Modulation of pain-descending inhibitory pathway using transcranial direct current stimulation priming protocols in healthy subjects: systematic review

ABSTRACT

BACKGROUND AND OBJECTIVES:

Priming is a phenomenon in which brain activity can shift in an inhibitory or excitatory direction, potentially increasing synaptic efficiency in response to a previous input. Transcranial direct current stimulation (tDCS) is a neuromodulation technique that has been extensively investigated as an alternative treatment in pain processing changes. Priming techniques can improve pain relief mechanisms in healthy subjects. However, no systematic reviews have been published that summarize these findings. The objective of this review was to identify and evaluate studies that used tDCS as priming or testing protocols and investigate its effects on the descending inhibitory pathway of pain in healthy people.

CONTENTS:

Two independent reviewers searched Medline, Embase, CINAHL, Web of Science, PsycINFO, PEDro, Scopus, and Cochrane databases until January 2024 for studies using tDCS as a priming or testing protocol in healthy subjects to assess changes in the pain descending pathway. Four studies were eligible. Two studies showed that cathodic tDCS increases pain threshold when applied before 1Hz rTMS (repetitive transcranial magnetic stimulation), and this may be mediated by homeostatic metaplasticity mechanisms. Two studies have shown that anodal tDCS combined with exercise can activate central pain control mechanisms; the use of both at the same time may have resulted in a synergistic effect and greater analgesia.

CONCLUSION:

The priming approach of cathodal or anodal tDCS appears to change the pain threshold in healthy people, however, the effect is reliant on the test stimulus used and may increase or reverse the intended effect.

Keywords:
Diffuse noxious inhibitory control; Repetition priming; Transcranial direct current stimulation

RESUMO

JUSTIFICATIVA E OBJETIVOS:

Priming é um fenômeno no qual a atividade cerebral pode mudar em uma direção inibitória ou excitatória, aumentando potencialmente a eficiência sináptica em resposta a um estímulo anterior. A estimulação transcraniana por corrente contínua (ETCC) é uma técnica de neuromodulação extensivamente investigada como uma alternativa de tratamento para alterações no processamento da dor. As técnicas de priming podem melhorar mecanismos de analgesia, no entanto, nenhuma revisão sistemática foi publicada sumarizando esses achados. O objetivo desta revisão foi identificar e avaliar estudos que utilizaram ETCC como protocolos priming ou teste e investigar seus efeitos na via inibitória descendente da dor em pessoas saudáveis.

CONTEÚDO:

Dois revisores independentes consultaram nas bases de dados Medline, Embase, CINAHL, Web of Science, PsycINFO, PEDro, Scopus e Cochrane, até janeiro de 2024, estudos que utilizaram ETCC como priming ou teste em indivíduos saudáveis para avaliar alterações na via descendente da dor. Quatro estudos foram elegíveis. Dois estudos mostraram que a ETCC catódica aumenta o limiar de dor quando aplicada antes da EMTr (estimulação magnética transcraniana repetitiva) de 1 Hz, podendo ser mediada por mecanismos de metaplasticidade homeostática. Dois estudos demonstraram que a ETCC anódica combinada ao exercício pode ativar mecanismos centrais de controle da dor; o uso concomitante teve efeito sinérgico, resultando em maior analgesia.

CONCLUSÃO:

A abordagem de priming da ETCC catodal ou anodal parece alterar o limiar da dor em pessoas saudáveis, entretanto, o efeito depende do estímulo de teste utilizado e pode aumentar ou reverter o efeito pretendido.

Descritores:
Controle inibitório nociceptivo difuso; Estimulação transcraniana por corrente contínua; Priming de repetição

HIGHLIGHTS

This systematic review provides important insights into the use of a non-invasive neuromodulation strategy as a potential priming technique to pain relief.

Metaplasticity mechanisms are possible mediators of the priming phenomena.

Priming tDCS effects depend on the parameters and type of subsequent intervention.

