Hypertension is a global, chronic condition that affects ~25% of adults between 20 and 79 years (Zhou et al., 2021a). The prevalence of hypertension is divergent between developed and undeveloped countries. Approximately 350 million individuals experience hypertension in developed countries, and ~35% more cases are seen in undeveloped countries (Zhou et al., 2021a,b). Patients with hypertension also present with several comorbidities, including increased risk of stroke, neurovascular dysfunction, and cognitive impairments (Olsen et al., 2016; Zhou et al., 2021b).

Hypertension is typically treated with a regiment consisting of pharmacological and non-pharmacological interventions (Pescatello et al., 2019; Flack and Adekola, 2020). Aerobic exercise can reduce inflammatory processes and modulate heart rate variability (Masson et al., 2015; Besnier et al., 2017). Cardiovascular functioning can be managed through sympathovagal balance generated by physical exercise (Besnier et al., 2017), and the engagement of the sympathetic nervous system serves as a mechanism of action for alleviating hypertension (Hirooka, 2020). Several studies have investigated different means of treating hypertension with exercise by modulating the sympathetic nervous system. However, these studies have yet to present concrete recommendations for clinical use and application (Almeida et al., 2021). Interventions focused on cortical control of the autonomic nervous system have become crucial for improved understanding and management of blood pressure. Studies suggest that stimulation or inhibition of specific brain areas can decrease blood pressure and change autonomic responses in hypertensive patients (Rodrigues et al., 2021; Silva-Filho et al., 2021). Neuromodulation paired with aerobic exercise may acutely dampen hypertensive effects (Heinz et al., 2020; Silva-Filho et al., 2021).

Transcranial direct current stimulation (tDCS) is a safe and low-cost neuromodulation method that is used to interact with the central and autonomic nervous systems (Okano et al., 2015; Morya et al., 2019). tDCS is suggested to improve neuroplasticity in areas related to blood pressure control, such as the insular cortex, thalamus, and the medial prefrontal cortex (Okano et al., 2015; Farinatti et al., 2019; Silva-Filho et al., 2021). The insular cortex can be targeted with tDCS via electrodes placed over the temporal cortex (T3 area according to electroencephalogram 10/20). Okano et al. (2015) showed that anodal tDCS over the temporal cortex can modulate the autonomic nervous system in athletes by increasing parasympathetic activity. The temporal cortex is involved in the control of autonomic cardiac function and perceived exertion (Okano et al., 2015), making it an ideal target in investigating the association between tDCS and aerobic exercise to improve blood pressure in hypertensive individuals. It is important to highlight that tDCS was able to decrease sympathetic activity and increase the vagal modulation of hypertensive individuals, leading to a fall in peripheral vascular resistance and an adjustment in blood pressure and heart rate variability (Heinz et al., 2020; Rodrigues et al., 2021).

Although several successful pharmacological approaches have been adopted to control blood pressure, some critical intervention aspects must be considered when applying new types of treatment. Low-cost, safe, and effective non-pharmacological treatments targeting the central nervous system to control blood pressure are necessary to circumvent the use and dependence on pharmacological interventions. We hypothesize that the application of tDCS associated with aerobic exercise can decrease hypertensive metrics in patients affected by hypertension. Moreover, tDCS can be considered a non-pharmaceutical associated strategy with pharmacological approaches to manage hypertension. As the association between the targeted cortical area and effects on blood pressure are not well-understood, as well as the number of tDCS and aerobic exercise sessions required to reach a clinically meaningful effect on blood pressure, this study aimed to investigate the effects of anodal tDCS over the temporal cortex associated with moderate-intensity aerobic exercise on blood pressure and heart rate variability of hypertensive individuals.

A total of sixty-three participants were screened for eligibility. We excluded forty-three participants for not meeting the inclusion criteria. Twenty patients were randomized to each group (active or sham) and all of them completed all experimental procedures. All participants tolerated tDCS and aerobic exercise well. Socio-demographic and clinical data of both groups are summarized in Table 1. There were no differences between groups for all variables, except body mass index (p < 0.05).

