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| ORIGINAL ARTICLE |
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| Year : 2017 | Volume
: 1
| Issue : 3 | Page : 112-118 |
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Greater N-Acetylaspartate to creatine ratio within left anterior insula predicts sympathetic imbalance in postmenopausal women living with hypertension and/or HIV
Roger C McIntosh1, Judith D Lobo1, Olumide Fajolu1, Elizabet Reyes1, Pradip M Pattany2, Michael A Kolber3
1 Department of Psychology, University of Miami, FL, USA
2 Department of Radiology; Department of Biomedical Engineering, Miller School of Medicine, FL, USA
3 Department of Medicine, Miller School of Medicine, FL, USA
| Date of Web Publication | 17-Jul-2018 |
Correspondence Address:
Dr. Roger C McIntosh
1120 NW 14th Street RM 1527, Miami, Florida 33136
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_18_17
Context: Brain metabolite ratios derived from magnetic resonance spectroscopy (MRS) has been used to document changes in neuronal viability, glial activation and inflammation associated with Human Immunodeficiency Virus (HIV) infection and cardiovascular disease. Aims: To determine whether brain metabolite ratios in the left anterioar insula predicts cardio-autonomic regulation indexed by the ratio of low- to high-frequency heart rate varaibility (LF:HF) after accounting for post-menopausal age, HIV and hypertensive (HTN) status. Design: Thirty women, (n=14 HIV+ and n=16 HTN+) with an average age of 54.5 (SD=6.4) years and no history of neurological disease were recruited for the study. Methods: After conventional MR imaging, single-voxel 1H-MRS (TR = 1500 msec; TE = 35 msec) was performed by using a PROBE-SV system implemented on a 3T GE Discovery MR750 scanner. Shift-selective imaging pulses for water suppression were acquired from a voxel placed in the midline of the left anterior insula with an average voxel size of 15×15×15 mm. Heart rate variability was estimated over a 7 minutes resting state scan using an MR-compatible photoplethysmogram. Statistics: A stepwise regression analysis controlling for (1) age, disease status (HIV+ and HTN+) was modelled separately for the ratio of N-acetylaspartate (NAA), Myo-inostol (mI), and Choline (Ch) to Creatine (Cr) ratios to predict LF:HF. Results: Higher ratios of NAA/Cr were associated with lower LF:HF (β= -.393, t(29)= -2.26, p= .033). Ratios of mI:Cr and Cho:Cr did not predict LF:HF. Conclusions: Decreased neuronal viability in the left anterior insula, indexed by lower NAA/Cr metabolite ratios explain a significant proportion of the variance in the skew towards sympathetic overarusal in postmenopausal women at risk for cerebrovacular disease. Keywords: Blood pressure, chronic disease, human immunodeficiency virus, menopause, parasympathetic, sympathetic
How to cite this article:
McIntosh RC, Lobo JD, Fajolu O, Reyes E, Pattany PM, Kolber MA. Greater N-Acetylaspartate to creatine ratio within left anterior insula predicts sympathetic imbalance in postmenopausal women living with hypertension and/or HIV. Heart Mind 2017;1:112-8 |
How to cite this URL:
McIntosh RC, Lobo JD, Fajolu O, Reyes E, Pattany PM, Kolber MA. Greater N-Acetylaspartate to creatine ratio within left anterior insula predicts sympathetic imbalance in postmenopausal women living with hypertension and/or HIV. Heart Mind [serial online] 2017 [cited 2023 May 31];1:112-8. Available from: http://www.heartmindjournal.org/text.asp?2017/1/3/112/236928 |
| Introduction | |  |
The symptoms of cardiovascular disease (CVD) consist of chronic cerebral circulatory disorders, ischemia, hypoxic changes, and volumetric thinning. The application of magnetic resonance spectroscopy (MRS) is a noninvasive diagnostic test to measure the biochemical changes in the brains of the patients with neurodegenerative disease.[1] The metabolic moieties of N-acetylaspartate (NAA), myoinositol (ml), choline (Ch), and creatine (Cr) are often used to assess the statuses of neuronal glial activation and inflammation. Of all, the NAA level is widely accepted as a prognostic marker of neuronal density and viability, in those patients with inflammation, an increased ml level predicts glial proliferation and the changes in cell sizes and the Ch level is an established marker for evaluating membrane density and integrity.