INTRODUCTION

The descending pain inhibitory pathway is an endogenous analgesic mechanism that arises in the periaqueductal gray matter (PAG), which has reciprocal communication with the rostral ventromedial medulla (RVM), locus coeruleus (LC), and dorsal reticular subnucleus (DRS)¹. Nociceptive afferents reach the PAG, which, through direct serotonergic and noradrenergic neuronal projections with the RVM, triggers inhibition of the nociceptive stimulus². However, this pathway may change in both healthy and unhealthy people, serving as a predictor of pain chronification and poor treatment response³.

Individuals suffering from chronic pain may experience morphophysiological changes in cortical and subcortical structures as a result of the pain⁴, ⁵, ⁶, affecting regions such as the PAG and impairing pain inhibition mediated by the descending inhibitory pathway⁷, ⁸. These changes could be linked to maladaptive neuroplasticity in various cortical areas involved in pain processing⁹, ¹⁰. In this regard, studies utilizing neuromodulation techniques for pain control¹¹, cortical function modulation¹², and the neuroplasticity process have been developed¹³.

The transcranial direct current stimulation (tDCS) technique can promote reversible and long-lasting changes in cortex excitability by changing neuronal transmembrane potential, with anodal tDCS mostly triggering neuronal depolarization and increasing cortical excitability, and cathodal tDCS hyperpolarizing the neuronal membrane and decreasing cortical excitability¹⁴.

tDCS is a non-pharmacological, non-invasive, and safe neuromodulation technique that has been extensively studied as an alternative or complementary therapy option for a variety of health issues, including pain processing modifications¹⁵, ¹⁶. It acts on neurophysiological mechanisms to enhance or decrease cortical excitability, inducing lasting or reversible changes and targeting specific brain areas¹⁴. Age, gender, application timing, and sleep are just a few variables that can influence tDCS effects¹⁷, which are also affected by previous neuronal activity¹⁸.

Although tDCS may activate the pain mechanisms system¹⁹, its effect appears to be insufficient when applied in healthy individuals¹⁶. On the other hand, when combined with another neuromodulatory technique, tDCS’s analgesic effect can be enhanced. For example, in patients with chronic low back pain (CLBP), tDCS combined with peripheral electrical stimulation (PES) results in significant clinical pain relief that can last up to three months²⁰. These approaches may be related to the priming phenomenon, which involves preparing the brain by modulating excitability in an inhibitory or excitatory manner, thereby increasing synaptic efficiency based on a preceding stimulus²¹.

There is evidence that the priming phenomenon can occur during a combination of neuromodulatory techniques via homeostatic or non-homeostatic metaplasticity buttons, which regulate the cortical excitability threshold, shifting it towards long-term potentiation (LTP) or long-term depression (LDP)²². Homeostatic controls are bidirectional, adjusted based on previous neuronal activity, and reliant on N-methyl D-Aspartate (NMDA) receptor activation and increased intracellular calcium¹⁸. Non-homeostatic switches, which are associated with voltage-gated calcium channels, are also linked to the prolongation of the metaplastic effect²¹, ²³. As a result, prior use of a technique such as the priming protocol can enhance the effect of the subsequent intervention known as testing. These findings show that priming phenomena using neuromodulatory techniques can enhance analgesic effects.

Previous systematic reviews have investigated the effects of various priming protocols with noninvasive neuromodulation techniques on primary motor cortex excitability. These reviews have shown that the effects vary depending on the type of priming used. Specifically, using an inhibitory priming technique followed by an excitatory test stimulus can increase cortical excitability, in the same way that equal stimuli provide a reversal effect¹⁸, ²³. However, no systematic reviews were conducted to summarize the effect of tDCS as priming or test protocols on clinical outcomes of the descending pain inhibitory pathway, including pain threshold and conditioned pain modulation (CPM). The primary goal of this review was to identify and assess studies that used tDCS as priming and testing protocols, as well as to investigate their effects on the descending inhibitory pathway of pain in healthy people.

