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1.  Early life stress impacts dorsolateral prefrontal cortex functional connectivity in healthy adults: informing future studies of antidepressant treatments 
Exposure to early life stress (ELS) is strongly associated with poor treatment outcomes, particularly for trauma-associated disorders such as depression. Little research to date, however, has examined the potential effects of ELS on outcomes with newer treatments, such as repetitive transcranial magnetic stimulation (rTMS). This study evaluated whether ELS exposure impacts resting state functional connectivity associated with brain regions targeted by rTMS. Twenty-seven medication-free adults without psychiatric or medical illness (14 with a history of at least moderate ELS) were scanned using a 3T magnetic resonance imaging (MRI) scanner during two 4-minute rest periods. The primary targets of rTMS, the left and right dorsolateral prefrontal cortex (DLPFC), were utilized as seed regions in connectivity analyses. Relative to controls, when seeding the left DLPFC, ELS subjects demonstrated significantly increased local connectivity with the left middle frontal gyrus and negative connectivity with the left precuneus. ELS status was also associated with negative connectivity from the right DLPFC to the left precuneus and left inferior parietal lobule. These findings demonstrate greater dissociation between the executive and default mode networks in individuals with a history of ELS, and these results may inform neuroimaging assessments in future rTMS studies of ELS-related conditions.
PMCID: PMC3955403  PMID: 24513500
Early life stress; repetitive transcranial magnetic stimulation; dorsolateral prefrontal cortex; default mode network; functional connectivity; functional magnetic resonance imaging
2.  Regional homogeneity and resting state functional connectivity: associations with exposure to early life stress 
Psychiatry research  2013;214(3):10.1016/j.pscychresns.2013.07.013.
Early life stress (ELS) confers risk for psychiatric illness. Previous literature suggests ELS is associated with decreased resting-state functional connectivity (rs-FC) in adulthood, but there are no studies of resting-state neuronal activity in this population. This study investigated whether ELS-exposed individuals demonstrate resting-state activity patterns similar to those found in PTSD. Twenty-seven adults (14 with at least moderate ELS), who were medication-free and without psychiatric or medical illness, underwent MRI scans during two 4-minute rest periods. Resting-state activity was examined using regional homogeneity (ReHo), which estimates regional activation patterns through indices of localized concordance. ReHo values were compared between groups, followed by rs-FC analyses utilizing ReHo-localized areas as seeds to identify other involved regions. Relative to controls, ELS subjects demonstrated diminished ReHo in the inferior parietal lobule (IPL) and superior temporal gyrus (STG). ReHo values were inversely correlated with ELS severity. Secondary analyses revealed decreased rs-FC between the IPL and right precuneus/posterior cingulate, left fusiform gyrus, cerebellum and caudate in ELS subjects. These findings indicate that ELS is associated with altered resting-state activity and connectivity in brain regions involved in trauma-related psychiatric disorders. Future studies are needed to evaluate whether these associations represent potential imaging biomarkers of stress exposure.
PMCID: PMC3849340  PMID: 24090510
posttraumatic stress disorder; resting state activity; inferior parietal lobule; superior temporal gyrus
3.  Early Life Stress is Associated with Greater Default Network Deactivation During Working Memory in Healthy Controls: A Preliminary Report 
Brain imaging and behavior  2013;7(2):204-212.
Early life stress (ELS) is a common risk factor for psychopathology, but there are few functional neuroimaging studies investigating its effects. In this preliminary study, we investigated the correlates of ELS exposure on the default network (DN) through measurements of task-associated DN deactivation. Data were analyzed from 19 subjects without psychiatric illness (10 with ELS). Subjects performed the working memory (WM) N-back task (including a 2-back WM and 0-back control condition) while undergoing functional MRI. We compared brain responses in the two groups across 5 bilateral DN regions using an a priori region of interest (ROI) analysis. The ELS group demonstrated significantly greater DN deactivation, observed in the right posterior cingulate cortex PCC, bilateral medial prefrontal cortex, left middle/superior frontal gyrus and right middle temporal region. These preliminary results indicate subjects with ELS demonstrate greater DN deactivations to WM challenges compared to non-ELS controls, potentially reflecting a biomarker of long-term effects of ELS exposure.
