Publications by authors named "Howard J Aizenstein"

167 Publications

Midazolam and Ketamine Produce Distinct Neural Changes in Memory, Pain, and Fear Networks during Pain.

Anesthesiology 2021 Apr 19. Epub 2021 Apr 19.

Background: Despite the well-known clinical effects of midazolam and ketamine, including sedation and memory impairment, the neural mechanisms of these distinct drugs in humans are incompletely understood. The authors hypothesized that both drugs would decrease recollection memory, task-related brain activity, and long-range connectivity between components of the brain systems for memory encoding, pain processing, and fear learning.

Methods: In this randomized within-subject crossover study of 26 healthy adults, the authors used behavioral measures and functional magnetic resonance imaging to study these two anesthetics, at sedative doses, in an experimental memory paradigm using periodic pain. The primary outcome, recollection memory performance, was quantified with d' (a difference of z scores between successful recognition versus false identifications). Secondary outcomes were familiarity memory performance, serial task response times, task-related brain responses, and underlying brain connectivity from 17 preselected anatomical seed regions. All measures were determined under saline and steady-state concentrations of the drugs.

Results: Recollection memory was reduced under midazolam (median [95% CI], d' = 0.73 [0.43 to 1.02]) compared with saline (d' = 1.78 [1.61 to 1.96]) and ketamine (d' = 1.55 [1.12 to 1.97]; P < 0.0001). Task-related brain activity was detected under saline in areas involved in memory, pain, and fear, particularly the hippocampus, insula, and amygdala. Compared with saline, midazolam increased functional connectivity to 20 brain areas and decreased to 8, from seed regions in the precuneus, posterior cingulate, and left insula. Compared with saline, ketamine decreased connectivity to 17 brain areas and increased to 2, from 8 seed regions including the hippocampus, parahippocampus, amygdala, and anterior and primary somatosensory cortex.

Conclusions: Painful stimulation during light sedation with midazolam, but not ketamine, can be accompanied by increased coherence in brain connectivity, even though details are less likely to be recollected as explicit memories.

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http://dx.doi.org/10.1097/ALN.0000000000003774DOI Listing
April 2021

An Effect of Education on Memory-Encoding Activation in Subjective Cognitive Decline.

J Alzheimers Dis 2021 Apr 3. Epub 2021 Apr 3.

Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer's disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates.

Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations.

Methods: We measured brain activation during the "face-name" memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education.

Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education.

Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve.
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http://dx.doi.org/10.3233/JAD-201087DOI Listing
April 2021

Opposing relationships of childhood threat and deprivation with stria terminalis white matter.

Hum Brain Mapp 2021 Jun 19;42(8):2445-2460. Epub 2021 Mar 19.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post-traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms.
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http://dx.doi.org/10.1002/hbm.25378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090789PMC
June 2021

Improved 7 Tesla transmit field homogeneity with reduced electromagnetic power deposition using coupled Tic Tac Toe antennas.

Sci Rep 2021 Feb 9;11(1):3370. Epub 2021 Feb 9.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.

Recently cleared by the FDA, 7 Tesla (7 T) MRI is a rapidly growing technology that can provide higher resolution and enhanced contrast in human MRI images. However, the increased operational frequency (~ 297 MHz) hinders its full potential since it causes inhomogeneities in the images and increases the power deposition in the tissues. This work describes the optimization of an innovative radiofrequency (RF) head coil coupled design, named Tic Tac Toe, currently used in large scale human MRI scanning at 7 T; to date, this device was used in more than 1,300 neuro 7 T MRI scans. Electromagnetic simulations of the coil were performed using the finite-difference time-domain method. Numerical optimizations were used to combine the calculated electromagnetic fields produced by these antennas, based on the superposition principle, resulting in homogeneous magnetic field distributions at low levels of power deposition in the tissues. The simulations were validated in-vivo using the Tic Tac Toe RF head coil system on a 7 T MRI scanner.
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http://dx.doi.org/10.1038/s41598-020-79807-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873125PMC
February 2021

Aging faster: worry and rumination in late life are associated with greater brain age.

