Neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT), now enable the study of specific cerebral regions involved in the brain-heart connection in humans in response to experimentally induced acute stress, including structures involved in the CAN. These responses can be investigated by correlating measures of regional cerebral blood flow (rCBF) or blood oxygen level-dependent (BOLD) signals in the brain with cardiovascular measures such as heart rate, blood pressure, or HRV. We performed a systematic review of the literature to reveal brain areas that are associated with HRV during mental stress-inducing tasks. This systematic literature review was conducted in accordance with the PRISMA guidelines [20
], which are in line with other review strategies such as the Cochrane criteria [21
]. Research articles reporting on studies examining HRV and functional brain imaging during mental stress-inducing tasks were included in this review. Inclusion criteria for studies were: 1) original research articles (i.e. abstracts, posters, review articles, and methodological papers were excluded); 2) published in a peer-reviewed journal; and 3) abstract available in English (no other language constraints). Papers were excluded if: 1) the study was based on a clinical or otherwise selected sample; 2) performance of a mental challenge task was not part of the study; 3) there was no simultaneous determination of HRV and functional brain imaging measures; and 4) no correlational analyses were reported between HRV indices and measures of functional brain imaging. No other restrictions were applied regarding study designs.
Articles published between 1 January 1990 and 15 September 2012 (the date when the literature search was completed) were searched using the Medline database (PubMed). The following a priori determined search terms were used: ((“heart rate variability”) OR (“heart period variability”)) AND (brain) AND ((functional imaging) OR (fMRI) OR (PET) OR (SPECT)). The search was limited to studies involving human participants. A total of 55 articles were found during this first selection. Titles and abstracts were screened first and potentially eligible articles were examined in full text. Of the initial selection of 55 papers, seven were excluded because they were review papers or methodological papers, 25 because they were based on clinical or otherwise selected samples, 15 because they did not include a mental challenge task, and five because they did not measure HRV indices and functional brain imaging simultaneously or they did not report correlational analyses between HRV indices and measures of functional brain imaging. The reference lists of selected journal articles were inspected for additional published articles that fulfilled the inclusion criteria. This reference list search did not yield any additional studies. Therefore, three papers were included in the final selection covering data on 121 participants. Data included in the article and any supplementary materials were extracted for patient characteristics, methods, and results. Table shows a summary of the stress protocol, the imaging methodology, the HRV indices and the results of the studies that met the criteria for this review.
Overview of the methods and results of studies included in the systematic review of research on stress-induced brain responses and autonomic nervous system activity
These studies revealed several brain areas involved in the association between the psychological stress response and autonomic nervous system modulation. The three areas that consistently correlated with HRV in all three studies were: 1) the insula, 2) the medial prefrontal cortex, and 3) the cerebellum. The insula, which is part of the CAN, functions as the primary viscerosensory cortex and as a higher-order somatosensory cortex. This paralimbic region has afferent and efferent connections with many other CAN areas and can thereby affect cardiovascular function [18
]. The (ventro)medial prefrontal cortex is part of the CAN and is involved in high-level emotional and cognitive functions. This paralimbic region integrates exteroceptive and viscerosomatic information, via connections with the amygdala and other CAN regions [18
]. The cerebellum is not part of the CAN, but may be involved in stress-induced autonomic activation by 1) modulation related to motor activity and balance and 2) inter-connections with CAN structures such as the hypothalamus [22
]. In addition to the insula, medial prefrontal cortex, and cerebellum, two of the selected studies documented involvement of the (anterior) cingulate cortex, parietal cortex, somatomotor cortex/precentral gyrus, and temporal cortex.
These results are in agreement with other studies investigating HRV and functional brain imaging responses to various tasks that did not meet the criteria for this systematic review. For example, Matthews and colleagues correlated HRV and fMRI BOLD signal changes, which were measured during two separate task sessions. A positive correlation was found between peak HF-HRV and fMRI BOLD signal in the left ventral anterior cingulate cortex during a counting Stroop task [23
]. No correlational analyses were reported for other brain areas. Napadow and colleagues used novel methodologies to study continuous HRV and cardiac-gated fMRI BOLD signals during a physical perturbation task (dynamic handgrip exercise). Changes in HF-HRV were positively related to fMRI BOLD signal in the right dorsomedial and dorsolateral prefrontal cortex, left amygdala, left hypothalamus and right anterior hippocampus, and negative associations were found between changes in HF-HRV and the left posterior insula, right cerebellum, right mediodorsal thalamus, right parabrachial nucleus/locus ceruleus, left periaqueductal grey, right posterior hippocampus, left caudate nucleus, right septal nucleus, and right medial temporal gyrus [22
]. Moreover, Lane and colleagues reported that during emotion induction tasks, HF-HRV correlates with emotion-specific rCBF in the left insula, the medial prefrontal cortex, caudate nucleus, and midbrain (including periaqueductal grey) [24
The findings of the present systematic review and other studies on HRV and functional brain imaging are consistent with research on the brain areas implicated in stressor-evoked blood pressure reactivity [25
]. Those studies indicated that the insula, cingulate cortex, and amygdala are the core components implicated in the blood pressure responses to stress. Blood pressure responses were also related to altered rCBF or BOLD signal changes in the medial, lateral, and dorsal prefrontal cortices, the parietal cortex, occipital cortex, somatosensory cortex, cuneus, lentiform area, caudate, thalamus, and cerebellum [25
]. Interpretation and generalisation of the results of the present systematic review and other summary articles in this area are complicated by methodological differences, the potential of statistical type I error related to the analysis of multiple brain structures, and the relatively small number of studies that simultaneously assessed cardiovascular measures and brain responses to psychological distress.