We examined the reliability of measures of fMRI, subjective, and cardiovascular reactions to standardized versions of a Stroop color-word task and a multi-source interference task. A sample of 14 men and 12 women (30–49 years old) completed the tasks on two occasions, separated by a median of 88 days. The reliability of fMRI BOLD signal changes in brain areas engaged by the tasks was moderate, and aggregating fMRI BOLD signal changes across the tasks improved test-retest reliability metrics. These metrics included voxel-wise intraclass correlation coefficients (ICCs) and overlap ratio statistics. Task-aggregated ratings of subjective arousal, valence, and control, as well as cardiovascular reactions evoked by the tasks showed ICCs of 0.57 to 0.87 (ps < 0.001), indicating moderate-to-strong reliability. These findings support using these tasks as a battery for fMRI studies of cardiovascular reactivity.
fMRI; cardiovascular reactivity; test-retest reliability
Accumulating evidence from animal models and human studies of essential hypertension suggest that brain regulation of the vasculature is impacted by the disease. Human neuroimaging findings suggest that the brain may be an early target of the disease. This observation reinforces earlier research suggesting that psychological factors may be one of the many contributory factors to the initiation of the disease. Alternatively or in addition, initial blood pressure increases may impact cognitive and/or affective function. Evidence for an impact of blood pressure on the perception and experience of affect is reviewed vis-a-vis brain imaging findings suggesting that such involvement in hypertensive individuals is likely.
We asked whether different forms of inhibition are altered differently by aging using a Motor and Perceptual Inhibition Test (MAPIT) based on Nassauer and Halperin (Nassauer & Halperin, 2003). Ninety-eight individuals participating in studies of balance and attention were separated into younger (mean age 25 years) and older participants (mean age 73). Older participants showed less Perceptual and Motor Inhibition than younger participant with moderation of this effect by gender. The two scores were uncorrelated in the young but significantly correlated in the older group. Overall, the MAPIT appeared to yield reliable measures of two aspects of inhibition that demonstrate a differential impact of age.
Reaction time; executive function; reliability; human performance; processing speed; response choice
Hypertension is associated with mild decrements in cognition. Additionally, regional cerebral blood flow responses during memory processing are blunted in parietal and thalamic areas among untreated hypertensive adults, who compared to normotensives, manifest greater correlation in blood flow response across task-related brain regions. Here, we test whether pharmacologic treatment of hypertension normalizes regional cerebral blood flow responses and does so differentially according to drug class. Treatment with lisinopril, an angiotensin converting enzyme blocker, known to enhance vasodilative responsivity, was compared to treatment with atenolol, a beta blocker. Untreated hypertensive volunteers, n=28, were randomized and treated for one year. Whole brain and regional cerebral flow response to memory processing and acutely administered acetazolamide, a vasodilator, was assessed pre- and post-treatment. Peripheral brachial artery dilation during reactive hyperemia was also measured. Quantitative blood flow measures showed no difference in the magnitude of regional cerebral blood flow responses pre-and post-treatment to either memory tasks or acetazolamide injection. Brachial artery flow-mediated dilation increased with treatment. No differences between medications were observed. In brain regions active in memory processing, however, regional cerebral blood flow responses were more highly correlated after treatment. Specificity of cerebral blood flow to different regions appears to decline with treatment of hypertension. This greater correlation among active brain regions, which is present as well in untreated hypertensive relative to normotensive volunteers, may represent compensation in the face of less region-specific responsivity in individuals with hypertension.
