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1.  Regional cerebral blood flow correlates with heart period and high-frequency heart period variability during working-memory tasks: Implications for the cortical and subcortical regulation of cardiac autonomic activity 
Psychophysiology  2004;41(4):521-530.
The aim of the present study was to characterize the functional relationships between behaviorally evoked regional brain activation and cardiac autonomic activity in humans. Concurrent estimates of regional cerebral blood flow (rCBF; obtained by positron emission tomography), heart period, and high-frequency heart period variability (HFHPV; an indicator of cardiac parasympathetic activity) were examined in 93 adults (aged 50–70 years) who performed a series of increasingly difficult working-memory tasks. Increased task difficulty resulted in decreased heart period (indicating cardioacceleration) and decreased HF-HPV (indicating decreased cardiac parasympathetic activity). Task-induced decreases in heart period and HF-HPV were associated with concurrent increases and decreases in rCBF to cortical and subcortical brain regions that are speculated to regulate cardiac autonomic activity during behavioral processes: the medial-prefrontal, insular, and anterior cingulate cortices, the amygdala–hippocampal complex, and the cerebellum. These findings replicate and extend a small number of functional neuroimaging studies that suggest an important role for both cortical and subcortical brain systems in human cardiac autonomic regulation.
doi:10.1111/1469-8986.2004.00179.x
PMCID: PMC4301264  PMID: 15189475
Central cardiac autonomic regulation; Heart period; High-frequency heart period variability; Positron emission tomography
2.  Sleep Duration and Cardiovascular Responses to Stress in Undergraduate Men 
Psychophysiology  2013;51(1):10.1111/psyp.12144.
Short sleep has been related to incident cardiovascular disease, but physiological mechanisms accounting for this relationship are largely unknown. This study examines sleep duration and cardiovascular stress responses in 79 healthy, young men. Sleep duration was assessed by wrist actigraphy for seven nights. Participants then completed a series of laboratory stress tasks while heart rate and blood pressure were monitored. Shorter total sleep time was related to a greater reduction in high-frequency heart rate variability during stress tasks, and to prolonged elevations in heart rate and diastolic pressure following tasks. Associations were independent of age, race, body mass index, caffeine intake, and smoking status. In sum, healthy young men with shorter actigraphy-assessed sleep exhibit less cardiac vagal activity, and poorer heart rate and diastolic blood pressure recovery, upon encountering stressful stimuli, than those with longer sleep.
doi:10.1111/psyp.12144
PMCID: PMC3883723  PMID: 24016263
sleep; actigraphy; reactivity; recovery; heart rate; blood pressure; vagal; stress; heart rate variability
3.  UTILITY OF TOTAL CEREBRAL BLOOD FLOW AS AN IMAGING BIOMARKER OF KNOWN CARDIOVASCULAR RISKS 
Stroke; a journal of cerebral circulation  2013;44(9):10.1161/STROKEAHA.113.001716.
Background and Purpose
This study examined whether overall cerebral blood flow was associated with known vascular risk factors, including cardiometabolic risk factors that comprise the metabolic syndrome, carotid artery intima-media thickness, and the Framingham risk score.
Methods
Three separate samples were available for analysis. Two comparable samples were combined to form a primary sample of middle-aged participants (n=576, 30 to 55 years of age) that completed both a risk factor assessment and a resting brain scan. Samples were recruited via mailings and advertisements within an urban area. Quantitative measures of cerebral blood flow were derived from Arterial Spin Labeled magnetic resonance imaging in this and a validation/generalization sample (n=76, 30 to 55 years).
Results
Cerebral blood flow was inversely associated with cardiometabolic risk indices, i.e., associated with lower waist circumference, systolic blood pressure, glucose, and triglyceride and higher high density lipoprotein. Moreover, cerebral blood flow was also related to Framingham Risk and carotid intima-media thickness. In the validation sample, which employed a slightly different brain imaging technique, significant relationships were replicated for cardiometabolic risk, but not for Framingham risk.
Conclusions
Reduced cerebral blood flow appears to be a correlate of vascular disease risk factors associated with cardio-metabolic dysregulation. Cerebral blood flow may provide a valid imaging biomarker for cardiovascular risk.
doi:10.1161/STROKEAHA.113.001716
PMCID: PMC3808030  PMID: 23881956
4.  The Catechol-O-Methyltransferase Val158Met Polymorphism Modulates Organization of Regional Cerebral Blood Flow Response to Working Memory in Adults 
This study examined the effect of Catechol-O-Methyltransferase (COMT) Val158Met genotypes on the co-activation of brain areas involved in cognition during a working memory (WM) task. The pattern of concomitant region of interest (ROI) activation during WM performance varied by genotype: Val/Val showing the least and Met/Met the most covariance. There were no differences of performance on the WM task between the COMT genotypes. However, relatively better performance was associated with less concomitance of dorsolateral prefrontal cortex (DLPFC) and cingulate cortex for Val/Val, but more concomitance of DLPFC with AH for Met/Met. Within genotypes WM performance was significantly correlated with rCBF to the amygdala/hippocampus (AH) for Val/Val (r= 0.44, p=0.009), to the parietal lobe for Val/Met (r= 0.29, p=0.03), and to the thalamus for Met/Met (r= 0.32, p= 0.04). Different genotypes showed different regional specificity and concomitant activation patterns suggesting that varying dopamine availability induces different brain processing pathways to achieve similar WM performance.