[2] Although much of this work has focused on age-related neurodegenerative diseases, there has been increased interest in status of brain neuroglia in individuals with CVD. In patients with postoperative carotid endarterectomy a significant decrease in ratio of NAA/Cr and Cho/Cr was reported along with a decrease in cognitive function.[3] In the elderly patients with increased carotid artery intima-media thickness, a lower ratio of NAA/Cr was also present.[4] In a study that compared healthy controls to diabetic patients with hypertension (HTN) lower NAA ratio and an increased Cho ratio within the bilateral prefrontal cortex were observed in the patient group.[5] The results revealed that peripheral small artery disease was related to the decreases in neuronal integrity and the increases in membrane disintegration, respectively. Some interpret the localization of CVD-related alterations in metabolite concentration as a causative factor leading to the manifestation of cardiovascular complications. Cardio-autonomic neuroscience has implicated structural alterations to the medial prefrontal, anterior cingulate, and most notably insular cortex in the regulation of heart rate and blood pressure (BP).[6],[7],[8] For example, compared to normotensive controls patients with controlled and resistant HTN show decreases in frontal NAA/Cr along with increases in ml/Cr ratio.[9] Most recently, hypertensive patients were found to have lower NAA and Cho ratios within the bilateral anterior insula and thalamus when compared to normotensive individuals.[10] Altogether, a bidirectional link between small vessel peripheral disease or cardiovacular regulation and metabolite indices of change in neural viability of frontal brain regions implicated in cardio-autonomic regulation.
CVD comorbidity is prevalent in persons living with human immunodeficiency virus (HIV).[11] Also evident are increased rates of HIV-related neurodegeneration with advancing age [12],[13] There is ample literature supporting the clinical relevance of brain metabolite ratios in HIV disease. HIV + individuals both on and off combination antiretroviral therapy (ART) show lower NAA and Cho ratios throughout the cingulate gyrus, deep frontal white matter, and subcortical parietal white matter.[14],[15] There is also MRS evidence to suggest both CVD-comorbidity and advancing age interact to exacerbate HIV-related neurodegeneration. A study of patients on ART compared to healthy controls found an interaction between age and HIV on reduced frontal NAA.[12] Moreover, elevated Framingham risk scores were associated with the lower posterior cingulate cortex and caudate NAA in this study. HIV patients also have elevated risk for HTN which may be contributed to by autonomic derangement and show a skew toward sympathetic over-arousal that has been observed in this population.[16],[17],[18] The aim of the current study was to determine whether metabolite ratios of the left anterior insula predict sympathetic/parasympathetic ratio in HIV + and HIV-negative postmenopausal women with elevated risk for HTN. Based on prior research implicating the anterior insula in cardioautonomic regulation,[19],[20] reports of lower metabolite concentrations within this region in HIV + patients,[10] and the compounding effects of age and menopause on cardioautonomic regulation,[21],[22],[23],[24] ratios indicative of greater insula neurodegeneration are hypothesized to be associated with a skew toward greater sympathetic tone.
| Subjects and Methods | | |
A total of 44 patients (21 HIV+) were enrolled in the study. Inclusion criteria for the HIV+ group included postmenopausal status, (≥12 months since the past menstrual cycle) and on stable ART (≥6 months) with HIV+ serostatus confirmed by blood test. Criteria for exclusion included: (1) current or lifetime history of a diagnosed CVD condition, (e.g., HTN, congestive heart disease, etc.), or heart surgery; (2) current or lifetime diagnoses of cancer, kidney/liver disease, type 1 or type 2 diabetes; (3) cerebrovascular accident or infarction; (4) current substance abuse or treatment; (5) current treatment for mental illness; (6) history of cerebrovascular accident, loss of consciousness; (7) current treatment or diagnosis of psychiatric illness including Axis 1 or 2 disorders; (8) metal implants or debris within the body; (9) current pregnancy or breast feeding; or (10) current hormone replacement therapy.