CONTENTS

This literature review was carried out in accordance with the PRISMA Guidelines²⁴ and was registered in PROSPERO under the identification number CRD42023412986. Two independent authors (RSRJ and AMCB) conducted database searches in the following databases: PubMed, Embase, CINAHL, Web of Science, PsycINFO, Physiotherapy Evidence database (PEDro), Scopus, and the Cochrane Database of Systematic Reviews. In cases of disagreement, a third reviewer (FAH) was brought in to help make the decision. Additional references were found by searching the reference lists of the articles. The Rayyan software was utilized to remove duplicates and filter out titles and abstracts. This application employs a semi-automated procedure to streamline the evaluation of articles for review²⁵.The articles were chosen for analysis after duplicates were removed. The following terms were used as keywords, and MeSH terms: “Transcranial Direct Current Stimulation”, and “Repetition Priming” OR “Priming”, and “Descending pain inhibitory pathway”. None filter was applied in the search strategy and all keywords were inserted into the database search page, enclosed in quotation marks. The complete strategy is available in the table 1.

Table 1
Characteristics of the included studies

Authors	Study design	Subjects	tDCS priming	Application site	Test protocol	Pain threshold	CPM	Adverse effects	Results
Moloney and Witney29	Sham-controlled, single-blind study	n = 12 (men)	a-tDCS; 1mA; 25cm2; 10min c-tDCS; 1mA;-25cm2; 10min	A= Left M1 C= Right SO	rTMS; 1Hz; RMT90; M1; 15 min	Thermal stimuli; palmar thenar eminence; 1° to 32°C; 4 times	NA	NR	Priming a-tDCS ↓ CPT Priming c-tDCS ↑ CPT and HTP
Moloney and Witney30	Sham-controlled, single-blind study	n =15 (men)	a-tDCS;1mA; 25 cm2;10min. c-tDCS;1mA; 25 cm2;10min	A= Left M1 C= Right SO	rTMS; 1Hz; RMT90; M1; 15 min	Algometer; palmar thenar eminence of the hand; 4 times	NA	NR	Priming a-tDCS no effect PPT Priming c-tDCS ↑ PPT
Borovskis et al.27	Double-blind randomized sham-controlled trial	n =24 (10 men)	a-tDCS;1mA; 25 cm2;10min	A= Left M1 C= Right SO	IHE; 25%±5% MVC; 3 min;	Algometer; Right and Left ECRB, TA muscle bellies; 3 times	Algometer in right ECRB; left hand immersed in cold water; 2 min	NR	Priming a-tDCS ↓ NRS but doesn’t affect PPT and CPM
Sato et al.28	Single-blind experimental study with a cross-over	n = 10 (6 men)	a-tDCS;2mA; 35 cm2; 20min	A= Left M1 C= Right SO	AE on the cycle ergometer; 20 min	Algometer; nail of the middle finger on the right side	NA	NR	Priming a-tDCS/AE ↑ PPT Priming sham-tD-CS/AE and a-tDCS doesn’t affect PPT significantly

• tDCS = Transcranial direct current stimulation; a-tDCS = anodal tDCS; c-tDCS = cathodal tDCS; rTMS = Repetitive transcranial magnetic stimulation; RMT = Resting motor threshold; M1 = Primary motor cortex; SO: Supraorbital; A = Anodal; C = Cathodal; PPT = Pressure pain threshold; CPM = Conditioned pain modulation; QTS = Quantitative sensory testing; AE = Aerobic exercise; CPT = Cold pain threshold; HPT = Heat pain threshold; ECRB = Extensor carpi radialis brevis; TA = Tibialis anterior; IHE = Isometric handgrip exercise; MVC = maximum voluntary contraction; NRS = Numeric Rating Scale; NA = Not assessed; NR = Not reported.