Neurobiol Aging 2021 May 20;101:13-21. Epub 2021 Jan 20.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Older adults with anxiety have lower gray matter brain volume-a component of accelerated aging. We have previously validated a machine learning model to predict brain age, an estimate of an individual's age based on voxel-wise gray matter images. We investigated associations between brain age and anxiety, depression, stress, and emotion regulation. We recruited 78 participants (≥50 years) along a wide range of worry severity. We collected imaging data and computed voxel-wise gray matter images, which were input into an existing machine learning model to estimate brain age. We conducted a multivariable linear regression between brain age and age, sex, race, education, worry, anxiety, depression, rumination, neuroticism, stress, reappraisal, and suppression. We found that greater brain age was significantly associated with greater age, male sex, greater worry, greater rumination, and lower suppression. Male sex, worry, and rumination are associated with accelerated aging in late life and expressive suppression may have a protective effect. These results provide evidence for the transdiagnostic model of negative repetitive thoughts, which are associated with cognitive decline, amyloid, and tau.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.009DOI Listing
May 2021

Accelerated brain aging in chronic low back pain.

Brain Res 2021 Mar 7;1755:147263. Epub 2021 Jan 7.

Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Chronic low back pain (CLBP) is a leading cause of disability and is associated with neurodegenerative changes in brain structure. These changes lead to impairments in cognitive function and are consistent with those seen in aging, suggesting an accelerated aging pattern. In this study we assessed this using machine-learning estimated brain age (BA) as a holistic metric of morphometric changes associated with aging. Structural imaging data from 31 non-depressed CLBP patients and 32 healthy controls from the Pain and Interoception Imaging Network were included. Using our previously developed algorithm, we estimated BA per individual based on grey matter density. We then conducted multivariable linear modeling for effects of group, chronological age, and their interaction on BA. We also performed two voxel-wise analyses comparing grey matter density between CLBP and control individuals and the association between gray matter density and BA. There was an interaction between CLBP and greater chronological age on BA such that the discrepancy in BA between healthy and CLBP individuals was greater for older individuals. In CLBP individuals, BA was not associated with sex, current level of pain, duration of CLBP, or mild to moderate depressive symptoms. CLBP individuals had lower cerebellar grey matter density compared to healthy individuals. Brain age was associated with lower gray matter density in numerous brain regions. CLBP was associated with greater BA, which was more profound in later life. BA as a holistic metric was sensitive to differences in gray matter density in numerous regions which eluded direct comparison between groups.
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http://dx.doi.org/10.1016/j.brainres.2020.147263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939694PMC
March 2021

Long-Term Cocaine Self-administration Produces Structural Brain Changes That Correlate With Altered Cognition.

Biol Psychiatry 2021 02 18;89(4):376-385. Epub 2020 Aug 18.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland. Electronic address:

Background: An enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed.

Methods: We addressed this fundamental question of causality using longitudinal anatomical magnetic resonance imaging and neurocognitive assessments in rhesus macaques. Cognitive tasks employed were stimulus reversal learning as a measure of cognitive flexibility/inhibitory control and delayed match to sample as a measure of visual working memory. Time points examined were before and following 12 months of chronic cocaine (n = 8) or water (n = 6) self-administration. A magnetic resonance imaging-only time point was also obtained following 2 years of forced abstinence.

Results: We identified localized patterns of gray matter density (GMD) changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. GMD decreases were significantly correlated with cognitive impairments across individuals only in select cortical regions. Following abstinence, changes in GMD in some regions, including the orbitofrontal cortex, insula, and amygdala, were persistent and thus may play an important role in risk of relapse following extended abstinence.

Conclusions: Cocaine use is causal in producing regional changes in GMD, and those changes appear to drive cognitive impairments.
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http://dx.doi.org/10.1016/j.biopsych.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855373PMC
February 2021

Resting-state function connectivity associated with being a "morning-type" dementia caregiver and having lower depression symptom severity.

J Gerontol B Psychol Sci Soc Sci 2020 Aug 5. Epub 2020 Aug 5.

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Objectives: A lack of "morningness" predicts greater depression symptom severity over time, including in a vulnerable group of older adults: family dementia caregivers (dCGs). Evidence regarding the neurobiological basis of these correlations is needed to guide future research towards biomarker-informed detection and prevention approaches. We therefore primarily aimed to identify simple resting-state biomarkers that correlated with a lack of "morningness" in dCGs.

Methods: We examined 54 dCGs (mean age=70, range: 61-84; 70% female) of whom 40% were definite "morning types" according to Composite Scale of Morningness (CSM). Using a 7 Tesla resting-state sequence, we compared the functional connectivity of nodes in networks previously implicated in depression (fronto-parietal, default mode, limbic, and salience) between caregivers who were and were not "morning types."