Of the enrolled patients whom completed the MRS scan, a total of 14 women were excluded due to excessively noisy or incomplete psychophysiological data recorded during the resting state period. This resulted in a total of 14 HIV+ and 16 HIV− women that were included in the final data analysis. BP was measured during physical intake to confirm hypertensive status after the participant had rested for at least 5 min in a seated position, using an appropriately sized cuff placed on the left arm using a continuous digital BP monitor (CNAP ® Monitor 500 HD; Graz, Austria). Anthropometrics including weight and height were also collected. Psychological data were collected in face-to-face interviews using standardized questionnaires administered by a graduate psychology trainee. Prior to the MRS scanning session subjects were oriented to a mock MRI scanner where they were introduced to the various scanner noises and timing of study protocols. The 7 min resting state scan and 5 min MRS probe were preceded an interspersed by 4–6 min T1-weighted structural scans. The study design was approved by the independent ethnic committee at the study site. All participants signed informed consent before participating in the study.
1H-magnetic resonance spectroscopy data acquisition
1H-MRS data were acquired using a 3-T GE Discovery MR750 MRI scanner (GE Medical Systems, Milwaukee, WI, USA), using a 32-channel-phased array head coil to provide the highest signal to noise. The scan protocol consisted of a T1-weighted Magnetization Prepared Rapid Gradient-Echo (MPRAGE) sequence with following parameters: Sagittal slices, repetition time (TR) = 9.18 ms, time to echo (TE) = 3.68 ms, flip angle = 12°, field of view 256 mm, in-plane matrix 256 × 256, which results in 1.0-mm isotropic voxels. These images were used to aid in placement of the MRS voxel. Single voxel 1H-MRS Point Resolved Spectroscopy acquisition was used, the Extended dynamic range option was selected for the acquisition. Chemical shift-selective pulse was used for water suppression, and the voxel was placed in the midline of the left anterior insula, with the following parameters: TE = 35 ms, TR = 1500 ms, with 128 averages voxel size of 15 mm × 15 mm × 15 mm. Anatomical localization of voxel placement was based on the Montreal Neurological Institute-152 Atlas More Details and positioning was guided by the T1 MPRAGE image as shown in [Figure 1]. All spectra were shimmed (using automatic and manual higher-order shimming). All spectra were visually inspected and poorly fitted metabolite peaks as reflected by excessive noise. The RMS noise of the experimental data was measured after baseline correction in the spectral range between −1.8 and −3.6 ppm.[25] In addition, signal to noise ratios for Cr were excluded from further analysis if the signal to noise ratio was <40.0. | Figure 1: Magnetic resonance spectroscopy seed region for the left anterior insula probe and corresponding metabolite ratios
Click here to view |
Photoplethysmography
Participants were outfitted with an MRI-compatible photoplethysmogram (PPG) to identify inter-beat intervals and estimate heart rate variability (HRV) per standards recommended by the Task Force of the European Society of Cardiology.[26] The assessment of HRV from finger-tip photoplethysmography is shown to have very high correspondence with that derived from electrocardiography.[27] Resting heart rate was recorded from the index finger of the left hand and averaged over the entire period of the 7 min resting state scan. The PPG signal was conveyed through an A/D converter (Biopac MP150, Biopac system Inc., Santa Barbara, CA) continuously sampled at 500 Hz. Before visual inspection and flagging of a peak detection algorithm was used to determine the interbeat intervals for assessment of both average HR and as raw data for the analysis of HRV.
Sympathetic/parasympathetic balance
Heart rate variation during normal breathing was recorded, with subject supine, awake, and resting for 7 min. The time series was subjected to frequency domain analysis of HRV using a nonparametric method of fast Fourier transformation after being edited manually for artifacts and ectopic beats. The Biopac software provides a peak detection algorithm to find the “R” wave at a resampling rate of 6 Hz. A minimum of 256 data points were required to perform a spectral analysis over the course of 7 min of recording. The power frequency spectrum was then quantified into standard frequency-domain measurements including high-frequency (HF 0.15–0.4 Hz), low-frequency (LF 0.04–0.15 Hz). The ratio of LF/HF was then quantified as a final estimate of sympathetic/parasympathetic balance.
