Heart Rate Variability and Cognitive Function: A Systematic Review

1Cognitive functions are mental abilities that allow the correct interpretation and management of environmental information. These skills are distributed along a continuum that involves optimal cognitive functioning at one extreme and dementia at the other. Proper cognitive functioning is essential to perform both the simplest tasks of everyday life and the most complex activities. Many factors can contribute to the physiological decline of cognitive functions in general, or of a specific domain, linked to the aging process.

2Sometimes, the cognitive changes associated with aging became clinically significant and severe enough to compromise social and daily life functioning. The challenge of modern science, given the current sociodemographic conditions (i.e., population aging), is precisely to understand the reasons for this pathological decline, as well as to try to identify the early markers of cognitive impairment.

3Cognitive functioning worsens under conditions of autonomic and cardiovascular dysfunctions. Within this perspective, a promising physiological correlate of cognitive functioning is heart rate variability (HRV) that is considered an index of autonomic control of the heart. HRV reflects the oscillations in the interval (ms) between consecutive heartbeats (R-R intervals) that result mainly from the dynamic interaction between the parasympathetic and the sympathetic inputs to the heart through the sinoatrial node.

4Heart rate variability analysis can be conducted in the time domain, frequency domain, and by using non-linear analyses. In the time-domain, it is possible to calculate: (a) the standard deviation of all R–R intervals (SDNN) that reveals the components responsible for variability in the recording period; and (b) the root mean square of successive standard deviation (RMSSD) and the percentage of consecutive regular sinus RR intervals over 50 ms (pNN50) that should reflect vagal tone.

5In the frequency domain, the oscillatory components are usually differentiated into different spectral profiles. Ultra-low frequencies (ULF; <0.0033 Hz) can only be evaluated using 24-h recordings, and reflect circadian oscillations, body temperature, metabolism, and activity of the renin-angiotensin system. Very-low frequencies (VLF; 0.0033–0.04 Hz) represent long-term regulation mechanisms, thermoregulation, and hormonal mechanisms. The low frequencies (LF; 0.04–0.15 Hz) reflect a mix between the sympathetic and vagal influences and are considered a marker of cardiac outflow influenced by both sympathetic and parasympathetic branches of the autonomic nervous system (ANS). Initially, it was assumed that only sympathetic outflow contributes to the LF-HRV. However, this view is not without controversial opinions. In particular, some authors suggest that LF-HRV primarily reflects parasympathetic influence, and it is potentially affected by other cardiac mechanisms such as baroreflex sensitivity (e.g., ). High frequencies (HF; 0.15–0.40 Hz) reflect vagal tone and can be taken as an index of cardiac parasympathetic tone. Finally, the LF/HF-HRV ratio has long been considered as an index of sympathovagal balance. However, this viewpoint has been strongly criticized (e.g., ), because the physiological bases are not clear. For these reasons, this index, although widely used, would have a low predictive value.

6The cardiac vagal tone has frequently been linked to cognitive and emotional control (e.g.,;; ). Within the HRV spectrum, the high-frequency band corresponds to parasympathetic cardiac activity. Parasympathetic influences are essential for the successful adaptation of the individual to changing environmental demands. A reduction in vagal control (i.e., decreased HF-HRV) could indicate a lack of ability to respond flexibly to changing demands, reducing the range of possible options and thus limiting the individuals’ ability to generate appropriate responses and inhibit inappropriate ones.

7According to the Neurovisceral Integration Model, there is an association between cardiac vagal tone and the functioning of attentional and emotional self-regulatory systems. The neurovisceral integration hypothesis has suggested that the brain areas involved in self-regulation are also involved in cardiac autonomic activity through the vagus nerve. These areas include the anterior, insular, and orbitofrontal cortices; amygdala; periaqueductal gray matter; ventral striatum; and autonomic motor nuclei of the brainstem.

8Further studies have confirmed the existence of an association between higher resting HRV and active inhibitory prefrontal-subcortical circuits. In particular, higher resting-state HRV appears to be related to increased activity in executive brain regions, while lower resting HRV seems to be related to hypoactive prefrontal regulation. Consequently, a vagal control of the heart appear to be associated with the effective functioning of self-regulatory neural circuits, which permit the organism to respond quickly and flexibly to environmental demands.