Results: Correcting for voxel-wise comparisons, "morning type" dCGs had less amygdala-posterior cingulate connectivity (Cohen's d=-1.3), which statistically mediated ~32% of the association between the degree of "morningness" and lower depression severity. Post-hoc analyses of CSM items found significant correlations, with both amygdala-posterior cingulate FC and depression severity, for: 4/6 items pertaining to difficulty, 2/5 items pertaining to preference, and 0/2 items pertaining to typical patterns.

Discussion: Prior research shows that amygdala-posterior cingulate connectivity increases when allocating attention to peripheral aspects of negative emotional stimuli. As such, difficulty with morning activation may relate to the ongoing direction of focus around distressing content; in contrast, morning activity participation may serve to limit focus on distress. Replication and experimental studies are required to confirm these associations and their modifiability.
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http://dx.doi.org/10.1093/geronb/gbaa115DOI Listing
August 2020

Predicting resistance to amyloid-beta deposition and cognitive resilience in the oldest-old.

Neurology 2020 08 22;95(8):e984-e994. Epub 2020 Jul 22.

From the Departments of Neurology (B.E.S., O.L.L., W.E.K.), Neurological Surgery (Y.C.), Medicine (D.L.T.), Radiology (B.J.L.), Psychiatry (A.D.C., H.J.A., W.E.K.), Human Genetics (M.I.K.), and Epidemiology (L.H.K.), University of Pittsburgh, PA; Department of Neurology (S.T.D.), University of Florida, Gainesville; and Department of Mental Health (M.C.C.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Objective: To explore long-term predictors of avoiding β-amyloid (Aβ) deposition and maintaining unimpaired cognition as outcomes in the oldest old.

Methods: In a longitudinal observational cohort study, 100 former participants of the Ginkgo Evaluation of Memory Study (GEMS; 2000-2008) completed biannual Pittsburgh compound B-PET imaging and annual clinical-cognitive evaluations beginning in 2010. Most recent Aβ status and cognitive status were selected for each participant. Longitudinal outcomes included change in serial Aβ and cognitive tests. Baseline predictors from GEMS included neuropsychological tests, daily functioning, genotype, lifestyle variables, occupational measures, health history, sleep, subjective memory, physical and cognitive activities, depressive symptoms, and physical performance and health indices, among others.

Results: Mean age at the last cognitive evaluation was 92.0 (range 86-100) years. Mean follow-up time from baseline to last measured Aβ status was 12.3 (SD 1.9) years and to last cognitive evaluation was 14.1 (SD 1.9) years. The allele predicted last Aβ status (n = 34 Aβ negative vs n = 66 Aβ positive). Baseline cognition predicted cognitive status (n = 30 unimpaired vs n = 70 impaired). Predictors of cognitive status among Aβ-positive participants only (n = 14 normal cognition vs n = 52 impaired) were baseline cognitive test scores and smoking history. Baseline pulse pressure predicted longitudinal Aβ increase; paid work engagement and life satisfaction predicted less cognitive decline.

Conclusions: The allele and lower pulse pressure predict resistance to Aβ deposition in advanced aging. Cognitive test scores 14 years prior, likely reflecting premorbid abilities, predict cognitive status and maintenance of unimpaired cognition in the presence of Aβ. Several lifestyle factors appear protective.
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http://dx.doi.org/10.1212/WNL.0000000000010239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668550PMC
August 2020

Influence of apolipoprotein-E genotype on brain amyloid load and longitudinal trajectories.

Neurobiol Aging 2020 10 31;94:111-120. Epub 2020 May 31.

Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

To characterize the influence of apolipoprotein-E (APOE) genotype on cerebral Aβ load and longitudinal Aβ trajectories, [C]Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants with known APOE genotype. Serial [C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aβ burden and an earlier age of onset of Aβ positivity, whereas APOE-ε2 appeared to have modest protective effects against Aβ. APOE class did not predict rates of Aβ accumulation. The present study suggests that APOE modifies Alzheimer's disease risk through a direct influence on amyloidogenic processes, which manifests as an earlier age of onset of Aβ positivity, although it is likely that other genetic, environmental, and lifestyle factors are important.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483397PMC
October 2020

Associations between NIH Toolbox Cognition Battery and brain amyloid and tau pathology in non-demented older adults.