Statistical analyses
All the statistical analyses were performed with 30 participants. First, Pearson coefficients were estimated among all study variables to produce a correlation matrix [Table 1] that was evaluated by a statistical significance of P < 0.05. Three hierarchical regression models were specified with the primary aim of assessing the amount of variance in sympathetic/parasympathetic balance accounted for by NAA, Cho, and mI ratios after controlling for postmenopausal age in the first stage of the model and disease status (HIV + and HTN+) in the second stage of the model. Each of the three models were distinguished by the brain metabolite ratio entered into the third step of the model, i.e.,, (NAA/Cr, Cho/Cr, and mI/Cr). A significance test for the change in variance (ΔR 2) at each step of the model was evaluated in addition to beta coefficients and overall significance for each model was evaluated at the P < 0.05 level. All analysis were performed using PASW, Statistics 24 (Release 24.0.0; SPSS Inc., Chicago, IL, USA). | Table 1: Bivariate correlations between study variables separated by human immunodeficiency virus + (bottom left) human immunodeficiency virus - (top right)
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| Results | | |
Demographics
Demographic and CVD information is provided in [Table 2]. The average age post-menopause of the sample was 8.1 years. Of the 14 HIV + subjects, 6 (42.9%) had a past diagnosis of AIDS, and 14 (100%) were currently taking ART. Of the 12 (40%) women in the sample reporting HTN diagnosis, 6 (50%) were currently taking anti-hypertensive medication.
Cross-correlations
[Table 1] presents correlation coefficients for the study variables separated as a function of HIV + and HIV-negative status. When the associations of the LF: HF ratio with the various SPEC metabolites were evaluated, only the NAA/Cr values significantly decreased with increasing LF: HF ratios (r = −0.469, P = 0.009). There were no associations found between mI and Cho ratios and LF:HF ratio. The correlation between HTN status and LF: HF ratio also trended toward significance in the full sample (r = 0.326, P = 0.078). There were no other significant correlations present.
Hierarchical regression
[Table 3] displays results from the stepwise regression model for NAA/Cr was significant F (4, 29) = 3.04, P = 0.036. The model revealed that the increase in the LF: HF ratio significantly predicted lower NAA/Cr in the left anterior insula t (29) = −2.26, P = 0.033. The models for Cho/Cr and mI/Cr were not significant, nor were the effects for these metabolites on LF:HF ratio. | Table 3: Multiple linear regression models predicting ratio of low-frequency to high frequency heart rate variability by brain metabolite ratio
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| Discussion | | |
Alterations in brain metabolite ratios are evident in older adults living with HIV and HTN. In this study, we sought to examine the regional specificity of those metabolite changes on the balance of resting autonomic tone women of post-menopausal age while accounting for disease status. Lower NAA to Cr ratios were found to predict higher ratio of sympathetic to parasympathetic tone after controlling for post-menopausal age, HTN and HIV status. These findings suggest that in older adult women decreased neuronal viability in the left anterior insula may an indicator of autonomic derangement evidenced by greater skew toward sympathetic arousal, independent of hormonal, HIV, or hypertensive status.
The findings of lower NAA ratios in persons diagnosed with HTN coincide with prior reports of lower NAA ratios among individuals with controlled and resistant HTN within frontal and bilateral anterior insula regions.[9],[10] Although this association for NAA and HTN status was not replicated in the HIV + group, here, greater Cho ratios were found in HIV + individuals endorsing HTN status. Prior studies examining brain metabolite markers of CVD risk in HIV have implicated posterior cingulate and caudate NAA values rather than Cho.[12] Another notable finding was the positive association between postmenopausal age and LF:HF ratio in the HIV + group. This finding appears to support prior literature showing a greater skew towards sympathetic arousal in older adult women, in part due to estrogen depletion during the postmenopausal period.[28],[29] Altogether, these findings suggest that NAA/Cr metabolite ratios within the left anterior insula may be markers for the sympathetic imbalance in post-menopausal women and that these effects appear to be more evident in aging HIV + women.
