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Abstract
Objective Impaired blood flow of the carotid artery can result in cognitive impairment, but how these vascular impairments lead to global cognitive disturbances is largely unknown. Problems in functional connectivity between brain areas may be responsible for these widespread effects. Therefore, the aim of this study was to examine the association between carotid stiffness, functional connectivity and cognitive performance in relatively young and healthy adults before clinical vascular pathology occurs.
Design The Amsterdam Growth and Health Longitudinal Study: an observational study.
Setting Participants were included by attending 1 of the 2 selected secondary schools in The Netherlands.
Participants Men (n=110) and women (n=120) aged 41–44 years (42±0.7).
Primary and secondary outcome measures Data were obtained with regard to local carotid stiffness captured measured with the Young's elastic modulus (YEM). All participants underwent a commonly used Dutch intelligence test and resting-state eyes-closed magnetoencephalography (MEG). Five artefact-free epochs were analysed. The phase lag index (PLI) was used as a measure of functional connectivity between all sensors and was assessed in six frequency bands (δ–γ).
Results Carotid stiffness was significantly associated with increased functional connectivity in the α2 band in men (β: 0.287; p=0.008). The same results were found for women in the β band (β: 0.216; p=0.040). Furthermore, carotid stiffness was associated with superior cognitive function in men (β: 0.238; p=0.007). In addition, there was neither a significant association nor a consistent pattern between cognitive function and functional connectivity.
Conclusions The increased connectivity might be a maladaptive phenomenon caused by disinhibition of neurons which may explain the direction of the results. This study suggests that detection of increased (local) carotid stiffness may be promising to identify a disturbance in the organisation of the functional brain network, even before clinical vascular pathology occurs.
- NEUROPHYSIOLOGY
- ARTERIAL STIFFNESS
- MAGNETOENCEPHALOGRAPHY
- CAROTID ARTERY
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Strengths and limitations of this study
Magnetoencephalography recording has not been performed on such a large scale in apparently healthy individuals; therefore, this study gives a good indication of the relation between carotid stiffness and functional connectivity in a healthy population.
Our sample size allows us to stratify the results by gender, which is an important advantage since it is known that the brain organisation differs between men and women.
Since MRI is not available for the participants within the Amsterdam Growth and Health Longitudinal Study, we were not able to apply the source-space technique in order to provide a detailed topographic view of the brain.
The population is homogeneous concerning age, which indicates that secular trends cannot be investigated within this cohort.
A limitation of this study is the fact that we are not able to support a temporal or causal relation between arterial stiffness, functional connectivity and intelligent quotient.
Introduction
Arterial stiffness, which describes the rigidity of the arterial walls, is increasingly seen as a useful diagnostic tool in daily medical practice to predict cardiovascular events in patients at risk.1 ,2 Research has shown that vessel wall stiffness leads to increased cardiovascular risk, and also that there is also a close relationship between vessel wall stiffness and cognitive functioning, that is, higher vessel wall stiffness is related to cognitive decline.3 This relationship persists in the elderly, those with a disease and even in middle-aged individuals suffering from impaired brain function.4–11 The pathophysiological mechanism behind arterial stiffness and cognitive function might be explained by the fact that higher levels of pulsatile pressure might cause structural changes and a dysfunction of the microcirculation.12 This may result in microvascular damage and impaired microvascular function, with impaired cognition or loss of cognitive function as a result.12 ,13 A recent longitudinal study showed an association between increased arterial stiffness, subclinical vascular brain injury and greater neurocognitive decline in healthy older adults.14 However, little is known about this relationship in the preceding period, namely in healthy middle-aged adults.