PMCID: PMC3632656  PMID: 23269472
Early Life Stress; Default Network; Working Memory; Medial Prefrontal Cortex; FMRI
4.  Decreased Default Network Connectivity is Associated with Early Life Stress in Medication-Free Healthy Adults 
Early life stress (ELS) is a significant risk factor for psychopathology, although there are few functional imaging studies investigating its effects. Previous literature suggests that ELS is associated with changes in structure and function in the medial prefrontal cortex (MPFC), which forms the main anterior node of the default network (DN). This study investigated the impact of ELS history on resting state DN connectivity, using seed-based correlation analyses (SCA) involving the posterior cingulate cortex (PCC). Data were analyzed from 22 adult subjects without psychiatric or medical illness (13 with and 9 without ELS); none were taking psychotropic medication. Relative to controls, the ELS group had significant decreases in DN connectivity, observed between the PCC seed and the MPFC and inferior temporal cortex. Further analyses revealed a trend-level increase in connectivity between the amygdala and MPFC associated with ELS history. In conclusion, this study found that subjects with ELS, in the absence of psychiatric illness and medication exposure, demonstrated decreased DN connectivity, and trend-level increases in connectivity between the amygdala and MPFC. These findings suggest that altered resting state connectivity is a correlate of stress exposure, rather than a product of medication or psychiatric morbidity.
PMCID: PMC3581700  PMID: 23141153
Default Network; Early Life Stress; Resilience; Functional Connectivity; Post Traumatic Stress Disorder; Medial Prefrontal Cortex
5.  Decreases in BMI After Cardiac Rehabilitation Predict Improved Cognitive Function in Older Adults with Heart Failure 
PMCID: PMC4243583  PMID: 25413196
Cardiac rehabilitation; heart failure; cognitive function; body mass index
6.  Cognitive Dysfunction Mediates the Effects of Poor Physical Fitness on Decreased Functional Independence in Heart Failure 
Heart failure (HF) patients require assistance with activities of daily living (ADL). Poor physical fitness has recently been identified as a contributor to the high rates of disability in HF, though the mechanisms for such effects are unclear. Although not previously examined, decreased fitness may adversely impact ADLs in HF through its known association with cognitive impairment, a key correlate of self-care abilities in this population. We sought to test this possibility using a model-based approach.
197 patients with HF completed a physical fitness test and a neuropsychological test battery. A total ADL composite was derived from the Lawton Brody scale. Structural equation modeling tested whether cognitive function mediated the association between physical fitness and total ADLs.
Fitness was reduced and cognitive dysfunction and impaired ADLs were prevalent. The initially significant association between fitness and total ADLs was attenuated when cognitive function was introduced as a mediator. This model demonstrated good fit (CFI = .91: RMSEA = .077) with a significant indirect pathway between physical fitness and total ADLs through cognitive function: Decreased physical fitness was associated with cognitive dysfunction (β = 0.35), which predicted greater assistance with ADLs (β = 0.22).
Poor physical fitness may lead to decreased functional independence in HF through its negative effects on cognitive function. Prospective studies are needed to confirm our findings, identify other mechanisms by which poor fitness impacts ADLs, and examine whether exercise interventions can improve cognition and help preserve ADL independence in HF.
PMCID: PMC4136991  PMID: 24533907
Physical fitness; cognitive function; heart failure; activities of daily living
7.  Atrial Fibrillation Exacerbates Cognitive Dysfunction and Cerebral Perfusion in Heart Failure 
Heart failure (HF) increases risk for cognitive impairment in part due to the negative effects of cardiac dysfunction on cerebral perfusion. Atrial fibrillation (AF), an independent risk factor for cognitive impairment, often accompanies HF and is associated with lower systemic perfusion. However, no study has examined the associations among AF, cognitive function, and cerebral perfusion in patients with HF.