The exact neural mechanisms linking decreased NAA/Cr ratios to sympathetic imbalance are unclear, particularly within the context of HIV infection. A plausible explanation requires insight into the specific role of the left anterior insula in cardioautonomic regulation. Although the entirety of the central autonomic network, (i.e., medulla, hypothalamus, thalamus, somatosensory cortex, insular cortex, cingulate cortex, medial prefrontal cortex and amygdala) is thought to play a coordinated role in the regulation of HR, the left anterior insula is thought to play a critical role in the processing of interoceptive information via pulmonary stretch and baroreceptors of the lungs and heart; providing critical information for maintaining cardioautonomic tone.[30],[31],[32],[33] With regards to the effect of laterality it is important to note that in animal models of neurogenic HTN right insula activation and left anterior insula de-activation are observed during periods of sympathetic overarousal.[34],[35],[36] Similarly, neural stimulation, BP reactivity, and brain morphological studies also implicate structure and function of the left anterior insula in parasympathetic regulation with right insula playing a more integral role in sympathetic or pressor response.[19],[20],[37],[38],[39],[40],[41] Lesion studies also support the role of the left insula in the regulation of parasympathetic tone as damage to these areas have been linked to elevations in systolic BP, tachycardia as well as plasma norepinephrine spillover, indices of sympathetic imbalance.[42],[43],[44] Although the effects of small artery disease cannot be ruled out, our findings implicate neural integrity of the left anterior insula in cardio-autonomic regulation amongst postmenopausal women at risk for cerebrovascular diease.
Implications
Sympathetic overarousal and parasympathetic withdrawal are independent predictors of all-cause mortality associated with congestive heart failure, acute myocardial infarction, acute ischemic stroke, malignant cardiac arrhythmias, renal failure, chronic obstructive pulmonary disease, in addition to essential, masked, and chronic HTN. Depletion of estrogen during menopause has been linked to a rapid increase in CVD in adult women. Although we were not able to measure levels of estrogen, progesterone or other sex hormones, our findings beg the question of how menopause and aging may interact differently in HIV and HTN. What is known is that a dense array of estrogen receptors are located on nuclei throughout the brainstem, for example, nucleus of the solitary tract and dorsal motor nucleus of the vagus, that are involved in baroreceptor reflex and autonomic tone, and that many of these structures have dense afferent and efferent connections to the insula and other cardio-autonomic network structures though gamma-aminobutyric acid-ergic and Glutamatergic pathways [37],[45],[46],[47],[48],[49],[50],[51],[52] and their alteration during may associated with increased risk for CVD during the female reproductive period of estrogen withdrawal.[46],[53],[54] Future studies may need to explore brain metabolite changes to cardioautonomic network in the context of hormone replacement therapy.
Strengths and limitations
Several limitations of the present study should be considered. First, although we tout findings with regards to aging and cardio-autonomic function in HIV + women, the cross-sectional design of this study does not allow for an evaluation of causuality or disease etiology. Second, despite a relatively balanced distribution of HIV + and HTN + diagnoses, the study sample consisted of a relatively small number of participants, which may have led to an underestimation of the associations between brain metabolites and HRV. Third, HRV is very vulnerable to diurnal, postural, and psychological perturbations, however, we managed to obtain what we believe is a stable index of HRV by capturing beat-to-beat intervals gathered over 7 min in the supine position while the participant was at rest inside of the bore of the scanner, just prior to the MRS scan. As a result, these findings may not translate to indices of HRV derived from 24 h Holter monitor recordings. Nonetheless, short-order stationary HRV can provide very useful information about the autonomic function.[55] It is also important to note that presence of the metabolic syndrome can also impact cardio-autonomic regulation.[56] However, those women included in the study had not history or past treatment for cardiometabolic complications such as diabetes. Finally, it should be taken into consideration that although ratios of metabolite moieties regarding Cr are commonly reported in studies using MRS in HIV infection,[14],[15] Cr may be a less robust measure for comparing metabolite ratios in aging cohorts since they can vary across the brain in normal aging.[57] Thus, an alternative approach taken by some is to measure absolute values of each metabolite which would have gone undetected had the metabolites been measured solely as ratios.[58] Nonetheless, we took the current approach to be commensurate with the HTN literature as it pertains to metabolite concentrations in the anterior insula.
| Conclusions | | |
Our data confirm an association between decreased NAA/Cr ratios and increased sympathetic imbalance suggesting neural integrity of the left anterior insula is relates to the balance of sympathetic to parasympathetic tone independent of age and chronic disease status, i.e., HIV + and HTN + diagnoses. We found that the strength of association was particularly strong in HIV + individuals. Moreover, older HIV + women are more likely to reveal this cardio-autonomic phenotype, thus supporting the clinical importance of spectral analysis of brain metabolites within central cardio autonomic brain structures such as the anterior insula. A more inclusive assessment of neuronal health of bilateral insula and other integral structures throughout the cardio-autonomic network may provide greater insight into the autonomic derangements and hypertensive risk observed in persons living with infectious chronic neurodegenerative and neuroinflammatory diseases such as HIV.