Hypertension; Cerebral Blood Flow; Magnetic Resonance Imaging; Positron Emission Tomography; Beta-blocker; Angiotensin Converting Enzyme Inhibitor
The brain is typically considered a target for late stage hypertensive disease due to the high prevalence of stroke among hypertensive patients. Research is reviewed, however, that suggests that the brain is implicated in the initiation of high blood pressure and is itself altered by early disease processes. A substantial literature establishes neural control of the vasculature and kidney as candidate etiological factors in essential hypertension. This research, largely done in animals, is now supplemented by behavioral and brain imaging studies in humans. This review suggests that the brain and vasculature may be independently and concurrently targeted by the factors inducing essential hypertension. Early stage hypertension is associated with cognitive deficits, altered cerebral blood flow support for cognitive processing, and decreased grey matter in specific cortical regions. Pharmacological reversal of hypertension is less successful in patients with premature brain aging and fails to reverse either the progression of functional or structural changes within the cerebral cortex. Furthermore, magnetic resonance imaging Blood Oxygen Level-Dependent (BOLD) responses during psychological challenge differ between normotensive individuals at risk and those not at risk for hypertension because of their exaggerated blood pressure responses to psychological challenge. Further examination of mechanisms of action and early influences of the disease on the brain are required to understand the pathophysiological mechanisms having concurrent influences on the brain and the peripheral vasculature.
hypertension; regional cerebral blood flow; neuropsychology; brain morphology; cognitive processing; positron emission tomography; magnetic resonance imaging
Hypertension appears to alter brain morphology as well as the cerebrovascular support for information processing. As these effects might reflect progressive effects of essential hypertension on the brain, we asked whether structural and functional brain indices would predict the success of pharmacological treatment of hypertension among 45 previously unmedicated individuals. After initial structural magnetic resonance imaging and functional positron emission tomography imaging, subjects were randomized in a double blind fashion for treatment for one year with either lisinopril or atenolol. Systolic and diastolic blood pressure decreases after treatment stabilization were correlated to a pretreatment index of brain aging (combined ratings of ventricle and sulcal size and white matter hyperintensities) and the pretreatment change in regional cerebral blood flow during working memory in the thalamus and posterior parietal regions of interest. In multiple regression analyses, the structural brain index and the blood flow response in the thalamus predicted 20% of the variance in the systolic blood pressure response to treatment controlling for pre-treatment blood pressure, age, gender, and type and dose of medication. Alcohol use influenced the thalamic response measure, but covariates did not alter the relation between greater indices of brain aging and less successful blood pressure response to treatment. The state of the brain may be an important factor in the remediation of blood pressure.
Hypertension; magnetic resonance imaging; positron emission imaging; atenolol; lisinopril; cerebral blood flow; blood pressure treatment
Researchers are interested in respiratory sinus arrhythmia (RSA) as an index of cardiac vagal activity. Yet, debate exists about how to account for respiratory influences on quantitative indices of RSA. Ritz and colleagues (2001) developed a within-individual correction procedure by which the effects of respiration on RSA may be estimated using regression models. We replicated their procedure substituting a spectral high-frequency measure of RSA for a time-domain statistic and a respiratory belt’s relative measure of tidal volume for the direct assessment provided by a pneumotachograph. The standardized slopes from the respiratory belt and pneumotachography-derived regression equations (estimated across a 6 mins paced breathing protocol) were positively correlated (r = 0.93, p < 0.001); correlations were similar across 2 and 4-min time courses parsed from the 6-min protocol. Our results offer methodological alternatives to the research community.
In Parkinson's disease (PD), neurodegenerative changes have been observed in autonomic pathways involving multiple organ systems. We explore pupillary and cardiac autonomic measures as physiological manifestations of PD neurodegeneration.
Pupil measures (pupillary unrest (spontaneous changes of pupil diameter in darkness), constriction velocity and redilation velocity) were assessed in 35 participants (17 PD, 18 controls). Simultaneous cardiac measures (respiratory sinus arrythmia during deep breathing, Valsalva ratio, resting heart rate variability (HRV), orthostatic change in blood pressure and orthostatic change in heart rate) were obtained. Nonparametric statistics were used to compare PD with control participants and to calculate correlation coefficients between pupillary and cardiac measures.
Pupillary unrest and orthostatic decreases in systolic blood pressure were greater in PD than controls. Respiratory sinus arrythmia during deep breathing and resting HRV were lower in PD. Among all participants, there was a negative correlation between HRV and redilation velocity and a positive correlation between orthostatic change in heart rate and pupillary unrest. A modifying effect of PD was found on the association between high frequency HRV and pupillary unrest.