Papers were included if they met the following criteria: Clinical trials; involved human subjects without pain, neurodegenerative, musculoskeletal, psychiatric, or neurological disorders; used tDCS like a priming protocol; and had outcome measures regarding changes in the descending inhibitory pathway of pain.

Exclusion criteria: (1) Neither priming nor the test protocol included NIBS, and (2) the mean results did not assess changes in the descending pain inhibitory pathway.

Data extraction

Following the inclusion of articles, both authors, (RSRJ and AMCB), extracted the subsequent information from each article: study design, sample size, priming intervention and test protocol characteristics, method of assessing pain threshold and CPM, and results (Table 1). The obtained data was inputted into an Excel spreadsheet and subsequently incorporated into the text. Disagreements in interpretation were settled through discussion and mutual agreement.

Quality assessment

Two independent researchers (RSRJ and AMCB) reviewed each included article and assigned a quality score based on the PEDro scale²⁶, with a third reviewer (FAH) arbitrating any disagreements. The PEDro scale includes several items that are rated on a ‘yes/no’ basis to assess for each article the external and internal validity. The PEDro scale yields total scores ranging from 0 to 10, with a higher PEDro score indicating higher quality (Table 2).

Table 2
Study quality and outcomes

PEDro Scale Criteria
Studies	1	2	3	4	5	6	7	8	9	10	11	Total
Moloney and Witney29	Y	N	Y	Y	Y	N	N	Y	Y	Y	Y	7
Moloney and Witney30	Y	N	Y	Y	Y	N	N	Y	Y	Y	Y	7
Borovskis et al.27	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	9
Sato et al.28	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	8
Mean												7.75

RESULTS

The initial search yielded 1130 articles, of which 4 were deemed appropriate for inclusion in this review (Figure 1).

Figure 1
Flowchart of studies included in this review²⁴.

Characteristics of the studies

Four clinical trials were included, with 61 healthy participants aged 20 to 30 years old. Two of the four articles included in the results synthesis used transcranial direct current stimulation (tDCS) as a priming strategy previously used with transcranial magnetic stimulation (TMS). Prior application of cathodal tDCS increased cold pain thresholds from 11.5±52 °C to 5.8±3.8 °C and heat pain thresholds from 45.9±1.6 °C to 47.8±1.0 °C (21), as well as pressure pain thresholds from 365.73±90.92 KPa to 405.07±97.44 KPa (22) in relation to the groups that received anodal and sham tDCS priming.

The authors²⁷ conducted a study where they found that anodal tDCS followed by isometric contraction exercise reduced the intensity of experimental pain caused by the application of Intramuscular Injection of nerve growth factor (NGF). The pain intensity decreased from 0.83±0.94 to 0.33±0.49 immediately after the exercise and 0.42±0.51 fifteen minutes after the intervention in the wrist flexion movement. In the wrist extension movement, the pain intensity decreased from 1.25±0.87 to 0.92±0.51 immediately after the exercise and 0.92±0.51 fifteen minutes after the intervention. These reductions were observed in comparison to a group that received sham-tDCS. However, there were no statistically significant changes in PPT and CPM²⁷.

The study²⁸ found that the addition of anodal tDCS to aerobic exercise (AE) resulted in an 83.4% rise in pain threshold. This increase was significantly higher compared to the tDCS (40.7%) and AE/sham tDCS (51.5%). Furthermore, the tDCS/AE group saw earlier and more significant changes in pain threshold compared to the sessions of tDCS and AE/sham tDCS (28). To verify changes in pain perception, all studies used at least one quantitative sensory test (Table 1).

Study quality

All clinical trials included in the review were assessed using the PEDro scale¹⁹ and had an average of 7.75 indicating good methodological quality and a low risk of bias (Table 2). Two studies did not clearly report or describe the method of randomization and group allocation (29,30). Three trials failed to blind the therapists and the evaluator to the delivery or evaluation of the intervention (28-30). Furthermore, despite the risk of bias mentioned, the authors’ findings did not take these issues into account.