Financial support and sponsorship
1K01HL139722-01 (RM).
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Martin WR. MR spectroscopy in neurodegenerative disease. Mol Imaging Biol 2007;9:196-203.  |
| 2. | Soares DP, Law M. Magnetic resonance spectroscopy of the brain: Review of metabolites and clinical applications. Clin Radiol 2009;64:12-21. |
| 3. | Saito H, Ogasawara K, Nishimoto H, Yoshioka Y, Murakami T, Fujiwara S, et al. Postoperative changes in cerebral metabolites associated with cognitive improvement and impairment after carotid endarterectomy: A 3T proton MR spectroscopy study. AJNR Am J Neuroradiol 2013;34:976-82. |
| 4. | Haley AP, Tarumi T, Gonzales MM, Sugawara J, Tanaka H. Subclinical atherosclerosis is related to lower neuronal viability in middle-aged adults: A 1H MRS study. Brain Res 2010;1344:54-61. |
| 5. | Cao Z, Ye BD, Shen ZW, Cheng XF, Yang ZX, Liu YY, et al. 2D-1H proton magnetic resonance spectroscopic imaging study on brain metabolite alterations in patients with diabetic hypertension. Mol Med Rep 2015;11:4232-8. |
| 6. | Benarroch EE. The central autonomic network: Functional organization, dysfunction, and perspective. Mayo Clin Proc 1993;68:988-1001. |
| 7. | Müller-Ribeiro FC, Zaretsky DV, Zaretskaia MV, Santos RA, DiMicco JA, Fontes MA. Contribution of infralimbic cortex in the cardiovascular response to acute stress. Am J Physiol Regul Integr Comp Physiol 2012;303:R639-50. |
| 8. | Gianaros PJ, Sheu LK. A review of neuroimaging studies of stressor-evoked blood pressure reactivity: Emerging evidence for a brain-body pathway to coronary heart disease risk. Neuroimage 2009;47:922-36. |
| 9. | García Santos JM, Fuentes LJ, Vidal JB, Carrillo A, Antequera M, Campoy G, et al. Posterior paralimbic and frontal metabolite impairments in asymptomatic hypertension with different treatment outcomes. Hypertens Res 2010;33:67-75. |
| 10. | Ben Salem D, Walker PM, Bejot Y, Aho SL, Tavernier B, Rouaud O, et al. N-acetylaspartate/creatine and choline/creatine ratios in the thalami, insular cortex and white matter as markers of hypertension and cognitive impairment in the elderly. Hypertens Res 2008;31:1851-7. |
| 11. | So-Armah K, Freiberg MS. Cardiovascular disease risk in an aging HIV population: Not just a question of biology. Curr Opin HIV AIDS 2014;9:346-54. |
| 12. | Cysique LA, Moffat K, Moore DM, Lane TA, Davies NW, Carr A, et al. HIV, vascular and aging injuries in the brain of clinically stable HIV-infected adults: A (1) H MRS study. PLoS One 2013;8:e61738. |
| 13. | Lee PL, Yiannoutsos CT, Ernst T, Chang L, Marra CM, Jarvik JG, et al. Amulti-center 1H MRS study of the AIDS dementia complex: Validation and preliminary analysis. J Magn Reson Imaging 2003;17:625-33. |
| 14. | Boban J, Kozic D, Turkulov V, Ostojic J, Semnic R, Lendak D, et al. HIV-associated neurodegeneration and neuroimmunity: Multivoxel MR spectroscopy study in drug-naïve and treated patients. Eur Radiol 2017;27:4218-36. |
| 15. | Bairwa D, Kumar V, Vyas S, Das BK, Srivastava AK, Pandey RM, et al. Case control study: Magnetic resonance spectroscopy of brain in HIV infected patients. BMC Neurol 2016;16:99. |
| 16. | McIntosh RC. A meta-analysis of HIV and heart rate variability in the era of antiretroviral therapy. Clin Auton Res 2016;26:287-94. |
| 17. | Palatini P, Julius S. The role of cardiac autonomic function in hypertension and cardiovascular disease. Curr Hypertens Rep 2009;11:199-205. |
| 18. | Nduka CU, Stranges S, Sarki AM, Kimani PK, Uthman OA. Evidence of increased blood pressure and hypertension risk among people living with HIV on antiretroviral therapy: A systematic review with meta-analysis. J Hum Hypertens 2016;30:355-62. |