187 HF patients completed neuropsychological testing and underwent transcranial Doppler ultrasonography. Cerebral blood flow velocity of the middle cerebral artery (CBF-V) operationalized cerebral perfusion. A medical chart review ascertained AF.
32.1% of HF patients had a history of AF. HF patients with AF exhibited worse global cognition, memory, and CBF-V relative to patients without AF. These effects remained after HF severity and other demographic and medical factors were taken into account. Partial correlations controlling for possible confounds showed decreased CBF-V predicted worse cognition in multiple domains in the overall sample (r = 0.13 to 0.15, p < 0.05) and in the subgroup of HF patients with AF (r = 0.26 to r = 0.28, p < 0.05), but not among HF patients without AF.
AF exacerbates cognitive deficits in HF possibly through its association with decreased cerebral perfusion. Longitudinal studies are needed to determine whether AF accelerates cognitive decline in HF and whether medical (e.g., ablation) and lifestyle interventions (e.g., exercise programs) that target cerebral perfusion improve cognitive outcomes in patients with HF and AF.
PMCID: PMC4308558  PMID: 25492027
Heart failure; atrial fibrillation; cognitive function; cerebral blood flow
8.  Clarifying the Neural Basis for Incentive Salience of Tobacco Cues in Smokers 
Psychiatry research  2014;223(3):218-225.
In functional magnetic resonance imaging (fMRI) studies, smoking cues have been found to elicit increases in brain activity in regions associated with processing rewarding and emotional stimuli. However, most smoking cue studies to date have reported effects relative to neutral control stimuli with no incentive properties, making it unclear whether the observed activation pertains to value in general or the value of cigarettes in particular. The current fMRI study sought to clarify the neural activity reflecting tobacco-specific incentive value versus domain-general incentive value by examining smoking cues, neutral cues, and a third set of cues, monetary cues, which served as an active control condition. Participants were 42 male daily smokers. Compared to neutral cues, significantly greater activation was found in the left ventral striatum in response to tobacco and money cues. Monetary cues also elicited significantly increased activation in the right inferior frontal gyrus and cuneus compared to the other two cue types. Overall, the results suggest that the salience of monetary cues was the highest and, as a result, may have reduced the incentive salience of tobacco cues.
PMCID: PMC4125499  PMID: 25035299
Tobacco; Nicotine; Cues; Incentive Salience; Money; fMRI
9.  Brain response to food stimulation in obese, normal weight, and successful weight loss maintainers 
Obesity (Silver Spring, Md.)  2012;20(11):2220-2225.
As many people struggle with maintenance of weight loss, the study of successful weight loss maintainers (SWLM) can yield important insights into factors contributing to weight loss maintenance. However, little research has examined how SWLM differ from people who are obese or normal weight (NW) in brain response to orosensory stimulation. The goal of this study was to determine if SWLM exhibit different brain responses to orosensory stimulation. Brain response to one-minute orosensory stimulation with a lemon lollipop was assessed using functional magnetic resonance imaging (FMRI) among 49 participants, including SWLM (n=17), NW (n=18) and obese (n=14) controls. Significant brain responses were observed in nine brain regions, including the bilateral insula, left inferior frontal gyrus, left putamen, and other sensory regions. All regions also exhibited significant attenuation of this response over one minute. The SWLM exhibited greater response compared to the other groups in all brain regions. Findings suggest that the response to orosensory stimulation peaks within 40 seconds and attenuates significantly between 40-60 seconds in regions associated with sensation, reward, and inhibitory control. Greater reactivity among the SWLM suggests that greater sensory reactivity to orosensory stimulation, increased anticipated reward, and subsequently greater inhibitory processing are associated with weight loss maintenance.
PMCID: PMC3483466  PMID: 22569002
Functional Magnetic Resonance Imaging; Functional Neuroimaging; Weight Loss Maintenance
10.  The Impact of Hypertension on Cerebral Perfusion and Cortical Thickness in Older Adults 
Hypertension may increase risk for dementia possibly because of its association with decreased cortical thickness. Disturbed cerebral autoregulation is one plausible mechanism by which hypertension impacts the cerebral structure, but the associations among hypertension, brain perfusion, and cortical thickness are poorly understood.