The generalized mixed model showed no statistically significant interaction between groups on blood pressure after interventions during wake, sleep, over 24 and 3 h after the last intervention (Table 2). It is important to note that systolic and diastolic blood pressure individual responses, considering baseline and post-interventions, showed high variability (Figure 2). Heart rate variability variables showed no significant difference for time, groups and interaction analysis, except for HF (ms²) between groups (p < 0.05; Table 3).

In this study, we introduced a pioneering trial combining twelve sessions of tDCS with aerobic exercise to improve the blood pressure and heart rate variability in hypertensive individuals. Following the intervention, our analysis revealed no significant results in blood pressure and heart rate variability across the groups. Despite the initial appearance of these outcomes as discouraging, they hold significant importance in advancing research within this domain. As aerobic exercise has been considered a gold standard non-pharmacological treatment to decrease blood pressure in hypertensive individuals (Besnier et al., 2017; Pescatello et al., 2019), we hypothesize that the ceiling effect generated by 40-min physical exercise made tDCS hard to potentiate the results (Lopes et al., 2021).

The use of tDCS and aerobic exercise for modulating autonomic nervous activity was previously reported for young men (Farinatti et al., 2019), post-stroke (Heinz et al., 2020), athletes (Montenegro et al., 2011), and hypertensive participants (Rodrigues et al., 2021), however these studies consisted of single session interventions. Consequently, they only evaluated the immediate short-term effect of tDCS and aerobic exercise (Montenegro et al., 2011; Farinatti et al., 2019; Heinz et al., 2020; Rodrigues et al., 2021). Non-invasive brain stimulation strategies, such as repetitive transcranial magnetic stimulation and tDCS have been tested to modulate the brain-heart pathway in cardiovascular disease (Makovac et al., 2017). It has been suggested that non-invasive brain stimulation is an effective tool for controlling blood pressure and heart rate variability (Makovac et al., 2017). The stimulation dose, including cortical target, current intensity, and the number of sessions play a crucial role in cardiovascular responses (Makovac et al., 2017).

A few trials tested the vagal stimulation effects on outcomes such as sleep (Jackowska et al., 2022), chronic pain (Muthulingam et al., 2021), and inflammatory response after surgery (Salama et al., 2020). Also, there is an ongoing trial, phase two, using transcutaneous vagal stimulation on adult patients with uncontrolled high blood pressure (Gupta, 2022). Although a few clinical trials analyzed the efficacy of vagal stimulation, the mechanism behind it is poorly understood. It is suggested that the effects of vagal stimulation in the heart involve the preganglionic nerve stimuli to activate synapses on parasympathetic ganglia in the epicardium and cardiac septum. The activation of parasympathetic ganglionic neurons is essential due to their postganglionic axon projections to the cardiac atrium, ventriculus, and all the structures in these regions, such as sinoatrial and atrioventricular nodes (Capilupi et al., 2020). So, theoretically, parasympathetic regulation through vagal and correlated areas of stimuli holds substantial significance in blood pressure control.

Different central and peripheral mechanisms have been described as important components to control blood pressure (Cogiamanian et al., 2010). One of the mechanisms involves heart rate variability analysis, which represents the autonomic function. Considering the up-down regulation, sympathetic and parasympathetic activity modulation by the insular cortex through projections over the solitary tract nucleus, ventrolateral rostral medulla, and periventricular/periaqueductal gray areas is a potential pathway involving in the cardiovascular adjustment (Cogiamanian et al., 2010). Based on these mechanisms, it is expected that non-invasive brain stimulation techniques, such as tDCS, interfere with cardiac parameters and decrease the blood pressure of hypertensive individuals.