Alzheimers Dement (Amst) 2020 15;12(1):e12018. Epub 2020 May 15.

Department of Psychiatry University of Pittsburgh School of Medicine Pittsburgh Pennsylvania.

Introduction: The National Institutes of Health (NIH) Toolbox Cognition Battery (NIHTB-CB) was developed to be a common assessment metric across a broad array of research studies. We investigated associations between NIHTB-CB and brain amyloid and tau deposition in cognitively unimpaired older adults.

Methods: One hundred eighteen community-based volunteers completed magnetic resonance imaging (MRI), Pittsburgh compound B (PiB)-PET (positron emission tomography) and AV-1451-PET neuroimaging, a neuropsychological evaluation, NIHTB-CB, and the Clinical Dementia Rating (CDR) scale. Demographically adjusted regression models evaluated cognition-biomarker associations; standardized effect sizes allowed comparison of association strength across measures.

Results: No NIHTB-CB measures were associated with amyloid deposition. NIHTB-CB measures of fluid cognition, including Pattern Comparison Processing Speed, Dimensional Change Card Sort, and Fluid Cognition Composite, were associated with tau deposition in higher Braak regions. Pattern Comparison Processing Speed was the most robust association with sensitivity analyses.

Discussion: NIHTB-CB tasks of processing speed and executive functions may be sensitive to pathologic tau deposition on imaging in normal aging.
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http://dx.doi.org/10.1002/dad2.12018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228102PMC
May 2020

Cognitive Reserve Moderates Effects of White Matter Hyperintensity on Depressive Symptoms and Cognitive Function in Late-Life Depression.

Front Psychiatry 2020 8;11:249. Epub 2020 Apr 8.

College of Medicine, Chang Gung University, Taoyuan County, Taiwan.

Introduction: White matter hyperintensity (WMH) has been regarded as one of the major contributor of the vascular hypothesis of late-life depression (LLD) and cognitive decline in the elderly. On the other hand, cognitive reserve (CR) has long been hypothesized to provide resilience and adaptability against age- and disease-related insults. This study examined the role of CR, using proxy of education, in moderating the association between WMH and clinical LLD expression.

Methods: A total of 54 elderly diagnosed with major depressive disorder and 38 matched healthy controls participated in this study. They received MRI scanning and a battery of neuropsychological tests. WMH was quantified by an automated segmentation algorithm. Linear regression analyses were conducted separately in the LLD and control groups to examine the effects of WMH, education and their interaction in depression severity and various cognitive domains.

Results: WMH was significantly and negatively associated with executive function only in the healthy controls. In patients with LLD, we observed a significant interactive effect in education on the association between WMH and depression severity and language domain (category fluency task). Specifically, those with high education showed less depressive symptoms and cognitive decline as WMH increased.

Conclusion: WMH is associated with lower cognitive function. However, in patients with LLD, high education attenuates the deleterious effect of WMH on mood and cognition. Therefore, CR appears to exert a protective effect on neurocognitive functioning in people with LLD.
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http://dx.doi.org/10.3389/fpsyt.2020.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158948PMC
April 2020

The effect of amyloid deposition on longitudinal resting-state functional connectivity in cognitively normal older adults.

Alzheimers Res Ther 2020 01 6;12(1). Epub 2020 Jan 6.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Pathological processes contributing to Alzheimer's disease begin decades prior to the onset of clinical symptoms. There is significant variation in cognitive changes in the presence of pathology, functional connectivity may be a marker of compensation to amyloid; however, this is not well understood.

Methods: We recruited 64 cognitively normal older adults who underwent neuropsychological testing and biannual magnetic resonance imaging (MRI), amyloid imaging with Pittsburgh compound B (PiB)-PET, and glucose metabolism (FDG)-PET imaging for up to 6 years. Resting-state MRI was used to estimate connectivity of seven canonical neural networks using template-based rotation. Using voxel-wise paired t-tests, we identified neural networks that displayed significant changes in connectivity across time. We investigated associations among amyloid and longitudinal changes in connectivity and cognitive function by domains.

Results: Left middle frontal gyrus connectivity within the memory encoding network increased over time, but the rate of change was lower with greater amyloid. This was no longer significant in an analysis where we limited the sample to only those with two time points. We found limited decline in cognitive domains overall. Greater functional connectivity was associated with better attention/processing speed and executive function (independent of time) in those with lower amyloid but was associated with worse function with greater amyloid.