PEDro criteria: (1) Eligibility criteria were specified; (2) Subjects were randomly allocated to groups (in a crossover study, subjects were randomly assigned an order in which treatments were received); (3) Allocation was concealed; (4) The groups were similar at baseline regarding the most important prognostic indicators; (5) There was blinding of all subjects; (6) There was blinding of all therapists who administered the therapy; (7) There was blinding of all assessors who measured at least one key outcome; (8) Measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups; (9) All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome was analyzed by “intention to treat”; (10) The results of between-group statistical comparisons are reported for at least one key outcome; (11) The study provides both point measures and measures of variability for at least one key outcome; Y = Yes; N = No.

DISCUSSION

The purpose of this systematic review was to identify and assess studies that used tDCS as priming and testing protocols, as well as to investigate their effects on the descending inhibitory pathway of pain in healthy people. The findings show that cathodal tDCS priming enhances analgesic responses and highlights the crucial role of metaplasticity mechanisms. The studies included in this review employed various priming strategies and evaluated pain thresholds as well as CPM.

According to the synaptic modification model³¹, metaplastic mechanisms regulate cortical excitability and can be classified as either homeostatic or non-homeostatic. This model suggests the existence of a bidirectional sliding threshold that adjusts based on presynaptic neuronal activity, promoting Long-Term Potentiation (LTP) or Long-term depression (LTD). Considering that tDCS is a neuromodulation technique dependent on neuronal activity, the choice of the priming stimulus, whether inhibitory or excitatory, can significantly affect the subsequent effects of the test stimulus.

Next, we present the different types of priming protocols identified in this review and discuss their repercussions on pain perception in healthy individuals.

Priming tDCS over rTMS

Two studies involving the application of tDCS before 1 Hz rTMS (transcranial magnetic stimulation) were conducted. In a clinical trial, pain thresholds were evaluated in healthy individuals before and after tDCS priming followed by 1 Hz rTMS. The study revealed that the group receiving cathodic tDCS in primary motor cortex (M1) experienced an increase in cold and heat thermal pain thresholds²⁹. The inhibitory preconditioning session caused by cathodic tDCS may be responsible for the increase in pain thresholds observed in the cathodic tDCS-1Hz rTMS protocol.

According to the metaplastic theory, the reduction in cortical activity caused by the cathodic tDCS inhibitory preconditioning session may facilitate a general increase in cortical excitability following the subsequent low frequency rTMS stimulation, resulting in elevated cortical excitation. Increasing M1 excitability may increase PAG activity, which is linked to the antinociceptive descending pathways²⁹. As a result, pain threshold and pain relief can be modulated.

The second study demonstrated that priming the primary motor cortex (M1) before 1 Hz rTMS stimulation modulates pain thresholds and analgesia³⁰. In this experiment, the group that received cathodal tDCS had a significant increase in their pressure pain threshold. The anodic tDCS group, on the other hand, showed a decrease in cortical excitability with no effect on PPT. Previous research has shown that the effects of both tDCS and rTMS techniques are dependent on the state of neuronal activity¹⁸. When two inhibitory techniques are used together, they produce a contrasting effect that leads to increased cortical excitability, which can be mediated by metaplasticity’s homeostatic mechanisms²³. Moreover, the activation of regions involved in the emotional processing of pain, such as the anterior cingulate cortex in the basal ganglia or insula, may have been indirectly influenced by M1 stimulation. This indicated that tDCS affects a complex pain-processing network, leading to higher pain thresholds and decreased pain intensity³². Taken together, these results suggest that an anterior stimulus may potentiate or suppress the subsequent stimulus. For instance, providing an anterior excitatory stimulus (tDCS anode) followed by an inhibitory stimulus (1 Hz rTMS) activates the inhibitory effect. This may explain the decrease in thermal pain thresholds into the group that received the anode stimulus²⁹. In other words, the plastic changes observed in the two clinical trials may be related to brain function, which can be altered by tDCS¹⁸, ²¹. Combining tDCS and rTMS can result in significant clinical benefits, and understanding the underlying mechanisms can aid in the optimization of treatment strategies³⁰.

