In this systematic review, we evaluated 37 studies (981 subjects) addressing the effects of NIBS techniques on several risk factors. We found that: (1) cortisol levels decrease or remain unchanged after NIBS; (2) NIBS effects on HRV and blood pressure presented mixed findings, with studies suggesting that HRV values can decrease or remain unchanged after NIBS (one study found that rTMS increased blood pressure levels); (3) a single study showed that glucose levels decrease after tDCS; (4) most studies found that NIBS can effectively decrease craving for alcohol, smoking, and food intake. We further discuss these findings.
First, some limitations should be underscored. Although the studies generally presented adequate methodology in terms of design and assessment, most of them explored the effects of NIBS after one single session. In addition, most studies were exploratory, without a clearly defined hypothesis. Therefore, the evidence here presented should be considered preliminary and hypothesis-driven for further studies.
The effects of NIBS on the HPA axis and cardiovascular mechanisms are likely to occur via a top-down modulation, i.e., changes in cortical activity that subsequently modify the activity of centers related to hormonal and cardiovascular regulation that are situated in subcortical areas and in the brain stem. Of note, NIBS effects on these systems occurred mostly in the context of stress response – e.g., negative image visualization (Brunoni et al., 2012b
) and 16
h fasting (Binkofski et al., 2011
) or in clinical samples, such as depression (Baeken et al., 2009a
), bulimia (Claudino et al., 2010
), and anxiety (Baeken et al., 2011
). Likewise, such effects occurred primarily during neuromodulation of DLPFC, an area implicated in the pathophysiology of stress and affective disorders (Koenigs and Grafman, 2009
). This suggests that NIBS effects might not act on these systems during their steady state; but rather when they are being activated – for instance, during a stress response. Further studies should investigate in which conditions blood pressure and cortisol expression can be modulated by NIBS; and also which brain areas should be targeted. In this context, using computer simulated models and/or neuroimaging studies to identify which brain areas are activated during brain stimulation might help to identify cortical areas that could be targeted in order to indirectly modulate the subcortical and brain stem areas related to cardiovascular control. Another option is to investigate the use of novel NIBS techniques, such as “deep rTMS” (Levkovitz et al., 2007
) and “high-definition” tDCS (Minhas et al., 2010
) that can theoretically target deeper brain areas and/or induce more focalized stimuli as to directly modulate those areas.
Most reviewed studies showed that NIBS effectively regulated craving and consumption for food, alcohol, and cigarette smoking. This is in agreement with the putative role of the prefrontal cortex as a brain region related to decision-making, either of non-emotional (“cold cognition”) and emotional (“hot cognition”) content (Koenigs and Grafman, 2009
), the latter including also the inhibitory control of appetitive impulses. This brain area is also connected with subcortical areas related to the “reward system,” which includes the ventral tegmental area and nucleus accumbens (Fecteau et al., 2010
). Modulation of food, alcohol, and cigarette intake could be a crucial contribution of NIBS for the cardiovascular field, since most risk factors are directly associated with poor dietary and lifestyle choices. However, since most studies evaluated the acute effects of tDCS, further investigation should focus on the long-term effects of tDCS in regulating craving.
Finally, Binkofski et al. (2011
) observed increased systemic glucose turnover with active tDCS. This is a proxy for insulin resistance that is impaired in diabetes mellitus. The authors suggested that their findings could be explained by the activation of ATP-dependent potassium channels (KATP) by tDCS in the hypothalamus, which would inhibit hepatic gluconeogenesis. Further studies could evaluate whether tDCS modifies other mechanisms of insulin metabolism in healthy and clinical samples.
Implications for MDD treatment
The activation of the HPA axis is an important link between MDD and cardiovascular illness (Maes et al., 2011
). Hypercortisolism leads to a dysregulation of glucose, lipid metabolism, and blood pressure, which contributes to the metabolic syndrome. Moreover, hypercortisolism has unfavorable effects on the immune system. In our review, we observed that some NIBS studies decreased cortisol levels, suggesting that these techniques might induce modulatory top-down effects that lead to a down-regulation of the HPA axis. Further research should explore whether such effects persist over time – for instance, evaluating other cortisol measures, such as cortisol awakening response and cortisol daily curve.
Major depressive disorder is also related to an autonomic shift toward sympathetic predominance, which also increases inflammatory response in the endothelium and platelet activation, hastening the formation of atherosclerotic plaques (Lett et al., 2004
). This sympathetic tone shift boosts sympatho-adrenal response, increasing catecholamines secretion in adrenal medulla, leading to a hypercortisolemic and hypercatecholaminergic state, contributing to this physiopathological mechanism. Our results showed that HRV is either non-affected or increased after NIBS (Evers et al., 2001
). A possible mechanism of action for NIBS is also top-down modulation, through activity increasing in cortical regions and down-regulation of the sympatho-adrenomedullary system, leading to a decrease in sympathetic activity.
Other brain stimulation techniques
Although NIBS seems to down-regulate stress response, this might not necessarily be true to other forms of brain stimulation. For instance, electroconvulsive therapy (ECT) has a characteristic biphasic response, i.e., a parasympathetic phase that lasts for approximately 20
s followed by a sympathetic phase of approximately 1
min (Geersing et al., 2011
). In addition, repetitive trans-spinal magnetic stimulation, i.e., a TMS coil applied over the sixth and seventh cervical vertebrae, showed no difference between sham and active groups on measures of HRV (Paxton et al., 2011
). However, deep brain stimulation seems to have favorable effects over the autonomic nervous system in patients with Parkinson’s disease, in contrast to levodopa that has unfavorable effects (Ludwig et al., 2007
Another potentially interesting therapy is vagus nerve stimulation (VNS). Recently, a HRV meta-analysis of epilepsy and epilepsy treatment suggested that could have favorable effects on sympathovagal balance, presumably through direct stimulation of the vagus nerve (Lotufo et al., 2012
). Further, it also seems to be a safe therapy from a cardiovascular perspective, according to a recent long-term follow-up in depressed patients (Bajbouj et al., 2010