A significant decrease in the high frequency (ms²) for the active tDCS associated with aerobic exercise was detected. However, there was a difference between the groups before the intervention. Previous studies with one session of aerobic exercise preceded by tDCS, applied over medial prefrontal cortex, induced postexercise hypotension in normotensive men (Farinatti et al., 2019). The authors found a significant decrease in systolic blood pressure and mean arterial pressure during 60-min of post-exercise recovery (Farinatti et al., 2019). Another study with hypertensive patients showed a positive acute adjustment in autonomic cardiac control and reduction in 24 h of blood pressure measurements after a single session of tDCS (C3/FP2 montage) (Rodrigues et al., 2021).

It is important to mention that the association between tDCS and aerobic exercise showed effects on controlling blood pressure and heart rate variability in young men (Farinatti et al., 2019). Nonetheless, some authors demonstrated that tDCS was not able to potentiate the aerobic exercise effects over systolic blood pressure and heart rate variability of hemiparetic patients (Heinz et al., 2020). These studies showed diverged results, possibly due to differing dosing parameters and stimulation target locations, the medial prefrontal (Farinatti et al., 2019), and the left temporal cortex (Heinz et al., 2020). Thus far, there is no standard stimulation target location to effectively engage the central nervous system to alter blood pressure and heart rate variability response.

Okano et al. (2015) previously showed the effect of tDCS over the T3 on the autonomic nervous system, rating of perceived exertion, and performance during a maximal dynamic exercise in trained cyclists. The authors suggest that brain stimulation over the temporal cortex during exercise modulates autonomic nervous system activity, sensory perception of effort, and exercise performance (Okano et al., 2015). They also demonstrated that stimulation targeting the left insular cortex increased parasympathetic modulation (Okano et al., 2015). These cortical stimulation targets are associated with better control of heart rate variability; however, little is known about the stimulation effect of the temporal and insular cortex on blood pressure (Okano et al., 2015; Silva-Filho et al., 2021). In a study with athletes and non-athletes, anodal tDCS applied over the temporal cortex significantly increased parasympathetic activity and decreased sympathetic activity in endurance-trained athletes, but no changes were observed for non-athletes (Montenegro et al., 2011). Thus, some parameters, including the aerobic exercise intensity, individual aerobic capacity, the target of stimulation, and the number of sessions, could help explain the results.

Innovation in the research field is challenging. Although there is a gap in the literature and a theory that supports the use of tDCS in hypertensive people, the human body and the technique parameters are complex. This is the first trial that mirrors clinical practice using tDCS associated with one of the non-pharmacological gold standard treatments for people affected by hypertension. We believe that several parameters must be adjusted in an attempt to reach the best results. Therefore, considering these assumptions, we can learn from null outcomes to improve the upcoming trials.

Some limitations of the present study must be acknowledged. We recognize that our modest sample size could not differentiate all effects of tDCS associated with moderate aerobic exercise on blood pressure and heart rate variability, increasing the risk of bias due to individual variability. Also, for all outcomes the results are powerless, so we cannot perform inferences. Long-term effects of hypertension can affect blood pressure outcomes, making reduction in such measures more difficult for chronic sufferers. The patient's time of diagnosis and treatment were not explicitly acquired throughout our trial. The eligibility criteria, randomization, and analysis did not consider the antihypertensive drug intake. However, future trials should account for these factors. It is imperative to underscore the absence of published studies providing a definitive basis for determining the sample size due to the divergence in methodologies presented. This deficit in prior information poses challenges in the accurate calculation of the sample size.

Aerobic exercise associated with anodal tDCS over the temporal cortex did not reduce blood pressure during wake, sleep, over 24 h, and 3 h after the last session. Also, no effects were found for heart rate variability between active and sham groups, except for high frequency. This study explored the targeting of tDCS associated with aerobic exercise for understanding the application of integrative therapies using non-invasive brain stimulation in hypertension.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Instituto de Educação Superior da Paraíba—IESP. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

ES-F, MS, and AC: conceptualization. ES-F and MS: methodology. ES-F: investigation. All authors: writing—original draft and writing—review and editing. RP and MS: supervision. All authors contributed to the article and approved the submitted version.