Cognitive functioning is considered to be dependent on interactions between different brain regions, rather than on a single brain region or structure.15 Therefore, viewing the brain as a complex network has become a widely applied framework in the field of neuroscience in recent years.16 ,17 One approach to map this complex network is by measuring the magnetic fields of the brain with magnetoencephalography (MEG). MEG reflects the brain's activity by measuring fluctuations in magnetic fields at the scalp with millisecond temporal resolution. This technique allows us to estimate functional connectivity, which refers to the statistical interdependencies between time series of neural activity recorded from different brain regions that reflect functional interactions and information exchange between the regions.18 A powerful method that can be used to detect this synchronous neuronal activity is the phase lag index (PLI).19
Since functional connectivity may partly explain cognitive function,20 significant changes in functional connectivity might account for cognitive deterioration in neurological disease21 and vessel wall stiffness is related to cognitive decline,3 it is important to examine the relation between carotid stiffness, functional connectivity and cognition. Therefore, the objective of this explorative study is to examine the cross-sectional associations between carotid stiffness, functional connectivity and cognitive performance in relatively young and healthy adults before clinical vascular pathology occurs. We hypothesise that higher carotid stiffness may lead to a disturbance in the functional connectivity of the brain and that this disturbance may be associated with poorer cognitive performance.
Methods
Participants and study design
All participants participated in the Amsterdam Growth Health and Longitudinal Study (AGHLS; approved by the medical ethical committee of the VU University, Amsterdam, The Netherlands; all participants gave written consent at each subsequent measurement occasion). The AGHLS is a population-based observational longitudinal study, started in 1976, that aims to describe the natural development of growth, health and lifestyle during adolescence and adulthood. The rationale and design of the AGHLS have been described elsewhere in detail.22–24 Of all participants invited to the measurement rounds in 2000 and 2006, 230 from the original cohort (n=698) attended both measurement rounds and had complete data.
Carotid stiffness
Young's elastic modulus (YEM) is an estimate of the intrinsic elastic properties of the vessel wall and represents the stiffness of the arterial wall material at operating pressure. This local estimate of arterial stiffness was obtained through an ultrasound imaging device connected to a computer equipped with vessel wall movement detector software (Wall Track System 2, Pie Medical, Maastricht, the Netherlands). In both measurement rounds, an identical protocol was followed. This protocol is described in detail elsewhere.25 ,26 During the measurement, the arterial diameter (D), intima-media-thickness (IMT) and distension (ΔD) were quantified by ultrasonography, determined according to the Van Bortel calibration method of distension waveforms.27 YEM was calculated as follows: YEM=D/(IMT×DC) in 103 kPa. In order to obtain a more stable indicator of arterial stiffness, the average value of YEM was taken from the two subsequent measurement rounds.
Cognitive performance
At the mean age 42, all participants underwent a validated short version of the Groningen Intelligence Test (GIT),28 which is a Dutch intelligence test that is commonly used in the Netherlands for purposes comparable to the Wechsler Adult Intelligence Scale (WAIS) to determine general intelligence, expressed in Intelligent Quotient (IQ).29 Higher scores on the cognitive test indicate superior performance. Luteijn and Van der Ploeg reported Cronbach's α of the total GIT to be 0.97 and a correlation with the shortened version of 0.94 with the complete test.28 The shortened version of the GIT was used as a measure of general ability and consisted of the subtest ‘spatial jigsaw puzzles’, ‘arithmetic’ and ‘word matrices’ with an average internal consistency of 0.92.30 It took ∼45 min to complete the test.
MEG acquisition
MEG recordings were obtained at the mean age 42, using a 151-channel whole-head MEG system (CTF Systems Inc., Port Coquitlam, British Columbia, Canada), while participants were seated inside a magnetically shielded room. During the measurement, magnetic fields were obtained during a 5 min no-task, eyes-closed condition. Head movements of at most 1.5 cm during acquisition were allowed. At the end of the measurements, five artefact-free epochs of 4096 samples (6.554s) were selected by one of the authors (BWvD).31 Those epochs were selected that did not contain system-related artefacts (SQUID jumps, noisy, saturated channels), physiological artefacts (eye movement, eye blinks, muscle artefacts) or excessive environmental noise.32 All data analyses were performed using BrainWave software (CJS, V.0.9.58 available from http://home.kpn.nl/stam7883/brainwave.html). The obtained epochs were band-pass filtered into the six frequency bands which were used separately in further analyses: δ (0.5–4 Hz), θ (4–8 Hz), α1 (8–10 Hz), α2 (10–13Hz), β (13–30 Hz) and γ (30–45 Hz). Sensor values for connectivity were averaged for five regions: frontal, central, parietal, occipital and temporal.