Conclusions: Increased functional connectivity serves to preserve cognitive function in normal aging and may fail in the presence of pathology consistent with compensatory models.
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http://dx.doi.org/10.1186/s13195-019-0573-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945413PMC
January 2020

White Matter Integrity Underlying Depressive Symptoms in Dementia Caregivers.

Am J Geriatr Psychiatry 2020 05 5;28(5):578-582. Epub 2019 Dec 5.

Department of Electrical and Computer Engineering, Swanson School of Engineering, University of Pittsburgh (LZ), Pittsburgh, PA.

Objective: We sought to determine whether the aspects of white matter connectivity implicated in major depression also relate to mild depressive symptoms in family dementia caregivers (dCGs).

Methods: Forty-one dCGs (average age=69 years, standard deviation=6.4) underwent a 7 Tesla 64-direction (12-minute) diffusion-weighted imaging sequence. We compared the fractional anisotropy (FA) of 11 white matter features between dCGs with (n=20) and without (n=21) depressive symptoms (Patient Health Questionnaire-9 scores ≥5).

Results: Caregivers reporting depression symptoms had lower FA in tracts connecting to the posterior cingulate cortex (Cohen's d = -0.9) and connecting dorsolateral prefrontal with rostral cingulate regions (Cohen's d = -1.2).

Conclusions: Posterior cingulate and dorsolateral prefrontal-to-rostral cingulate white matter, implicated in prior studies of major depression, appear relevant to mild depression in dCGs.
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http://dx.doi.org/10.1016/j.jagp.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170753PMC
May 2020

Gray Matter Regions Associated With Functional Mobility in Community-Dwelling Older Adults.

J Am Geriatr Soc 2020 05 30;68(5):1023-1028. Epub 2019 Dec 30.

Department of Physical Therapy, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background/objectives: Neuroimaging indicators of reduced brain health in the form of lower gray matter volume (GMV), lower fractional anisotropy (FA), and higher white matter hyperintensity volume (WMHV) have been related to global mobility measures, such as gait speed, in older adults. The purpose was to identify associations between brain regions and specific mobility functions to provide a greater understanding of the contribution of the central nervous system to independent living.

Design: Cross-sectional study.

Setting: Research laboratory.

Participants: Seventy community-ambulating healthy older adults (mean age = 76 ± 5 years).

Measurements: Participants performed the following tests: gait speed, Five Times Sit to Stand, Four Square Step Test (FSST), and Dynamic Gait Index (DGI). Structural magnetic resonance imaging of each participant's brain was collected. Measures of regional GMV, tract-specific WMHV, and FA were extracted. Correlational analyses between the mobility measures and neuroimaging measures were conducted using whole brain and regional and tract-specific measures. This was followed by linear regression models relating the mobility measures to regions or tracts identified in the correlation analysis, and adjusting for age, sex, and body mass index.

Results: Significant associations were found between higher GMV in multiple regions, primarily the parietal and temporal lobes, and better performance in gait speed, DGI, and FSST. After adjusting for personal factors, greater parahippocampus GMV was independently associated with greater gait speed. Greater inferior parietal lobe, supramarginal gyrus, and superior temporal gyrus GMVs were associated with gait function. Greater postcentral gyrus, parahippocampus, and superior temporal gyrus GMVs were associated with faster FSST performance. The WMHV and FA were not significantly correlated with the mobility measures.

Conclusions: Gray matter regions associated with higher performance in mobility measures serving gait function and multidirectional stepping were those structures related to vestibular sensation, spatial navigation, and somatosensation. J Am Geriatr Soc 68:1023-1028, 2020.
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http://dx.doi.org/10.1111/jgs.16309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234898PMC
May 2020

Sleep characteristics and white matter hyperintensities among midlife women.

Sleep 2020 06;43(6)

Department of Psychiatry, University of Illinois at Chicago, Chicago, IL.

Study Objectives: Sleep disturbance is common among midlife women. Poor self-reported sleep characteristics have been linked to cerebrovascular disease and dementia risk. However, little work has considered the relation of objectively assessed sleep characteristics and white matter hyperintensities (WMHs), a marker of small vessel disease in the brain. Among 122 midlife women, we tested whether women with short or disrupted sleep would have greater WMH, adjusting for cardiovascular disease (CVD) risk factors, estradiol, and physiologically assessed sleep hot flashes.