9This hypothesis was formulated for the first-time considering emotion regulation and dysregulation. According to this view, affective regulation requires selective attention to emotionally relevant stimuli and the inhibition of attention to irrelevant stimuli. Therefore, from a neurovisceral perspective, attentional and emotional regulations run together in the process of self-regulation and goal-directed behaviors. This extension of the neurovisceral hypothesis to other cognitive domains can allow improving the understanding of the relationship between the ANS and cognitive functioning.

10The general aims of this systematic review of the literature are: (a) to analyze the relationship between autonomic regulation and cognitive processes in the absence of affective dimensions and pathological aspects; (b) according to the hypothesis of the neurovisceral integration model, to understand the relationship between executive functioning and HRV; (c) to investigate the relationships between HRV and other cognitive domains (i.e., processing speed, attention, memory, language, visuospatial skills), to highlight whether HRV can be considered an index of general cognitive functioning; (d) to evaluate whether HRV can be considered as a predictor of cognitive performance.

11The review process was conducted according to the PRISMA-Statement.

12A systematic analysis of the international literature was carried out by selecting articles published in peer-review journals, using PubMed, PsycINFO, PsycARTICLES, and MEDLINE databases. The last research was conducted on June 10, 2018. Restrictions were made, limiting the study to academic publications in which the full text was published in English, and the study included human populations without age, gender, or ethnicity restrictions. The search strategy used the following syntax: “(cognit* or neuropsych*) and (HRV or heart rate variability or vagal tone or vagal activity).”

13From the list of potential articles produced by systematic research, we selected the studies that included one or more cognitive measures and the measurement of HRV. Studies that included participants with medical conditions, which could potentially influence this relationship and those that included participants with a diagnosis of dementia, psychiatric disorders, strokes, and traumatic brain injury were excluded.

14The first exclusion of non-inherent studies was made by analyzing titles and abstracts of the articles. Subsequently, the reading of the full text allowed further selection. Two researchers made the selection independently; inconsistent decisions between them were resolved by consulting a supervisor.

15According to the PICOS approach, the following information has been extracted from each selected study: (1) author(s) and year of publication (2) characteristics of participants (including age, years of education, gender); (3) type of HRV measures (including measurement in the time or frequency domain); (4) cognitive domain analyzed (global, executive functions, processing speed, language, memory, attention, visuospatial skills); (5) nature and direction of the identified relationship. These data are summarized in Table 1. Only HRV resting measurements have been considered because the heterogeneity of cognitive tasks could influence recovery measures hindering finest comparisons between the variables.

16The neuropsychological tests used in the selected studies were associated, as defined by the authors, with some cognitive a priori domains (global functioning, attention, executive functions, memory, visuospatial skills, language, and processing speed). Performance in the various domains was analyzed, considering a single test or a composite score based on the measures of multiple neuropsychological tests (see Table 2).

17The flowchart shows the number of studies identified from the databases and examined by the authors, the number of articles, assessed for eligibility, and included in the review; the reasons for possible exclusions are also reported (Figure 1). The final analysis included 20 studies.

18The 20 studies that met the inclusion criteria were conducted from 2001 to 2018 and involved 19,431 people. Participants were aged between 18.4 and 76.0 years. The percentage of men in the studies ranged from 0 to 72%. Three studies did not report information about the participants’ gender. Only one study presented a gender comparison. Almost all of the researchers carried out a cross-sectional analysis, and only one study performed a longitudinal evaluation.

19Many studies carried out statistical analysis controlling some confounding variables, such as demographics (age, gender, years of education, ethnicity), clinical (body mass index; blood pressure; heart rate; cardiovascular diseases, cholesterol, diabetes), and behavioral (smoking, exercise, alcohol consumption) variables.

20Except for one study, HRV measurement was conducted by a continuous ECG recording, which lasted at least 5 min, as recommended by the guidelines of the European society of cardiology and the North American society.

21Heart rate variability was evaluated considering time-domain analyses, frequency-domain analyses, or both.

22The HF-HRV analysis was the most frequently reported. The LF/HF HRV ratio, the LF-HRV band, the mid-frequency (MF) HRV band, the standard deviation of mean RR interval (SDNN) and the square root of the mean squared differences of successive RR intervals (RMSSD) were also evaluated.