Phase lag index
As a measure of functional connectivity, the PLI was calculated. The PLI calculates the asymmetry of the distribution of phase differences between two time series and ranges between 0 and 1. The asymmetry of the distribution of phase differences of two signals can be obtained from a time series of phase differences ΔΦ(tk), k=1…N samples:
The phase difference, Δφ, is defined in the interval [−2π, 2π]; the absolute value of the average sign of the phase difference mapped back to [−π, +π] and will be close to 1 if there is a stable phase difference unequal to kπ. A PLI of 0 (modulo pi) implies no coupling or coupling with a phase difference of 0° or ± 180°. The presence of a consistent, non-zero phase lag between two time series reflects true interaction instead of volume conduction or common sources. By calculating the PLI, it is more likely to find true interactions instead of volume conduction.19 Regional and overall (whole-brain) PLI were computed by averaging all values for the different brain regions.
Covariates
To adjust for known confounding factors, biological variables as well as lifestyle variables have been taken into account. In both examinations, we measured participants' height, mean arterial pressure, body fat percentage and level of triglyceride to HDL-C (TG/HDL-C) ratio and we obtained information on participants' smoking status and antihypertensive medication use. Body fat percentage was measured with a DEXA scan, and levels of triglyceride and HDL-cholesterol were measured by enzymatic techniques (Roche Diagnostics GmbH, Mannheim, Germany). Smoking status was examined with a validated questionnaire.33 Furthermore, antihypertensive medication was examined with a questionnaire and was presented as a dichotomous variable (yes/no).
Statistical analysis
The association between cognition and functional connectivity was assessed with linear regression analysis for all six frequency bands separately and stratified by gender and was adjusted for mean arterial pressure, height, body fat percentage, smoking, TG/HDL-C and antihypertensive medication use. The average value of YEM was used in all analyses and was stratified by gender and adjusted for mean arterial pressure and height. Results of all analyses were expressed as standardised regression coefficients (β), to enable comparison of the strengths of the association. All statistical analyses were performed with SPSS statistical software (IBM SPSS, statistics, V.21.0), and a two-sided p value of <0.05 was considered to be statistically significant.
Results
Participant characteristics
Table 1 summarises the characteristics of all participants included in the current analysis separately for men (n=110) and women (n=120). In both genders, higher values of YEM, increased stiffness, were found during the latter measurement round of 2006.
General characteristics of the study population
Carotid stiffness and cognitive performance
Tables 2 and 3 show the results of the association between average carotid stiffness and cognitive performance. For men, YEM was associated with superior cognitive function in men (table 2), while in women no association was identified (table 3).
Association between carotid stiffness and cognitive performance (IQ) in men
Association between carotid stiffness and cognitive performance (IQ) in women
Carotid stiffness and functional connectivity
Tables 4 and 5 show the results of the analyses correlating average carotid stiffness with functional connectivity. For YEM, which reflects the intrinsic elastic properties of the vessel wall, for almost all frequency bands, a positive association with PLI was found, suggesting a consistent pattern. Regarding significance, in the α2 band, for men, a significant positive association was found (table 4), while in the β band for women, a significant positive association was found (table 5).
Association between carotid stiffness and functional connectivity in men
Association between carotid stiffness and functional connectivity in women
The association between PLI and YEM is illustrated in more detail in figure 1. At the sensor level, p values for the association of PLI with YEM were not significant in men (figure 1A), while in women, a significant and global pattern could be noticed (figure 1B).
Significant sensor-specific associations between PLI and YEM. (A) A t-map of significant associations in the α2 band in men. Note: warm colours refer to positive associations, while cool colours indicate negative associations. (B) A t-map of significant associations in the β band in women. Note: warm colours refer to positive associations, while cool colours indicate negative associations.