Results demonstrate simultaneous autonomic dysfunction in both pupillary and cardiac systems in PD. The correlations between pupillary and cardiac measures suggest shared central centers of autonomic integration, while the modifying effect of PD may reflect autonomic effects of PD-related pathology not present in controls.
non-motor features; Parkinson's disease; pupillography; pupil; cardiac physiology; autonomic dysfunction
Extend evidence suggesting that essential hypertension influences neuropsychological performance and that brain function prior to treatment is related to the success of pharmacological lowering of blood pressure (BP).
A voxel-based examination of the whole brain was conducted among forty-three hypertensive patients treated for one year with assessment pre and post treatment using positron emission tomography (PET) and neuropsychological testing.
Neuropsychological performance improved over the year of treatment, but was unrelated to change in regional cerebral blood flow (rCBF). Neither mean resting rCBF nor responsivity to a working memory task changed significantly with treatment. However, patients with greater lowering of systolic BP during treatment showed increased rCBF responsivity to a working memory task in medial and orbital frontal areas, and decreased rCBF responsivity in mid frontal, parietal, thalamus, and pons (as well as lower thalamic rCBF pre-treatment). Improved working memory performance over the treatment period was related to decreased responsivity in medial frontal, medullary, and parietal areas. Patients showing greater lowering of BP with treatment appeared to reduce excitatory and enhance inhibitory coupling between memory processing and BP more than those with less treatment success.
Degree of treatment success for both blood pressure and cognitive performance among hypertensives is related to differing patterns of rCBF. Overall, the results emphasize the relevance of brain function to the treatment of hypertension.
Positron emission tomography (PET); hypertension; pharmacological treatment; working memory
A laboratory study of older adults with osteoarthritis and their spouses was conducted to examine the unique influence of exposure to suffering on caregivers’ risk for impaired psychological and physical health. Spouses’ blood pressure (BP) and heart rate (HR) were monitored during 2 tasks designed to capture their partners’ suffering. First, spouses watched their partners (and a stranger) carry heavy logs across an 8-ft space for 3 min, a task that elicited pain expression. Second, spouses spoke about their partners’ suffering (and also about a typical meal with their partners). Results showed that spouses’ BP and HR increased when watching and talking about their partners’ suffering, and exposure to a partner’s suffering was more physiologically stressful than to a stranger’s suffering. These findings suggest that heightened physiological stress caused by exposure to a loved one’s suffering may be one pathway to caregivers’ increased risk for cardiovascular disease.
Cardiovascular reactivity; Caregiving; Interpersonal relationships; Osteoarthritis; Suffering
In older adults, maintaining balance and processing information typically interfere with each other, suggesting that executive functions may be engaged for both. We investigated associations between measures of inhibitory processes and standing postural control in healthy young and older adults. Perceptual and motor inhibition was measured using a protocol adapted from Nassauer and Halperin (2003, Dissociation of perceptual and motor inhibition processes through the use of novel computerized conflict tasks. Journal of the International Neuropsychological Society, 9, 25–30). These measures were then correlated to postural sway during standing conditions that required resolving various levels of sensory conflict, for example, world-fixed versus sway-referenced floor and visual scene. In the older adults, perceptual inhibition was positively correlated with sway amplitude on a sway-referenced floor and with a fixed visual scene (r = .68, p < .001). Motor inhibition was not correlated with sway on either group. Perceptual inhibition may be a component of the sensory integration process important for maintaining balance in older adults.
Attention; Balance; Inhibition; Sensory
The aim of this study was to evaluate the association between resting baroreflex sensitivity (BRS) and carotid intima–media thickness (IMT), a putative marker of sub-clinical atherosclerosis. Participants were 64 men and 18 women (median age, 57 years; range, 40 to 70 years), who did not have a previous history of coronary artery disease or treatment for hypertension. Resting BRS was measured during a 9-min baseline period using the noninvasive sequence technique; carotid IMT was subsequently determined using ultrasonography. Hierarchical multiple regression analyses showed that greater IMT in the carotid bulb (an area with a high density of baroreceptors) was associated with reduced BRS. These findings remained after adjusting BRS for resting mean arterial pressure, age, body mass index, gender, and smoking history, R2 = 0.06, P = .03. In contrast, IMT in the common and internal carotid regions (areas with presumably lower baroreceptor densities) did not account for a significant proportion of the variance in BRS. These results suggest that subclinical atherosclerosis, specifically in a region with high baroreceptor density, is associated with a reduced sensitivity of the baroreflex.