Priming tDCS over exercises

Two studies examined the combination of tDCS with exercise. The authors²⁷ investigated the effects of anodic tDCS on experimentally induced muscle soreness prior to isometric manual pressure exercises²⁷. The Numerical Rating Scale (NRS), pressure pain threshold, and conditioned pain modulation were used as assessment tools in the study. The findings revealed an immediate decrease in NRS scores following the intervention, with greater significance observed in the anodic tDCS group compared to the sham group.

There were no significant differences between the groups in terms of pressure pain threshold or CPM. The authors proposed that while anodic tDCS during exercise accelerates the onset of hypoalgesia, this effect may be mediated by cortical and diencephalic regions rather than descending inhibitory pain pathways²⁷. The potential synergism between tDCS mechanisms and exercise, such as strength training, which promotes analgesia, could explain the analgesic effects³³, ³⁴, ³⁵. The effects of tDCS priming can increase corticomotor excitability and enhance the effects of subsequent techniques.

The second study found that combining anodic tDCS with aerobic exercise (AE) increased the pressure pain threshold, implying that anodic tDCS may have facilitated analgesic effects via a central pain control mechanism. The same findings were found in people with fibromyalgia³⁶, where the tDCS/AE combination had a significant analgesic effect. Because both tDCS³⁷, ³⁸ and AE³⁹ can activate central pain control mechanisms, using both at the same time may have resulted in a synergistic effect, resulting in greater analgesia²⁷.

However, when anodic tDCS was performed before exercise, there was no change in the pain threshold, contradicting the priming perspective, which would have anticipated a reverse effect favoring cortical inhibition. On the other hand, when tDCS was used at the same time as exercise, changes in the pressure pain threshold were seen. This demonstrates that exercise and tDCS work in tandem²⁸, and that the synergistic analgesic effects found may be mediated by mechanisms other than homeostatic metaplasticity.

Limitations and future perspectives

It is important to highlight some limitations of the present review. The lack of quantitative analysis, the heterogeneity of protocols and the small sample size of the included articles could somehow limit the study’s conclusion. The included studies mostly evaluated only male individuals, so future studies can be conducted with people of both genders. Thus, there is a need for larger controlled trials that perform assessment blinding, which could increase the power of results.

Furthermore, only one study includes a test and conditioned stimulus to evaluate the CPM test, a mechanism that allows researchers to measure the response of the descending pain inhibitory pathway. Second, different priming and testing protocols, as well as pain assessment methods, were used. Finally, the included studies differ significantly in terms of assessment methods and intervention protocols. These limitations underscore the important need for additional tDCS research to assess the efficacy of priming techniques for improving the descending pain inhibitory system.

CONCLUSION

In healthy people, using tDCS as a priming method can modulate descending inhibitory pathway activity, and raise pain threshold. The findings of this systematic review suggest that the priming phenomenon may enhance the descending pain inhibitory system in healthy people when cathodal tDCS is used before 1 Hz rTMS. However, no priming studies were found that attempted to improve the efficacy of tDCS. Priming and testing protocols must be carefully adjusted to ensure that the effects are accentuated rather than reversed, while also accounting for the shift in homeostatic metaplasticity.

• Sponsoring sources: This work was carried out with the support of CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (Coordination for the Improvement of Higher Education Personnel) - Funding Code 001.

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Edited by

Associate editor in charge: Kátia Nunes Sá https://orcid.org/0000-0002-0255-4379

Publication Dates

• Publication in this collection
  26 Aug 2024
• Date of issue
  2024

History

• Received
  05 Feb 2024
• Accepted
  28 May 2024