Cognitive performance and functional connectivity
There was neither a significant association nor a consistent pattern between cognition and PLI (tables 6 and 7).
Association between cognitive performance (IQ) and functional connectivity in men
Association between cognitive performance (IQ) and functional connectivity in women
Additional analysis
Some additional analyses were performed to examine whether the mean value of the carotid stiffness as an independent variable may cause an overestimation or underestimation of the association between carotid stiffness and functional connectivity. The relationship was examined with vessel wall stiffness data, expressed as YEM, in 2000 and 2006 separately. Using data from 2000 did not change the relation between carotid stiffness and functional connectivity, and nor did the use of the YEM data from the measurement round in 2006 (data not shown).
Discussion
The present study was undertaken to evaluate the association between local arterial stiffness of the carotid artery, the brain's functional connectivity and cognitive performance in healthy middle-aged participants. The main findings of this study are threefold. First, increased local arterial stiffness of the carotid artery, expressed in terms of YEM, was significantly positively related to cognitive performance in men. The second finding is that greater local arterial stiffness was related to higher functional connectivity in men and women. Finally, no association was observed between functional connectivity and cognitive performance in men and women.
This study shows that greater arterial stiffness is positively correlated with superior cognitive performance in men. In contrast to our study, a recent systematic review reported fairly consistent evidence that greater arterial stiffness is related to a decrease in cognitive performance.3 However, studies that examined the cross-sectional association between arterial stiffness and global cognitive function via the Mini-mental Status Examination (MMSE) were inconsistent as opposed to studies that measured cognitive function with an array of neuropsychological tests.3 Furthermore, decreased executive function and lower memory scores in relatively healthy community-based participants were associated with arterial stiffness.6 ,13 ,34 Moreover, a longitudinal modelling study revealed an overall inverted-U shape (quadratic) trajectory across basic and everyday domains of cognition in a healthy cohort with a mean age of 74 years.35 This finding might explain the counterintuitive positive association between vessel wall stiffness and cognition that we report, since our study population is younger and their cognition is not buffered against decline yet. It still remains unclear at which point in time the alteration of the carotid artery will attribute to cognitive decline. In addition, a recent study found that aortic stiffness was associated with poorer cognitive function in those aged 45–65 years, but not in those aged 30–45 years.36
Previous research indicates that greater arterial stiffness is associated with a higher risk of developing cardiovascular diseases in those who are already at risk for cardiovascular problems.37 Furthermore, lower arterial stiffness is associated with higher levels of cardiorespiratory fitness (ie, VO2 max), which implies that a healthy lifestyle reduces cardiovascular disease.38 Here, we show a positive association between arterial stiffness and both functional connectivity and cognitive functioning in healthy, young participants. A recent paper based on the same cohort suggests that cognitive functioning and physical fitness (ie, VO2 max) are correlated to network organisation.39 Together with our current results, it seems that a healthy lifestyle promotes physical and mental fitness within the healthy population.