Atherosclerosis; baroreflex sensitivity; blood pressure; carotid arteries; intima–media thickness
Previous evidence suggests that the dual-specific A kinase-anchoring protein 2 functional polymorphism (AKAP10 (A/G) I646V) influences heart rate (HR) and heart rate variability (HRV) in mice and humans (N=122) with cardiovascular disease. Here, we asked whether this AKAP10 variant predicts HR and HRV in large sample of healthy humans. Resting HR and short-term time and frequency domain measures of HRV (5 min during paced and unpaced respiration conditions) were assessed in a U.S. community sample (N=1033) of generally healthy men and women (age 30–54) of European ancestry. Each person was genotyped for the AKAP10 variant. As with previous work, the AKAP10 Val allele predicted greater resting HR (Paced p<.01; Unpaced p<.03) and diminished HRV (Paced p’s<.05) suggesting that this variant may modulate the sensitivity of cardiac pacemaker cells to autonomic inputs possibly conferring risk for arrhythmias and sudden cardiac death.
The polyvagal theory states that social behavior is linked to cardiac vagal control. This theory has been tested widely in infants and children, but less so in adults. Thus, we examined if resting or stress-related changes in high-frequency heart rate variability (HF-HRV; a presumed index of vagal control) varied with social functioning in 50 healthy women (mean age 68 years). After completing assessments of social functioning, women were exposed to laboratory stressors with concurrent psychophysiological monitoring. Although stressor-induced suppression of HF-HRV was common, women with less stressor-induced suppression of HF-HRV reported more positive social functioning. Resting HF-HRV was not related to social functioning. These findings are at apparent odds with the polyvagal theory; however, they complement prior work suggesting that emotional self-regulation could plausibly modulate cardiac vagal control in association with social functioning.
Individual differences; Social factors; Blood pressure; Heart rate variability
To test whether current gray matter volume (GMV) covaried with previously obtained longitudinal measures of weight gain—as assessed by increases in body mass index (BMI)—among otherwise healthy postmenopausal women. Cross-sectional results indicate that reduced GMV may be associated with excess body weight.
Demographic, biometric, and behavioral measures were obtained from 48 women as part of the Pittsburgh Healthy Women Study, a longitudinal epidemiological investigation initiated between 1983 and 1984. In 2005 and 2006, these women took part in a brain imaging protocol.
Premenopausal BMI and a priori chosen confounding variables, including the number of years post menopause, an aggregate measure of perceived life stress spanning a 20-year period, resting blood pressure, total cerebral volume, and severity of white matter hyperintensities (a suspected indicator of aging-related silent cerebrovascular disease), explained ~22% of variance in total GMV. An additional 15% of the variance was uniquely explained by the change in BMI between pre- and postmenopausal longitudinal assessments, such that an increase in BMI predicted a greater reduction in GMV.
An increase in BMI during the menopausal transition and beyond is associated with reduced GMV among otherwise healthy women.
body mass index; gray matter volume; menopause; weight gain
The present study examines a measure of cardiac autonomic function, the heart rate variability (HRV), in a group of depressed elderly. Cardiac autonomic abnormalities have been implicated as a potential mediator of cardiovascular events and sudden death in depression. Because aging is associated with decreased cardiac vagal activity, it is possible that autonomic abnormalities are even more pronounced in the older depressed patients.
Cross-sectional comparison between those with or without depression. The groups were compared using the Wilcoxon matched-pair sign-rank test.
Advanced Center for Interventions and Services Research for Late-Life Mood Disorders at University of Pittsburgh Medical Center.
Fifty-three patients with major depression (mean age: 73.3; SD: 7.4; range: 60–93) and an equal number of age and gender-matched subjects as a comparison group.