The current sample consisted of 58 older adults with varying levels of vascular disease. Diagnostic history of hypertension and antihypertensive medication status was ascertained through self-report and, when available, confirmed by medical record review. All participants underwent arterial spin labeling and T1-weighted magnetic resonance imaging (MRI) to quantify total and regional cortical perfusion and thickness.
Analysis of covariance adjusting for medical variables showed that participants with hypertension exhibited reduced temporal and occipital brain perfusion as well as total and regional cortical thickness relative to those without hypertension. The effects of hypertension on total brain perfusion remained unchanged even after adjustment for age, though no such pattern emerged for cortical thickness. Decreased total brain perfusion predicted reduced thickness of the total brain as well as of the frontal, temporal, and parietal lobe cortices. Antihypertensive treatment was not associated with total cerebral perfusion or cortical thickness.
This study provides initial evidence for the adverse effects of a diagnostic history of hypertension on brain hypoperfusion and reduced cortical thickness. Longitudinal studies are needed to investigate the role of hypertension and its interaction with other contributing factors (e.g., age) in the manifestation of cerebral hypoperfusion and reduced cortical thickness.
PMCID: PMC4143798  PMID: 25151318
Hypertension; cerebral perfusion; arterial spin labeling; cortical thickness
11.  Dissociable Brain Signatures of Choice Conflict and Immediate Reward Preferences in Alcohol Use Disorders 
Addiction biology  2012;19(4):743-753.
Impulsive delayed reward discounting (DRD) is an important behavioral process in alcohol use disorders (AUDs), reflecting incapacity to delay gratification. Recent work in neuroeconomics has begun to unravel the neural mechanisms supporting DRD, but applications of neuroeconomics in relation to AUDs have been limited. This study examined the neural mechanisms of DRD preferences in AUDs, with emphasis on dissociating activation patterns based on DRD choice type and level of cognitive conflict. Heavy drinking adult males with (n = 13) and without (n = 12) a diagnosis of an AUD completed a monetary DRD task during a functional magnetic resonance imaging scan. Participant responses were coded based on choice type (impulsive vs. restrained) and level of cognitive conflict (easy vs. hard). AUD+ participants exhibited significantly more impulsive DRD decision-making. Significant activation during DRD was found in several decision-making regions, including dorsolateral prefrontal cortex (DLPFC), insula, posterior parietal cortex (PPC), and posterior cingulate. An axis of cognitive conflict was also observed, with hard choices associated with anterior cingulate cortex and easy choices associated with activation in supplementary motor area. AUD+ individuals exhibited significant hyperactivity in regions associated with cognitive control (DLPFC) and prospective thought (PPC) and exhibited less task-related deactivation of areas associated with the brain's default network during DRD decisions. This study provides further clarification of the brain systems supporting DRD in general and in relation to AUDs.
PMCID: PMC3871988  PMID: 23231650
Alcohol use disorders; delay discounting; neuroeconomics
12.  The Neuroeconomics of Alcohol Demand: An Initial Investigation of the Neural Correlates of Alcohol Cost–Benefit Decision Making in Heavy Drinking Men 
Neuropsychopharmacology  2014;39(8):1988-1995.