23All the cognitive domains were examined; global cognitive functioning (eight studies), memory (eight studies), language (two studies), attention (five studies), executive functions (thirteen studies), visuospatial skills (two studies), and processing speed (one study) (for references, see Table 1).

24An association between HRV and global cognitive performance was reported. Only fail to find this relationship. Specifically, a low HRV was related to poorer performance also after the adjustment of data for demographic, clinical and behavioral confounding variables.

25One study emphasized the role of the respiration rate, highlighting that poor reasoners had higher levels of sympathetic activity and respiratory rate than good reasoners.

26Three studies found a relationship between HRV and memory functionality, also after controlling demographic and clinical variables.

27People with higher HRV levels demonstrate a better ability to control over memory and a better ability to suppress unwanted memories. Lower HRV is independently associated with a worse performance both in short and long-term verbal memory.

28However, some studies did not find a relationship between verbal or visuospatial memory and HRV.

29reported that reduced HRV is associated with lower linguistic performance, also after the adjustment of data for demographic, clinical and behavioral confounding variables. Conversely, did not find any relationship between HRV and linguistic performance.

30Four studies found that individual differences in resting HRV predicted attentional performance. Lower HRV was associated with worse performance, also after the adjustment of the data for confounding variables. However, these results were not confirmed by, who did not find any relationship between HRV and attention.

31The executive domain was the most investigated. The studies demonstrated an association between lower HRV and poor executive performance; however, two studies did not confirm these findings.

32Lower HRV predicted poorer performance on tasks involving executive functioning independently from demographic, clinical and behavioral confounding variables.

33Considering visuospatial abilities, only observed a relationship with HRV. Lower HRV was associated with poor visuospatial performance, also after the adjustment of the data for demographic, clinical and behavioral confounding variables.

34The only study that investigated processing speed showed that people with lower HRV had worse performance and experienced a higher decline in processing speed, independently from demographic and clinical characteristics.

35The role of ANS on emotional regulation is well-known, whereas its links with cognitive functions are less well defined. Some studies concerning the general arousal, the attentional orienting, the alerting, and the regulation of actions have reported specific autonomic changes that were concurrent with cognitive functioning.

36The first studies that have tried to identify a specific relationship between vagal tone and cognitive functions have highlighted changes in HRV depending on the type or complexity of the task. Based on these findings, some theories have been developed to explain the relationship between HRV and cognitive functioning. Among these, there is the Polyvagal Theory of, which highlights the importance of the vagus nerve for cognitive functions and in particular for the attentional processes. More recently, developed the Neurovisceral Integration Model, which hypothesized a cortical integration between the executive, autonomic, and emotional functionality. The ANS is controlled by cortical circuits located in the prefrontal cortex, the anterior cingulate gyrus, the orbitofrontal cortex, and the amygdala, which are also crucial for cognitive and emotional processes. The authors hypothesized that a sympathetic hyperactivation, with consequent prefrontal hypoactivation, would facilitate the disinhibition of the amygdala, i.e., an adaptive response; the amygdala would promote a decrease in HRV and an increase in heart rate. This hypervigilant reaction would be related to reduced cognitive flexibility and vice versa; under parasympathetic activity conditions, the lack of prefrontal hypoactivation would be expressed through an increase in HRV with improved cognitive functions.

37One of the aims of this review was to analyze the neurovisceral integration hypothesis considering the performance that involved executive components in the absence of affective dimensions and pathological aspects.

38A close examination of the selected studies confirms the relationships between resting HF-HRV and cognitive functioning, supporting the neurovisceral hypothesis in the absence of affective dimensions. The early results of suggested a connection between resting HF-HRV, processing speed, and the accuracy of responses to monitoring tasks, with a stronger association when working memory was required; participants with high HF-HRV performed better than participants with low HF-HRV. The same set of tests was administered in a subsequent study, and the results were replicated. These results were also confirmed during a condition of a threat of shock.

39Subsequently, numerous studies have analyzed the association between executive functions and HRV, considering both time and frequency domains, and in some cases with a large sample. A relationship with HRV was confirmed considering different executive functions. Moreover, participants with high resting-state HRV (indexed by RMSSD), as compared to participants with low resting-state HRV, demonstrated better action cascading, underlining that high resting HRV is associated with the optimal functioning of the prefrontal-subcortical inhibitory circuits that sustain flexible and adaptive responses to environmental demands.