Methods: We recruited 122 women (mean age = 58 years) without a history of stroke or dementia who underwent 72 h of actigraphy to quantify sleep, 24 h of physiologic monitoring to quantify hot flashes; magnetic resonance imaging to assess WMH; phlebotomy, questionnaires, and physical measures (blood pressure, height, and weight). Associations between actigraphy-assessed sleep (wake after sleep onset and total sleep time) and WMH were tested in linear regression models. Covariates included demographics, CVD risk factors (blood pressure, lipids, and diabetes), estradiol, mood, and sleep hot flashes.

Results: Greater actigraphy-assessed waking after sleep onset was associated with more WMH [B(SE) = .008 (.002), p = 0.002], adjusting for demographics, CVD risk factors, and sleep hot flashes. Findings persisted adjusting for estradiol and mood. Neither total sleep time nor subjective sleep quality was related to WMH.

Conclusions: Greater actigraphy-assessed waking after sleep onset but not subjective sleep was related to greater brain WMH among midlife women. Poor sleep may be associated with brain small vessel disease at midlife, which can increase the risk for brain disorders.
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http://dx.doi.org/10.1093/sleep/zsz298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294405PMC
June 2020

Improving brain age prediction models: incorporation of amyloid status in Alzheimer's disease.

Neurobiol Aging 2020 03 14;87:44-48. Epub 2019 Nov 14.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Brain age prediction is a machine learning method that estimates an individual's chronological age from their neuroimaging scans. Brain age indicates whether an individual's brain appears "older" than age-matched healthy peers, suggesting that they may have experienced a higher cumulative exposure to brain insults or were more impacted by those pathological insults. However, contemporary brain age models include older participants with amyloid pathology in their training sets and thus may be confounded when studying Alzheimer's disease (AD). We showed that amyloid status is a critical feature for brain age prediction models. We trained a model on T1-weighted MRI images participants without amyloid pathology. MRI data were processed to estimate gray matter density voxel-wise, which were then used to predict chronological age. Our model performed accurately comparable to previous models. Notably, we demonstrated more significant differences between AD diagnostic groups than other models. In addition, our model was able to delineate significant differences in brain age relative to chronological age between cognitively normal individuals with and without amyloid. Incorporation of amyloid status in brain age prediction models ultimately improves the utility of brain age as a biomarker for AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064421PMC
March 2020

Neuroimaging of Small Vessel Disease in Late-Life Depression.

Adv Exp Med Biol 2019 ;1192:95-115

Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.

Cerebral small vessel disease is associated with late-life depression, cognitive impairment, executive dysfunction, distress, and loss of life for older adults. Late-life depression is becoming a substantial public health burden, and a considerable number of older adults presenting to primary care have significant clinical depression. Even though white matter hyperintensities are linked with small vessel disease, white matter hyperintensities are nonspecific to small vessel disease and can co-occur with other brain diseases. Advanced neuroimaging techniques at the ultrahigh field magnetic resonance imaging are enabling improved characterization, identification of cerebral small vessel disease and are elucidating some of the mechanisms that associate small vessel disease with late-life depression.
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http://dx.doi.org/10.1007/978-981-32-9721-0_5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939470PMC
November 2019

Activity patterns related to depression symptoms in stressed dementia caregivers.

Int Psychogeriatr 2019 Oct 29:1-8. Epub 2019 Oct 29.

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Objectives: Self-reported activity restriction is an established correlate of depression in dementia caregivers (dCGs). It is plausible that the daily distribution of objectively measured activity is also altered in dCGs with depression symptoms; if so, such activity characteristics could provide a passively measurable marker of depression or specific times to target preventive interventions. We therefore investigated how levels of activity throughout the day differed in dCGs with and without depression symptoms, then tested whether any such differences predicted changes in symptoms 6 months later.

Design, Setting, Participants, And Measurements: We examined 56 dCGs (mean age = 71, standard deviation (SD) = 6.7; 68% female) and used clustering to identify subgroups which had distinct depression symptom levels, leveraging baseline Center for Epidemiologic Studies of Depression Scale-Revised Edition and Patient Health Questionnaire-9 (PHQ-9) measures, as well as a PHQ-9 score from 6 months later. Using wrist activity (mean recording length = 12.9 days, minimum = 6 days), we calculated average hourly activity levels and then assessed when activity levels relate to depression symptoms and changes in symptoms 6 months later.