Neuroeconomics integrates concepts and methods from psychology, economics, and cognitive neuroscience to understand how the brain makes decisions. In economics, demand refers to the relationship between a commodity's consumption and its cost, and, in behavioral studies, high alcohol demand has been consistently associated with greater alcohol misuse. Relatively little is known about how the brain processes demand decision making, and the current study is an initial investigation of the neural correlates of alcohol demand among heavy drinkers. Using an event-related functional magnetic resonance imaging (fMRI) paradigm, participants (N=24) selected how much they would drink under varying levels of price. These choices determined access to alcohol during a subsequent bar laboratory self-administration period. During decisions to drink in general, greater activity was present in multiple distinct subunits of the prefrontal and parietal cortices. In contrast, during decisions to drink that were demonstrably affected by the cost of alcohol, significantly greater activation was evident in frontostriatal regions, suggesting an active interplay between cognitive deliberation and subjective reward value. These choices were also characterized by significant deactivation in default mode network regions, suggesting suppression resulting from greater cognitive load. Across choice types, the anterior insula was notably recruited in diverse roles, further implicating the importance of interoceptive processing in decision-making behavior. These findings reveal the neural signatures subserving alcohol cost–benefit decision making, providing a foundation for future clinical applications of this paradigm and extending this approach to understanding the neural correlates of demand for other addictive commodities.
PMCID: PMC4059908  PMID: 24584331
13.  Effects of Nicotine Deprivation and Replacement on BOLD-fMRI Response to Smoking Cues as a Function of DRD4 VNTR Genotype 
Nicotine & Tobacco Research  2014;16(7):939-947.
Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms.
Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥1 copy of ≥7 repeats] or short [S: 2 copies ≤6 repeats] genotype) of 6 a priori regions of interest.
Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch.
Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.
PMCID: PMC4072897  PMID: 24659022
14.  Higher BMI is associated with reduced brain volume in heart failure 
BMC obesity  2014;1(1):4-.
Heart failure (HF) patients are at risk for structural brain changes due to cerebral hypoperfusion. Past work shows obesity is linked with reduced cerebral blood flow and associated with brain atrophy in healthy individuals, although its effects on the brain in HF are unclear. This study examined the association among body mass index (BMI), cerebral perfusion, and brain volume in HF patients.
Eighty HF patients underwent transcranial Doppler sonography to quantify cerebral blood flow velocity of the middle cerebral artery (CBF-V of the MCA) and brain magnetic resonance imaging (MRI) to quantify total brain, total and subcortical gray matter, white matter volume, and white matter hyperintensities. Body mass index (BMI) operationalized weight status. Nearly 45% of HF patients exhibited a BMI consistent with obesity. Regression analyses adjusting for medical variables, demographic characteristics, and CBF-V of the MCA, showed increased BMI was associated with reduced white matter volume (p <.05). BMI also interacted with cerebral perfusion to impact total gray matter volume, but this pattern did not emerge for any other MRI indices (p < 0.05).
Our findings suggest increased BMI negatively affects brain volume in HF, and higher BMI interacts with cerebral perfusion to impact gray matter volume. The mechanisms for these findings remain unclear and likely involve multiple physiological processes. Prospective studies are needed to elucidate the exact pattern and rates of brain changes in obese HF persons.
PMCID: PMC4431695  PMID: 25984353
Brain volume; Cerebral blood flow; Heart failure; Neuroimaging; Obesity
16.  Decreased Physical Activity Predicts Cognitive Dysfunction and Reduced Cerebral Blood Flow in Heart Failure 
Cognitive impairment in heart failure (HF) is believed to result from brain hypoperfusion subsequent to cardiac dysfunction. Physical inactivity is prevalent in HF and correlated with reduced cardiac and cognitive function. Yet, no longitudinal studies have examined the neurocognitive effects of physical inactivity in HF. The current study examined whether reduced physical activity increases risk for cognitive impairment and brain hypoperfusion over time in HF.
At baseline and 12-months later, 65 HF patients underwent neuropsychological testing, transcranial doppler ultrasonography, and were asked to wear an accelerometer for seven days.
Lower baseline step count and less time spent in moderate free-living activity best predicted worse attention/executive function and decreased cerebral perfusion at the 12-month follow-up. Decreased baseline cerebral perfusion also emerged as a strong predictor of poorer 12-month attention/executive function.
Lower physical activity predicted worse cognition and cerebral perfusion 12-months later in HF. Physical inactivity in HF may contribute to cognitive impairment and exacerbate risk for conditions such as Alzheimer’s disease. Larger studies are needed to elucidate the mechanisms by which physical inactivity leads to cognitive dysfunction in HF, including clarification of the role of cerebral hypoperfusion.