40Another aim of this review was to analyze the relationship between HRV and different cognitive domains. Many studies have found that reduced HRV in both time domain (RMSSD, SDNN) and frequency domain (HF, LF, LF/HF) were associated with weaker cognitive performance in both global cognition and specific cognitive domains.

41Interestingly, the various HRV indices appear related to cognitive domains differently.

42Lower LF-HRV, which is influenced by both sympathetic and parasympathetic branches of ANS, was linked to worse cognitive performance, in particular considering memory, language and global cognitive scores. reported that high MF (Mid-Frequency band: 0.06–0.14 Hz), regulated by both the sympathetic and parasympathetic branches of the ANS, was associated with better performance in spatial tasks and to poorer verbal reasoning ability, while high HF-HRV was associated with better verbal reasoning ability. On the other hand, lower HF-HRV, which reflects vagal modulation, appears to be associated with weaker performance in global cognitive functions, such as those measured by the Mini-Mental State Examination, verbal reasoning abilities, inhibition of memory responses, or executive functions. These results can be due to the lateralisation of autonomic functions. In particular, sympathetic activation is related to visual and motor cortices, while parasympathetic activation is linked to the activity of prefrontal areas.

43Moreover, some studies reported a link between low HF-HRV and the risk of developing cognitive impairment. According to this hypothesis, low LF-HRV has been associated with white matter lesions in patients with Mild Cognitive Impairments and Alzheimer’s Disease. These results linked to others that identified a change in the LF/HF ratio based on the type and difficulty of the task, reinforce the idea that the various parameters of HRV are associated with different cognitive functions.

44The results under the umbrella of the memory domain are particularly fascinating. Although a general relationship between HRV and verbal memory was found, visual memory seems not to be associated with HRV. This finding can be explained by considering that many brain regions involved in visual functions, including parietal, temporal, and occipital lobes, all lie outside of the central autonomic network. Therefore, HRV may correlate with verbal, but not visual, memory performance because verbal memory more specifically involves the central autonomic network.

45In general, it is evident that executive functions, as well as global cognitive functioning, are the most investigated dimensions about HRV. The other cognitive domains (attention, processing speed, visuospatial skills, memory, and language) were the object of investigations that appear to be characterized by many methodological limits from both a quantitative and a qualitative point of view. A critical aspect of the studies measuring HRV is given by the numerous confounding variables. The results are particularly relevant when confounding variables are controlled; in some cases, the relationship became stronger, while in others, the adjustment for the confounding variables modifies the terms of the relationship. This pattern of results appears to indicate that other variables mediate the relationship between HRV and cognitive functions. HRV changes according to many factors, such as gender, BMI, anxiety, stress, heart rate, and smoking habits, and so became important controlling these variables. Consequently, the analyses of their specific influence in mediating HRV effects on cognitive functioning are compelling. It is interesting to note that, in contrast to the other domains, the executive domain was significantly associated with HRV, above and beyond significant confounding variables (i.e., cardiovascular risk, age, and gender). This association is not surprising and reinforces the idea that HRV is strongly associated with the neuronal activity of the prefrontal cortex, which in turn regulates the executive functions.

46In contrast to results of other studies, did not show any correlation between HRV parameters and cognitive functioning, even if they considered a large cohort of people with characteristics similar to those of other studies. These inconsistent results could be due to the high variability of the data, which is attributable to some methodological procedures; for example, the participants were selected in different phases of one longitudinal study and this procedure can have implied effects due to both the survival and the selection of the sample. Another explanation could be the high percentage of males present in the sample (72%). Several studies show that men, compared to women, had a higher RR interval, a higher LF-HRV, and a lower HF-HRV. Finally, the tests used in this study (Whitehall II cognitive test battery) did not assess executive functions in detail.