doi:10.1016/j.ijpsycho.2013.06.023
PMCID: PMC3818354  PMID: 23810996
Catechol-o-methyltransferase (COMT); Dopamine; Working Memory; PET
5.  Long-chain, n-3 fatty acids and physical activity – independent and interactive associations with cardiac autonomic control 
International journal of cardiology  2012;167(5):2102-2107.
Background/Objectives
Intake of the marine-based, n-3 fatty acids and engagement in physical activity are inversely related to cardiac morbidity and mortality. Among putative mechanisms, both n-3 fatty acids and physical activity may act through modulation of autonomic control of the cardiovascular system. This investigation examined the independent and interactive associations of n-3 fatty acids (eicosapentaenoic and docosahexanenoic acid; EPA, DHA) and physical activity with heart rate variability (HRV).
Methods
Subjects were 259 healthy 30–54 year-old adults. Serum phospholipid fatty acid composition was employed as biomarker of dietary n-3 fatty acid exposure. Physical activity based on the Paffenbarger questionnaire was coded as < or ≥ 2,000 kcal/week. Standard time-domain (standard deviation of normal-to-normal intervals and root-mean squared of successive differences; SDNN, RMSSD) and frequency domain (high frequency and low frequency power) measures of HRV were derived from resting electrocardiographic recordings.
Results
In linear regression models with covariate adjustment for age, gender and race, greater n-3 fatty acid exposure was associated with greater SDNN and RMSSD, and high physical activity was associated with greater RMSSD. n-3 fatty acid exposure also predicted variation in SDNN, RMSSD, and high-frequency power in interaction with physical activity. Specifically, n-3 fatty acid exposure covaried positively with these three HRV indices only among participants expending 2,000 kcal per week or more in physical activity. These latter findings were noted for DHA but not EPA.
Conclusions
These results suggest that the cardiovascular benefits of n-3 fatty acid consumption may be mediated by effects on cardiac autonomic control and may be dependent upon concomitant habitual exercise.
doi:10.1016/j.ijcard.2012.05.110
PMCID: PMC3484192  PMID: 22704872
Harbaugh; Manuck; Jennings; Conklin; Yao; Muldoon
6.  From Brain to Behavior: Hypertension's Modulation of Cognition and Affect 
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.
doi:10.1155/2012/701385
PMCID: PMC3296233  PMID: 22518290
7.  Test-retest Reliability of an fMRI Paradigm for Studies of Cardiovascular Reactivity 
Psychophysiology  2012;49(7):873-884.
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.
doi:10.1111/j.1469-8986.2012.01382.x
PMCID: PMC3376244  PMID: 22594784
fMRI; cardiovascular reactivity; test-retest reliability
8.  Brain function, cognition, and the blood pressure response to pharmacological treatment 
Psychosomatic medicine  2010;72(7):702-711.
Objective
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).
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/PSY.0b013e3181e7c1a2
PMCID: PMC2939313  PMID: 20639391
Positron emission tomography (PET); hypertension; pharmacological treatment; working memory
9.  Detecting age differences in inhibition processes with a test of perceptual and motor inhibition 
Experimental aging research  2011;37(2):179-197.
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.
doi:10.1080/0361073X.2011.554512
PMCID: PMC3064447  PMID: 21424956
Reaction time; executive function; reliability; human performance; processing speed; response choice
10.  Cerebrovascular support for cognitive processing in hypertensive patients is altered by blood pressure treatment 
Hypertension  2008;52(1):65-71.
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.
doi:10.1161/HYPERTENSIONAHA.108.110262
PMCID: PMC2980821  PMID: 18519845
Hypertension; Cerebral Blood Flow; Magnetic Resonance Imaging; Positron Emission Tomography; Beta-blocker; Angiotensin Converting Enzyme Inhibitor
11.  Is the brain the essential in hypertension? 
NeuroImage  2009;47(3):914-921.
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.
doi:10.1016/j.neuroimage.2009.04.072
PMCID: PMC2719688  PMID: 19410005
hypertension; regional cerebral blood flow; neuropsychology; brain morphology; cognitive processing; positron emission tomography; magnetic resonance imaging
12.  BRAIN IMAGING FINDINGS PREDICT BLOOD PRESSURE RESPONSE TO PHARMACOLOGICAL TREATMENT 
Hypertension  2008;52(6):1113-1119.