PMCID: PMC4009239  PMID: 24581672
Physical activity; heart failure; cognitive function; cerebral blood flow; sedentary; accelerometry; neuropsychology
17.  Reduced Cerebral Perfusion Predicts Greater Depressive Symptoms and Cognitive Dysfunction at a One Year Follow-up in Patients with Heart Failure 
Cerebral hypoperfusion is common in heart failure (HF) and believed to underlie poor neurocognitive outcomes in this population. Up to 42% of HF patients also exhibit depressive symptomatology that may stem from reduced cerebral blood flow. However, no study has examined this possibility or whether reduced brain perfusion increases risk for future cognitive dysfunction in older adults with HF.
100 HF patients underwent transcranial doppler ultrasonagraphy to quantify global cerebral blood flow velocity (CBF-V) and were administered a cognitive test battery to assess global cognition, attention/executive function, and memory abilities. All participants then completed the Beck Depression Inventory-II to assess depressive symptomatology. These procedures were performed at baseline and a 12-month follow-up.
Repeated measures revealed CBF-V declined over the 12-month period. Regression analyses showed reduced baseline CBF-V predicted worse performances in attention/executive function (p < 0.05 for all) and a trend for memory (p = 0.09) in addition to greater depressive symptomatology (p < 0.05) at the 12-month follow-up, even after controlling for baseline factors and medical and demographic variables.
Cerebral perfusion declined over time and was associated with poorer cognitive function and greater depressive symptoms at a 1-year follow-up in HF. Prospective studies with long-term follow-ups that employ neuroimaging are needed to examine whether cognitive dysfunction and depression in HF stems from the adverse effects of cerebral hypoperfusion on the cerebral structure.
PMCID: PMC3949179  PMID: 24022882
Cerebral blood flow; cognitive function; depression; heart failure
18.  Cognitive Performance in Older Adults with Stable Heart Failure: Longitudinal Evidence for Stability and Improvement 
Cognitive impairment is prevalent in heart failure (HF), though substantial variability in the pattern of cognitive impairment is found across studies. To clarify the nature of cognitive impairment in HF, we examined longitudinal trajectories across multiple domains of cognition in HF patients using latent growth class modeling. 115 HF patients completed a neuropsychological battery at baseline, 3-months and 12-months. Participants also completed the Beck Depression Inventory-II (BDI-II). Latent class growth analyses revealed a three-class model for attention/executive function, four-class model for memory, and a three-class model for language. The slope for attention/executive function and language remained stable, while improvements were noted in memory performance. Education and BDI-II significantly predicted the intercept for attention/executive function and language abilities. The BDI-II also predicted baseline memory. The current findings suggest that multiple performance-based classes of neuropsychological test performance exist within cognitive domains, though case-controlled prospective studies with extended follow-ups are needed to fully elucidate changes and predictors of cognitive function in HF.
PMCID: PMC3858403  PMID: 23906182
Heart failure; trajectories; cognitive function; longitudinal; cognitive profile
19.  Item-Based Analysis of Delayed Reward Discounting Decision Making 
Behavioural processes  2014;103:256-260.
Delayed reward discounting (DRD) is a behavioral economic index of time preference, referring to how much an individual devalues a reward based on its delay in time, and has been linked to a wide array of health behaviors. It is commonly assessed using a task that asks participants to make dichotomous choices between two monetary rewards, one available immediately and the other after a delay. This study sought to shorten an extended iterative DRD assessment to increase its versatility and efficiency. Data were drawn from two young adult samples, an exploratory sample (N = 130) and a confirmatory sample (N = 247). In the exploratory sample, eight items were identified as predicting the majority of the variance in the full task area under the curve (AUC) (R2 = .821; p < .001). In the confirmatory sample, the same eight items similarly predicted the majority of variance in the full task AUC (R2 = .844, p < .001). These results provide initial support for the validity of a brief 8-item assessment of DRD. Priorities for further validation and potential applications are discussed.