Time domain and frequency domain measures of HRV.
The groups did not differ in any of the time domain or frequency domain measures of HRV. As expected, subjects without depression displayed decreasing cardiac vagal function with aging (Spearman correlation coefficient rs = −0.33, p = 0.02). However, there was no significant change in vagal function with age in the depressed (r = 0.12, p = 0.38). Post-hoc analysis using Fisher’s zr transformation revealed that the relationship between age and cardiac vagal function was significantly different between the groups (z = 2.32, p = 0.02).
Our findings suggest that age has differential influence on vagal function in individuals with and without depression, a difference with implications for cardiovascular disease risk in depression. Prospective studies of cardiac vagal activity in depressed patients with or without preexisting cardiac disease in different age groups are needed to replicate and extend these findings.
Depression; cardiac vagal function; heart rate variability; aging; coronary artery disease
Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 μg/kg) was administered via nasal spray followed by mood, nicotine reward (e.g. “liking”) and perception (e.g. “feel effects”) measures, physiological responses, sensory processing (pre-pulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine vs. placebo spray choice procedure. For the dopamine D4 receptor (DRD4 VNTR), presence of the 7 repeat allele was associated with greater aversive responses to nicotine (decreases in “vigor”, positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased “feel effects” and greater startle response, but in men only. Also observed in men but not women were other genetic associations, such as greater “feel effects” and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T SNP) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3’ VNTR (SLC6A3), and the mu opioid receptor A118G SNP (OPRM1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine prior to the onset of dependence and may do so differentially between men and women.
nicotine; sensitivity; genetics; dopamine; reward; reinforcement
A substantial epidemiological literature now supports the existence of a J- or U-shaped association between alcohol consumption and a broad range cardiovascular health outcomes including stroke. Although it is well documented that alcoholics exhibit both global and regional cerebral hypoperfusion in the sober state, little is known regarding the effects of a broader range of alcohol consumption on cerebral blood flow (CBF). The present study employed positron emission tomography with H215O to assess quantitative global and regional CBF in 86 participants (51 men and 35 women; mean age 60.1) as a function of self-reported weekly alcohol consumption (none, <1, 1 to <7, 7 to <15, and >15 drinks per week). Analyses controlling for age, gender, and vascular health (carotid intima-media thickness) revealed that, relative to the weighted population mean, global CBF was greater in the lightest alcohol consumption group (<1 per week) and lower in the heaviest (>15 per week). Effects did not vary across regions of interest. This report is the first to describe an inverted J-shaped relationship between alcohol consumption and CBF in the absence of stroke.
alcohol consumption; cerebral blood flow; positron emission tomography
Individuals who exhibit exaggerated blood pressure reactions to psychological stressors are at risk for hypertension, ventricular hypertrophy, and premature atherosclerosis; however, the neural systems mediating exaggerated blood pressure reactivity and associated cardiovascular risk in humans remain poorly defined. Animal models indicate that the amygdala orchestrates stressor-evoked blood pressure reactions via reciprocal signaling with corticolimbic and brainstem cardiovascular-regulatory circuits. Based on these models, we used a multimodal neuroimaging approach to determine whether human individual differences in stressor-evoked blood pressure reactivity vary with amygdala activation, gray matter volume, and functional connectivity with corticolimbic and brainstem areas implicated in stressor processing and cardiovascular regulation. We monitored mean arterial pressure (MAP) and concurrent functional magnetic resonance imaging BOLD signal changes in healthy young individuals while they completed a Stroop color-word stressor task, validated previously in epidemiological studies of cardiovascular risk. Individuals exhibiting greater stressor-evoked MAP reactivity showed (1) greater amygdala activation, (2) lower amygdala gray matter volume, and (3) stronger positive functional connectivity between the amygdala and perigenual anterior cingulate cortex and brainstem pons. Individual differences in amygdala activation, gray matter volume, and functional connectivity with corticolimbic and brainstem circuitsmaypartly underpin cardiovascular disease risk by impacting stressor-evoked blood pressure reactivity.
