasticity mechanisms [
68]. Indeed, evidence shows that rTMS-induced changes are NMDAR-dependent, lead to enhanced BDNF function [
69] and able to induce potentiation [
70] and depression [
71] of excitability. Furthermore, rTMS application in rodents is observed to enhance cognition, facilitate hippocampal plasticity and increase the levels of various plasticity markers [
72]. Accordingly, accumulating evidence supports the hypothesis that rTMS accelerates recovery of sensory and motor functions after stroke, incomplete spinal cord injury and nerve injury by promoting synaptic plasticity and thereby reversing maladaptive plasticity [
73‐
75]. In addition, the LTP-like plasticity induced by rTMS treatment correlates with cognitive function improvement in Alzheimer’s disease patients [
76]. Similarly, early treatment with rTMS is proposed to block pain-associated maladaptive plasticity induced by surgery, spinal injury and brain trauma; thus, preventing acute-to-chronic pain transitioning [
77]. In a recent meta-analysis, Che and colleagues (2021) found that rTMS exerts a short-term analgesic effect that is specific to neuropathic pain, a long-term (average of 3 month) analgesic effect across multiple chronic pain conditions and significant analgesia of provoked pain, which could model either acute pain or acute-to-chronic pain transition [
78]. These findings support the general consensus that rTMS exerts a multitude of mechanisms that could differentially modulate specific types of pain and indicate an acute analgesic effect that could be independent from the maladaptive plasticity associated with chronic pain. Indeed, rTMS application is shown to activate opioid-mediated analgesia of acute pain in healthy individuals [
79], induce dose-dependent immediate analgesia following stimulation in patients with intractable neuropathic pain [
80] and elevate electrical pain thresholds up to 40 min following application over the somatosensory cortex of healthy subjects without altering the excitability of the M1 cortex [
81]. Therefore, rTMS carries significant potentials in both: prevention of acute-to-chronic pain transition, through acute analgesia and prevention of maladaptive plasticity, and treatment of chronic pain through reversal of maladaptive plasticity. On the other hand, the principle of tDCS is the passage of current between two electrodes; thus, anodal tDCS leads to depolarization while cathodal stimulation causes hyperpolarization. In contrast to TMS, which can stimulate cortical neuronal axons to fire action potentials, the effects of tDCS are more electrically subtle. This is due to weaker current pulses affecting membrane excitability (subthreshold potential alterations); however, depending on the duration and frequency of application it can also induce long-lasting effects mediated by intracortical inhibition and facilitation [
82]. In relation to neural plasticity, the application of tDCS is found in rodent models to promote BDNF-dependent synaptic plasticity [
83], enhance synaptic plasticity and memory [
84] and improve plasticity deficits and cognitive dysfunction associated with diabetes [
85]. Clinically, tDCS facilitates the formation of long-term motor memory, reflecting experience-dependent plasticity [
86], improves motor performance in the elderly via enhanced facilitation and reduced inhibition [
87] and, at short stimulation intervals, leads to LTP-like excitability enhancements in healthy participants [
88]. These findings indicate significant facilitatory effects of tDCS on neuronal plasticity, which could thereby accelerate the recovery from, or prevent the development of, maladaptive plasticity similar to rTMS. Various studies support the potential analgesic efficacy of tDCS in multiple chronic neuropathic pain conditions [
89] as well as migraine, osteoarthritis and capsaicin-induced mechanical sensitivity [
90‐
92]. Furthermore, tDCS has no impact on pain thresholds and mechanical detection in healthy individuals [
93]. However, the analgesic response to tDCS depends on many factors; hence, it is not effective in all patients with neuropathic pain [
94]. The mechanisms underlying direct tDCS-induced analgesia are not completely understood; however, the effects may not only be related to increased or decreased neuronal firing rates as reports suggest the engagement of endorphins [
95,
96] and, in addition to modulation of glutamatergic and GABAergic balance [
97], the alteration of certain neuromodulators such as dopamine [
98]. In rodent models, other neuromodulators are also found to significantly affect tDCS responses including serotine [
99] and norepinephrine [
100]. These neuromodulators are known to regulate neuronal activity, synaptic plasticity, input processing and associated neurological functions [
101]. Lastly, many other tDCS effects were proposed to mediate analgesia in relation to altered pain processing and modulation of its emotional aspects [
102].