PMCID: PMC4007755  PMID: 24440196
Decision Making; Delay Discounting; Impulsivity; Reward
20.  The Synergistic Effects of Anxiety and Cerebral Hypoperfusion on Cognitive Dysfunction in Older Adults with Cardiovascular Disease 
Anxiety is a risk factor for cardiovascular disease (CVD) and is associated with neurocognitive outcomes. The effect of anxiety on brain perfusion in a CVD population has yet to be examined and no study has investigated the interactive effects of anxiety and cerebral perfusion on cognition.
55 older adults with CVD completed the Beck Anxiety Inventory (BAI) and underwent arterial spin labeling to quantify cortical perfusion and thickness. Participants were administered the Mini Mental State Examination(MMSE) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
Reduced perfusion predicted poorer cognition and decreased cortical thickness. Higher anxiety score predicted worse memory performance and decreased frontal perfusion. Frontal lobe hypoperfusion combined with increased BAI scores exacerbated poorer MMSE performance.
Higher anxiety may exacerbate the effects of cerebral hypoperfusion on cognitive impairment. Longitudinal studies are needed to confirm our findings, and determine whether anxiety treatment improves neurocognitive outcomes in CVD.
PMCID: PMC4289129  PMID: 25009160
Arterial Spin Labeling; Anxiety; Cerebral blood flow; Cognitive Function; Cardiovascular Disease; Neuroimaging; Cerebrovascular disease; Magnetic Resonance Imaging
21.  Cerebrovascular Perfusion among Older Adults is Moderated by Strength Training and Gender 
Neuroscience letters  2013;560:26-30.
Cerebral perfusion is important in older adults as it is linked to cognitive declines. Physical activity can improve blood flow in the body but little is known about the relationship between physical activity and cerebral perfusion in older adults. In particular, no study has investigated the relation between strength training and cerebral perfusion. We examined whether different types of physical activity (assessed with the Rapid Assessment of Physical Activity questionnaire) were associated with MRI cerebrovascular perfusion in 59 older adults. There was a significant interaction between gender and strength training, such that women who engaged in strength training (weight lifting or calisthenics) at least once per week exhibited significantly greater cerebrovascular perfusion than women who did not. This interaction remained significant after controlling for other physical activity, demographics, and health variables. These findings suggest that regular strength training can be beneficial for cerebrovascular health in women.
PMCID: PMC3920729  PMID: 24355360
cerebral perfusion; strength training; sex; physical activity; ASL
22.  Left Atrial Size is Independently Associated with Cognitive Function 
Left atrial (LA) diameter is easily attainable from echocardiograph and sensitive to underlying cardiovascular disease severity, though its association with neurocognitive outcomes is not well understood. Fifty older adults (64.50 ± 9.41 years) recruited from outpatient cardiology clinics and local papers underwent magnetic resonance imaging (MRI), were administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and completed psychosocial self-report measures. LA diameter was quantified using echocardiogram. Hierarchical regression analyses revealed greater LA size was independently associated with reduced performance on the following RBANS composites: language, delayed memory, and total index (p < .05 for all). Hierarchical regression analysis demonstrated no significant association between LA diameter and whole brain volume (p > .05). The current study suggests that greater LA size is associated with cognitive dysfunction in older adults and prospective studies are needed to validate these findings and elucidate underlying mechanisms.
PMCID: PMC4166650  PMID: 23394115
Left Atrial Diameter; Cognitive Function; Cardiovascular Disease; Echocardiogram; Neuroimaging; Cerebrovascular disease
23.  The Interactive Effects of Cerebral Perfusion and Depression on Cognitive Function in Older Adults with Heart Failure 
Psychosomatic medicine  2013;75(7):632-639.
Depression is common among persons with heart failure (HF) and has been linked to cognitive impairment in this population. The mechanisms of this relationship are unclear, and the current study examined whether cerebral perfusion moderates the association between depressive symptomatology and cognitive impairment in patients with HF.