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.
doi:10.1161/HYPERTENSIONAHA.108.120196
PMCID: PMC2713360  PMID: 18981325
Hypertension; magnetic resonance imaging; positron emission imaging; atenolol; lisinopril; cerebral blood flow; blood pressure treatment
13.  Efficient and Cost-effective Estimation of the Influence of Respiratory Variables on Respiratory Sinus Arrhythmia 
Psychophysiology  2010;48(4):488-494.
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.
doi:10.1111/j.1469-8986.2010.01086.x
PMCID: PMC2990812  PMID: 20718933
14.  Autonomic Insufficiency in Pupillary and Cardiovascular Systems in Parkinson's Disease 
Parkinsonism & related disorders  2010;17(2):119-122.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.parkreldis.2010.11.005
PMCID: PMC3034773  PMID: 21115264
non-motor features; Parkinson's disease; pupillography; pupil; cardiac physiology; autonomic dysfunction
15.  Spouses’ Cardiovascular Reactivity to Their Partners’ Suffering 
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.
doi:10.1093/geronb/gbp133
PMCID: PMC2821945  PMID: 20067977
Cardiovascular reactivity; Caregiving; Interpersonal relationships; Osteoarthritis; Suffering
16.  Grand Challenges in Psychosomatic Research 
doi:10.3389/fpsyt.2010.00131
PMCID: PMC3059634  PMID: 21423442
17.  Perceptual Inhibition is Associated with Sensory Integration in Standing Postural Control Among Older Adults 
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.
doi:10.1093/geronb/gbp060
PMCID: PMC2800814  PMID: 19617457
Attention; Balance; Inhibition; Sensory
18.  Greater Intima–Media Thickness in the Carotid Bulb Is Associated With Reduced Baroreflex Sensitivity 
American journal of hypertension  2002;15(6):486-491.
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.
PMCID: PMC2914604  PMID: 12074348
Atherosclerosis; baroreflex sensitivity; blood pressure; carotid arteries; intima–media thickness
19.  AKAP10 (I646V) Functional Polymorphism Predicts Heart Rate and Heart Rate Variability in Apparently Healthy, Middle-aged European-Americans 
Psychophysiology  2009;46(3):466-472.
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.
PMCID: PMC2890278  PMID: 19496216
20.  Cardiac vagal activity during psychological stress varies with social functioning in older women 
Psychophysiology  2008;45(6):1046-1054.
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.
doi:10.1111/j.1469-8986.2008.00698.x
PMCID: PMC2866176  PMID: 18823424
Individual differences; Social factors; Blood pressure; Heart rate variability
21.  Gain in Adiposity Across 15 Years is Associated With Reduced Gray Matter Volume in Healthy Women 
Psychosomatic medicine  2009;71(5):485-490.
Objective
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.
Methods
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.
Results
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.
Conclusions
An increase in BMI during the menopausal transition and beyond is associated with reduced GMV among otherwise healthy women.
doi:10.1097/PSY.0b013e3181a5429d
PMCID: PMC2863115  PMID: 19483122
body mass index; gray matter volume; menopause; weight gain
22.  Heart Rate Variability in Depressed Elderly 
Objective
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.
Design
Cross-sectional comparison between those with or without depression. The groups were compared using the Wilcoxon matched-pair sign-rank test.
Setting
Advanced Center for Interventions and Services Research for Late-Life Mood Disorders at University of Pittsburgh Medical Center.
Participants
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.
Intervention
None.
Measurements
Time domain and frequency domain measures of HRV.
Results
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).
Conclusions
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.
doi:10.1097/JGP.0b013e318180053d
PMCID: PMC2768037  PMID: 18978247
Depression; cardiac vagal function; heart rate variability; aging; coronary artery disease
23.  GENE AND GENE BY SEX ASSOCIATIONS WITH INITIAL SENSITIVITY TO NICOTINE IN NONSMOKERS 
Behavioural pharmacology  2008;19(5-6):630-640.
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.
doi:10.1097/FBP.0b013e32830c3621
PMCID: PMC2743299  PMID: 18690117
nicotine; sensitivity; genetics; dopamine; reward; reinforcement
24.  Alcohol Consumption and Cerebral Blood Flow Among Older Adults 
Alcohol (Fayetteville, N.Y.)  2008;42(4):269-275.
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.
doi:10.1016/j.alcohol.2008.03.132
PMCID: PMC2527510  PMID: 18539247
alcohol consumption; cerebral blood flow; positron emission tomography
25.  Individual Differences in Stressor-Evoked Blood Pressure Reactivity Vary with Activation, Volume, and Functional Connectivity of the Amygdala 
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.
doi:10.1523/JNEUROSCI.3606-07.2008
PMCID: PMC2526972  PMID: 18216206
amygdala; blood pressure reactivity; cardiovascular disease risk; functional connectivity; individual differences; gray matter volume; stress

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