47Another aim of this study was to evaluate the predictive value of HRV for cognitive performance. The analyzed studies found that a higher HRV, both in time and frequency domains, were associated with finest cognitive performance, even after adjustment for the confounding variables commonly associated with HRV (i.e., age, gender, years of education, body mass index, blood pressure, cardiovascular diseases). Therefore, even if caution must be employed in defining the HRV as a predictor of performance in several cognitive domains, the results obtained from this review seem promising in that sense. However, more longitudinal studies and further research on poorly considered cognitive domains are needed to allow reliable inferences in this regard.

48This systematic review of the literature aimed to carry out an analysis of the scientific studies concerning the link between the activity of the autonomic system and cognitive functioning.

49Although we have tried to control the research methodology as much as possible, this study presents some limitations that could undermine the generalizability of the results. One weakness is given by the heterogeneity of the population and measures; this heterogeneity does not allow performing a quantitative analysis (i.e., meta-analysis) that would have given greater force to the conclusions.

50Another limitation could be indirectly linked to the publication bias. The choice to include only academic articles published in peer-review journals may have limited the selection of only those studies that have obtained results in line with the literature. As a consequence, the results may overestimate this relationship. Moreover, the choice to select only studies published in English could have led to the elimination of studies conducted on other populations and written in different languages, further limiting the generalizability of the results. Moreover, the marked interest in a specific domain, i.e., the executive functions, and the relatively small number of studies in this topic does not allow to a conclusion concerning the involvement of the other cognitive domains. Finally, another limitation is represented by the overwhelming presence of cross-sectional studies that do not enable to few causal inferences on the relationship between HRV and cognitive functioning to be made.

51To overcome these limitations, in future psychophysiological studies it will be useful to utilize the emerging guidelines for reporting HRV parameters (e.g., ), which can improve the quality of data, allow to more transparent reporting, and lead to more analysable data in quantitative analysis (e.g., meta-analysis).

52Further research should aim to increase the studies on the relationship between HRV and some cognitive domains, such as attention, language, processing speed, and visuospatial skills., that are disregarded by the studies until now. Likely these cognitive domains have been neglected because they are never associated with an early cognitive impairment.

53Of particular note is the attentional domain because it has been evaluated with tests that do not allow a complete assessment of this multidimensional construct.

54Other essential aspects to consider in future studies are the vagal reactivity and the recovery processes that have been linked to cognitive performance. Vagal reactivity represents the change between baseline and a specific event, like completing a task, and it is essential recording it to evaluate the individual’s adaptability to the situation. Recovery is usually seen as a process of restoration; it refers to the change between the event and a time point after the event when the vagal activity has to be similar to the baseline. Comparable to vagal reactivity, vagal recovery plays a crucial role in the adaptability of the organism. These two aspects are poorly analyzed with cognitive functioning. However, according to the vagal tank theory, considering the vagal activity and the vagal recovery during different cognitive tasks could be interesting. This type of study could allow us understanding better how cardiac vagal control influences several key self-regulatory aspects of behavior and also evaluating whether the differences between baseline, task execution, and recovery are related to cognitive impairment.

55In this review, we focused on the analysis of the autonomic baseline that allows us to make inferences about the predictive value of autonomic homeostasis on cognitive impairment. Despite providing very relevant information, this analysis does not adequately enable the understanding of the mechanisms involved. Some studies that have analyzed HRV changes during the performance of cognitive tasks have shown that autonomic functionality varies according to the complexity and type of the task.

56Although this review has highlighted how some cognitive domains are more heavily investigated than others, in general, higher resting HRV is related to better performance in cognitive tasks. In contrast, lower resting HRV is associated with a lack of prefrontal control of the subcortical activity, which results in poor functioning of self-regulatory systems. In summary, a higher HF-HRV has been linked to better cognitive performance, and a lower HF-HRV has been associated with cognitive impairment.

57In conclusion, this review highlights that the autonomous nervous system and the neurocognitive systems operate in close interaction. The results suggest that autonomic markers (LF, HF, LF/HF, SDNN) can be considered as early biomarkers for the measurement of cognitive impairment in populations without dementia or stroke. An initial analysis of these biomarkers could allow the implementation of preventative measures of autonomic control to prevent the worsening of cognitive decline.

58MC and GF were responsible for the conception of the review, the literature research, and writing the manuscript. FF supervised the selection of the studies and contributed to the revision of the manuscript. All authors revised, read, and approved the submitted version.

59The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.