Persons with HF (N=89; 67.61 (SD = 11.78) years of age) completed neuropsychological testing and impedance cardiography. Depressive symptomatology was assessed using the Beck Depression Inventory-II and transcranial doppler was used to quantify cerebral perfusion.
Depression was associated with reduced performance on tasks assessing attention/executive function (r=−0.28), language (r=−.0.30) and motor function (r=−.28) in unadjusted models (p-values < 0.05). Global cerebral blood flow was correlated with memory performance (r=0.22, p=.040) but not to other tasks. A moderation analysis was performed using hierarchical regression models for attention/executive function, memory, language, and motor function. For each model, medical and demographic characteristics were entered into the initial blocks, and the final block consisted of an interaction term between global cerebral blood flow velocity (CBF-V) and the BDI-II. The interaction between greater depressive symptomatology and decreased global CBF-V was associated with greater deficits in attention/executive function (β = .32, ΔR2 = .08, p = .003).
Depressive symptomatology and cerebral hypoperfusion interact to adversely affect cognitive performance in older adults with HF. Longitudinal studies are needed to clarify this relationship and elucidate subsequent neuropathology.
PMCID: PMC3770733  PMID: 23873714
Cognitive impairment; Cerebral Perfusion; Heart failure; Depression; Cardiovascular disease; Cerebral blood flow velocity
24.  Independent and Interactive Effects of Blood Pressure and Cardiac Function on Brain Volume and White Matter Hyperintensities in Heart Failure 
Reduced systemic perfusion and comorbid medical conditions are key contributors to adverse brain changes in heart failure (HF). Hypertension, the most common co-occurring condition in HF, accelerates brain atrophy in aging populations. However, the independent and interactive effects of blood pressure and systemic perfusion on brain structure in HF have yet to be investigated.
Forty-eight older adults with HF underwent impedance cardiography to assess current systolic blood pressure status, and cardiac index to quantify systemic perfusion. All participants underwent brain magnetic resonance imaging to quantify total brain, total and subcortical gray matter volume, and white matter hyperintensities (WMH) volume.
Regression analyses adjusting for medical and demographic factors showed decreased cardiac index was associated with smaller subcortical gray matter volume (p < .01) and higher systolic blood pressure predicted reduced total gray matter volume (p = .03). The combination of higher blood pressure and lower cardiac index exacerbated WMH (p = .048).
Higher blood pressure and systemic hypoperfusion are associated with smaller brain volume and these factors interact to exacerbate WMH in HF. Prospective studies are needed to clarify the effects of blood pressure on the brain in HF, including the role of long-term blood pressure fluctuations.
PMCID: PMC3770819  PMID: 23735419
Blood pressure; brain; cognition; heart failure; cardiac index; MRI
25.  Cerebral Perfusion is Associated with White Matter Hyperintensities in Older Adults with Heart Failure 
Cognitive impairment is common in heart failure (HF) and believed to be the result of cerebral hypoperfusion and subsequent brain changes including white matter hyperintensities (WMH). The current study examined the association between cerebral blood flow and WMH in HF patients and the relationship of WMH to cognitive impairment. Sixty-nine patients with HF completed the mini mental state examination (MMSE), echocardiogram, transcranial Doppler sonography (TCD) for cerebral blood flow velocity of the middle cerebral artery and brain magnetic resonance imaging (MRI). Multivariable hierarchical regression analyses controlling for medical and demographic characteristics as well as intracranial volume showed reduced cerebral blood flow velocity of the middle cerebral artery was associated with greater WMH (β = −.34, p = .02). Follow up regression analyses adjusting for the same medical and demographic factors in addition to cerebral perfusion also revealed marginal significance between increased WMH and poorer performance on the MMSE (β = −.26, p = .05). This study suggests that reduced cerebral perfusion is associated with greater WMH in older adults with HF. Our findings support the widely proposed mechanism of cognitive impairment in HF patients and prospective studies are needed to confirm our findings.
PMCID: PMC3692594  PMID: 23517434
Cardiovascular disease; cerebral blood flow; cognitive function; heat failure; white matter hyperintensities

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