amygdala; blood pressure reactivity; cardiovascular disease risk; functional connectivity; individual differences; gray matter volume; stress
Chronic stress in non-human animals decreases the volume of the hippocampus, a brain region that supports learning and memory and that regulates neuroendocrine activity. In humans with stress-related psychiatric syndromes characterized by impaired learning and memory and dysregulated neuroendocrine activity, surrogate and retrospective indicators of chronic stress are also associated with decreased hippocampal volume. However, it is unknown whether chronic stress is associated with decreased hippocampal volume in those without a clinical syndrome. We tested whether reports of life stress obtained prospectively over an approximate 20-year period predicted later hippocampal grey matter volume in 48 healthy postmenopausal women. Women completed the Perceived Stress Scale repeatedly from 1985 to 2004; in 2005 and 2006, their hippocampal grey matter volume was quantified by voxel-based morphometry. Higher Perceived Stress Scale scores from 1985 to 2004—an indicator of more chronic life stress—predicted decreased grey matter volume in the right orbitofrontal cortex and right hippocampus. These relationships persisted after accounting for age, total grey matter volume, time since menopause, use of hormone therapy, subclinical depressive symptoms, and other potentially confounding behavioral and age-related cerebrovascular risk factors. The relationship between chronic life stress and regional grey matter volume—particularly in the hippocampus and orbitofrontal cortex—appears to span a continuum that extends to otherwise healthy individuals. Consistent with animal and human clinical evidence, we speculate that chronic-stress-related variations in brain morphology are reciprocally and functionally related to adaptive and maladaptive changes in cognition, neuroendocrine activity, and psychiatric vulnerability.
chronic life stress; hippocampus; orbitofrontal cortex; voxel-based morphometry
Hypertension is a risk factor for diffuse brain atrophy. Yet, there is little evidence that higher blood pressure predicts focal brain atrophy, as indicated by a lower volume of regional brain tissue. This voxel-based morphometry study tested (a) whether higher blood pressure predicts lower regional grey or white matter volume and (b) whether a blood-pressure-related reduction in regional brain tissue volume predicts poorer neuropsychological test performance. Participants were 76 men (M age = 61.33, SD = 4.95 years) and 58 women (M age = 59.86, SD = 5.10 years) without a cardiovascular, cerebrovascular, or neuropsychiatric disease. Results showed that among men, higher resting systolic blood pressure predicted lower grey matter volume in the supplementary motor area and adjacent superior frontal gyrus, the anterior cingulate cortex, and middle temporal gyrus. Among men, lower grey matter volume in the supplementary motor area also predicted a slower time to complete the Trail Making Part B Test of executive control and a poorer recall of items from the Four-word Short-term Memory Test of working memory. These relationships were independent of age, total brain tissue volume, educational history, severity of carotid atherosclerosis, and the extent of periventricular and subcortical white matter lesions. Among women, no statistically significant relationships were found between blood pressure, regional brain tissue volume, and cognitive function. These findings suggest a functional relationship among men between higher blood pressure, lower regional grey matter volume, and poorer cognitive function that is independent of other risk factors and confounding medical conditions.
Brain atrophy; Blood pressure; Cognitive function; Grey matter; Voxel-based morphometry
The anterior cingulate cortex presumptively regulates blood pressure reactions to behavioral stressors. There is little evidence in humans, however, that stressor-evoked changes in blood pressure correlate with concurrent changes in anterior cingulate activity. Using fMRI, we tested whether changes in mean arterial blood pressure correlate with ongoing changes in blood oxygen level dependent (BOLD) activation in 9 women and 11 men who completed a stressful Stroop color-word interference task. Higher mean arterial pressure during the Stroop task correlated with greater BOLD activation in two regions of the cingulate cortex (perigenual and mid-anterior) and in other networked brain regions, including the insula, thalamus, and periaqueductal gray. These results support the hypothesis that the anterior cingulate cortex regulates blood pressure reactions to behavioral stressors in humans.
Blood pressure; Cardiovascular reactivity; Functional magnetic resonance imaging; Stress