| 19. | Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42:1727-32. |
| 20. | Oppenheimer SM, Kedem G, Martin WM. Left-insular cortex lesions perturb cardiac autonomic tone in humans. Clin Auton Res 1996;6:131-40. |
| 21. | Barnes JN, Hart EC, Curry TB, Nicholson WT, Eisenach JH, Wallin BG, et al. Aging enhances autonomic support of blood pressure in women. Hypertension 2014;63:303-8. |
| 22. | Hart EC, Charkoudian N. Sympathetic neural regulation of blood pressure: Influences of sex and aging. Physiology (Bethesda) 2014;29:8-15. |
| 23. | Barnett SR, Morin RJ, Kiely DK, Gagnon M, Azhar G, Knight EL, et al. Effects of age and gender on autonomic control of blood pressure dynamics. Hypertension 1999;33:1195-200. |
| 24. | Neufeld IW, Kiselev AR, Karavaev AS, Prokhorov MD, Gridnev VI, Ponomarenko VI, et al. Autonomic control of cardiovascular system in pre- and postmenopausal women: A cross-sectional study. J Turk Ger Gynecol Assoc 2015;16:11-20. |
| 25. | Young K, Soher BJ, Maudsley AA. Automated spectral analysis II: Application of wavelet shrinkage for characterization of non-parameterized signals. Magn Reson Med 1998;40:816-21. |
| 26. | Heart rate variability: Standards of measurement, physiological interpretation and clinical use. Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93:1043-65. |
| 27. | Selvaraj N, Jaryal A, Santhosh J, Deepak KK, Anand S. Assessment of heart rate variability derived from finger-tip photoplethysmography as compared to electrocardiography. J Med Eng Technol 2008;32:479-84. |
| 28. | Kaye DM, Esler MD. Autonomic control of the aging heart. Neuromolecular Med 2008;10:179-86. |
| 29. | Vongpatanasin W. Autonomic regulation of blood pressure in menopause. Semin Reprod Med 2009;27:338-45. |
| 30. | Shivkumar K, Ajijola OA, Anand I, Armour JA, Chen PS, Esler M, et al. Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol 2016;594:3911-54. |
| 31. | Uddin LQ. Salience processing and insular cortical function and dysfunction. Nat Rev Neurosci 2015;16:55-61. |
| 32. | Wiebking C, Duncan NW, Tiret B, Hayes DJ, Marjaǹska M, Doyon J, et al. GABA in the insula – A predictor of the neural response to interoceptive awareness. Neuroimage 2014;86:10-8. |
| 33. | Ernst J, Böker H, Hättenschwiler J, Schüpbach D, Northoff G, Seifritz E, et al. The association of interoceptive awareness and alexithymia with neurotransmitter concentrations in insula and anterior cingulate. Soc Cogn Affect Neurosci 2014;9:857-63. |
| 34. | Butcher KS, Cechetto DF. Autonomic responses of the insular cortex in hypertensive and normotensive rats. Am J Physiol 1995;268:R214-22. |
| 35. | Oppenheimer SM, Cechetto DF. Cardiac chronotropic organization of the rat insular cortex. Brain Res 1990;533:66-72. |
| 36. | Zhang Z, Oppenheimer SM. Characterization, distribution and lateralization of baroreceptor-related neurons in the rat insular cortex. Brain Res 1997;760:243-50. |
| 37. | Kimmerly DS, O'Leary DD, Menon RS, Gati JS, Shoemaker JK. Cortical regions associated with autonomic cardiovascular regulation during lower body negative pressure in humans. J Physiol 2005;569:331-45. |
| 38. | Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: A functional neuroimaging investigation in humans. J Physiol 2000;523 Pt 1:259-70. |
| 39. | Macey PM, Wu P, Kumar R, Ogren JA, Richardson HL, Woo MA, et al. Differential responses of the insular cortex gyri to autonomic challenges. Auton Neurosci 2012;168:72-81. |
| 40. | Colivicchi F, Bassi A, Santini M, Caltagirone C. Cardiac autonomic derangement and arrhythmias in right-sided stroke with insular involvement. Stroke 2004;35:2094-8. |