The present investigation shows that greater arterial stiffness is significantly associated with higher PLI values of the resting-state brain in the α2 band in men and β band in women. During task performance, higher spectral power in the α2 band is associated with attention and working memory,40 ,41 while the β band is involved in learning.41 ,42 However, the resting state shows a possibly reverse association between connectivity and cognitive functioning, at least in healthy participants or mildly impaired (prodromal) patients; several studies have shown associations between mild cognitive impairments and increased levels of synchronisation in the α and β frequencies at rest.43 ,44 However, in patients with Alzheimer's disease, lower MMSE scores are also characterised by decreased synchronisation in these frequency bands.45
The counterintuitive research findings with regard to the positive correlation between connectivity and carotid stiffness deserve further attention. It is hypothesised that greater brain activity is compensatory behaviour.46 ,47 Compensation behaviour is observed in older adults,48 but an increase in functional connectivity has also been reported in participants with mild cognitive impairment, which is a precursor of Alzheimer's disease.43 It is assumed that the network may work harder to compensate for its own declining efficiency and to deal with the failing parts in the brain. However, whether this hypothesis can be fully applied to connectivity of the brain remains unclear, since this hypothesis merely takes the activity of the brain into account, and we investigated resting-state connectivity. Another possible explanation for the increase in connectivity is that the increase in functional connectivity is not merely the effect of compensatory behaviour, but that it is partly pathological.49 A recent modelling study showed that when activity-dependent degeneration was simulated, the increase in neuronal activity leads to a degeneration, an inverted-U-relationship. It is assumed that the increase in neuronal activity can be explained by neuronal disinhibition, which makes the highly connected nodes (known as hubs) in the brain more vulnerable to Alzheimer's disease and other mild cognitive impairments.49 Since no association is found between functional connectivity and cognitive performance in our study sample, it is likely that a disturbance of the organisation of the functional brain network will be noticeable at a later time point if clinical vascular pathology occurs.
In this study, we used MEG to obtain a recording of the resting-state brain activity and to determine the functional connectivity using PLI. MEG makes it possible to measure real-time neural activity with great temporal precision. Therefore, this study gives a good indication of the relation between arterial stiffness and functional connectivity in healthy middle-aged participants at rest. Further, our findings were obtained in a fairly healthy, highly educated and slightly homogeneous population.22 As a consequence, our findings might be slightly underestimated. Furthermore, this study indicates that a difference in gender can be observed in the association between vessel wall stiffness and functional connectivity. Since it is known that the brain organisation differs between men and women, it is important to stratify the results by gender.50–53
A limitation of this study is the fact that we are not able to support a temporal or causal relation between arterial stiffness, functional connectivity and full-scale intelligence. This limits the ability to examine specific aspects of cognitive function that might be altered. Therefore, it is recommended in future work to examine executive functions, memory, verbal fluency, speed and attention in relation to carotid stiffness in addition to full-scale intelligence. Moreover, further research is needed in the same participants to determine whether the increase in functional connectivity is a result of greater stiffness of the carotid artery and to determine the long-term effects in relation to cognition. In addition, future work should examine at which point in time vessel wall stiffness is responsible for a decrease in specific aspects of cognitive performance.
Furthermore, it is recommended to apply source-space analyses on MEG data. For these analyses, a participant's MRI must be coregistered with the MEG data to provide a detailed topographical view of the (abnormal) brain activity.54 Since MRI scans are not available for the participants within the Amsterdam Growth and Health Longitudinal Study, we were not able to apply the source-space technique in order to provide a detailed topographic view of the brain.
This study shows that greater arterial stiffness of the carotid artery is related to higher functional connectivity in the α2 band and with cognitive performance in men. In women, a positive association of arterial stiffness and functional connectivity can be found in the β band. Longitudinal research is necessary to determine the predictive value of arterial stiffness in relation to functional connectivity and cognitive performance in order to grasp the underlying mechanisms of this association and to see whether the phenomenon we observed might be explained by compensatory behaviour. Our results indicate that early diagnostics of arterial stiffness may be promising to identify a disturbance in the organisation of the functional network in a relatively healthy and young population.
References
Footnotes
Contributors DN, LD, BWvD, MWH, CJS and JWRT conceived and designed the experiments; LD, BWvD and JWRT performed the experiments; DN, LD, BWvD, CJS and JWRT analysed the data; BWvD and CJS contributed reagents/materials/analysis tools; DN, LD, BWvD, CJS, MWH and JWRT wrote the paper.
Funding This work was supported by grants from the Dairy Foundation, the Netherlands Heart Foundation, the Dutch Prevention Fund, Heineken BV, the Ministry of Public Health, Well-being and Sport (VWS), the Scientific Board of Smoking and Health, the VU University and the VU University Medical Centre since the start of the study in 1976.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Approved by the medical ethical committee of the VU University, Amsterdam, The Netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All available data can be obtained by contacting the corresponding author.