| 41. | Kim JB, Suh SI, Seo WK, Koh SB, Kim JH. Right insular atrophy in neurocardiogenic syncope: A volumetric MRI study. AJNR Am J Neuroradiol 2014;35:113-8. |
| 42. | Inamasu J, Sugimoto K, Watanabe E, Kato Y, Hirose Y. Effect of insular injury on autonomic functions in patients with ruptured middle cerebral artery aneurysms. Stroke 2013;44:3550-2. |
| 43. | Meyer S, Strittmatter M, Fischer C, Georg T, Schmitz B. Lateralization in autonomic dysfunction in ischemic stroke involving the insular cortex. Neuroreport 2004;15:357-61. |
| 44. | Hachinski VC, Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Asymmetry of sympathetic consequences of experimental stroke. Arch Neurol 1992;49:697-702. |
| 45. | Jabbi M, Keysers C. Inferior frontal gyrus activity triggers anterior insula response to emotional facial expressions. Emotion 2008;8:775-80. |
| 46. | Schlenker EH, Hansen SN. Sex-specific densities of estrogen receptors alpha and beta in the subnuclei of the nucleus tractus solitarius, hypoglossal nucleus and dorsal vagal motor nucleus weanling rats. Brain Res 2006;1123:89-100. |
| 47. | Vanderhorst VG, Gustafsson JA, Ulfhake B. Estrogen receptor-alpha and -beta immunoreactive neurons in the brainstem and spinal cord of male and female mice: Relationships to monoaminergic, cholinergic, and spinal projection systems. J Comp Neurol 2005;488:152-79. |
| 48. | Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The women's health initiative memory study: A randomized controlled trial. JAMA 2003;289:2651-62. |
| 49. | Collins O, Dillon S, Finucane C, Lawlor B, Kenny RA. Parasympathetic autonomic dysfunction is common in mild cognitive impairment. Neurobiol Aging 2012;33:2324-33. |
| 50. | Haywood SA, Simonian SX, van der Beek EM, Bicknell RJ, Herbison AE. Fluctuating estrogen and progesterone receptor expression in brainstem norepinephrine neurons through the rat estrous cycle. Endocrinology 1999;140:3255-63. |
| 51. | Jabbi M, Bastiaansen J, Keysers C. A common anterior insula representation of disgust observation, experience and imagination shows divergent functional connectivity pathways. PLoS One 2008;3:e2939. |
| 52. | Shoemaker JK, Wong SW, Cechetto DF. Cortical circuitry associated with reflex cardiovascular control in humans: Does the cortical autonomic network “speak” or “listen” during cardiovascular arousal. Anat Rec (Hoboken) 2012;295:1375-84. |
| 53. | Alonso-Solís R, Abreu P, López-Coviella I, Hernández G, Fajardo N, Hernández-Díaz F, et al. Gonadal steroid modulation of neuroendocrine transduction: A transynaptic view. Cell Mol Neurobiol 1996;16:357-82. |
| 54. | Genazzani AR, Bernardi F, Pluchino N, Begliuomini S, Lenzi E, Casarosa E, et al. Endocrinology of menopausal transition and its brain implications. CNS Spectr 2005;10:449-57. |
| 55. | Sinnreich R, Kark JD, Friedlander Y, Sapoznikov D, Luria MH. Five minute recordings of heart rate variability for population studies: Repeatability and age-sex characteristics. Heart 1998;80:156-62. |
| 56. | Esler M, Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G. Sympathetic Nervous System and Insulin Resistance: From Obesity to Diabetes. American Journal of Hypertension: Oxford University Press; 2001. |
| 57. | Gruber S, Pinker K, Riederer F, Chmelík M, Stadlbauer A, Bittsanský M, et al. Metabolic changes in the normal ageing brain: Consistent findings from short and long echo time proton spectroscopy. Eur J Radiol 2008;68:320-7. |
| 58. | Pfefferbaum A, Adalsteinsson E, Sullivan EV. Cortical NAA deficits in HIV infection without dementia: Influence of alcoholism comorbidity. Neuropsychopharmacology 2005;30:1392-9. |
[Figure 1]
[Table 1], [Table 2], [Table 3]
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