Results: Clustering identified subgroups characterized by: (1) no/minimal symptoms (36%) and (2) depression symptoms (64%). After multiple comparison correction, the group of dCGs with depression symptoms was less active from 8 to 10 AM (Cohen's d ≤ -0.9). These morning activity levels predicted the degree of symptom change on the PHQ-9 6 months later (per SD unit β = -0.8, 95% confidence interval: -1.6, -0.1, p = 0.03) independent of self-reported activity restriction and other key factors.

Conclusions: These novel findings suggest that morning activity may protect dCGs from depression symptoms. Future studies should test whether helping dCGs get active in the morning influences the other features of depression in this population (i.e. insomnia, intrusive thoughts, and perceived activity restriction).
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http://dx.doi.org/10.1017/S1041610219001601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188574PMC
October 2019

Effects of soy isoflavones on cognitive function: a systematic review and meta-analysis of randomized controlled trials.

Nutr Rev 2020 02;78(2):134-144

C. Cui, L. Kuller, and A. Sekikawa are with the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Context: The results of preclinical and observational studies support the beneficial effect of soy isoflavones on cognition.

Objective: This review aimed to evaluate the effects of soy isoflavones on cognition in adults.

Data Sources: The PUBMED, EMBASE, Ovid Medline, Cochrane Library, and clinicaltrials.gov databases were searched.

Study Selection: Two researchers independently screened 1955 records, using the PICOS criteria: participants were adults; intervention was dietary sources with soy isoflavones or isolated soy isoflavones; comparator was any comparator; outcome was cognitive function; study type was randomized controlled trials (RCTs). A third researcher was consulted to resolve any discrepancies. Sixteen RCTs were included and their quality assessed.

Data Extraction: Information on study design, characteristics of participants, and outcomes was extracted. PRISMA guidelines were followed.

Data Analysis: A random-effects meta-analysis was used to pool estimates across studies. In the 16 RCTs (1386 participants, mean age = 60 y), soy isoflavones were found to improve overall cognitive function (standardized mean difference [SMD], 0.19; 95% confidence interval [CI], 0.07-0.32) and memory (SMD, 0.15; 95%CI, 0.03-0.26).

Conclusion: The results showed that soy isoflavones may improve cognitive function in adults.

Systematic Review Registration: PROSPERO registration no. CRD42018082070.
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http://dx.doi.org/10.1093/nutrit/nuz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808187PMC
February 2020

Disruption of Neural Homeostasis as a Model of Relapse and Recurrence in Late-Life Depression.

Am J Geriatr Psychiatry 2019 12 7;27(12):1316-1330. Epub 2019 Aug 7.

Department of Psychiatry and Behavioral Sciences (KA, WDT), The Center for Cognitive Medicine, Vanderbilt University Medical Center, Nashville, TN; Department of Veterans Affairs Medical Center (WDT), Geriatric Research, Education and Clinical Center, Tennessee Valley Healthcare System, Nashville, TN. Electronic address:

The significant public health burden associated with late-life depression (LLD) is magnified by the high rates of recurrence. In this manuscript, we review what is known about recurrence risk factors, conceptualize recurrence within a model of homeostatic disequilibrium, and discuss the potential significance and challenges of new research into LLD recurrence. The proposed model is anchored in the allostatic load theory of stress. We review the allostatic response characterized by neural changes in network function and connectivity and physiologic changes in the hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system, and circadian rhythm. We discuss the role of neural networks' instability following treatment response as a source of downstream disequilibrium, triggering and/or amplifying abnormal stress response, cognitive dysfunction and behavioral changes, ultimately precipitating a full-blown recurrent episode of depression. We propose strategies to identify and capture early change points that signal recurrence risk through mobile technology to collect ecologically measured symptoms, accompanied by automated algorithms that monitor for state shifts (persistent worsening) and variance shifts (increased variability) relative to a patient's baseline. Identifying such change points in relevant sensor data could potentially provide an automated tool that could alert clinicians to at-risk individuals or relevant symptom changes even in a large practice.
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http://dx.doi.org/10.1016/j.jagp.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842700PMC
December 2019

Relationships Between Executive Control Circuit Activity, Amyloid Burden, and Education in Cognitively Healthy Older Adults.

Am J Geriatr Psychiatry 2019 12 19;27(12):1360-1371. Epub 2019 Jul 19.

Department of Psychiatry (HTK, DLT, AC, HJA), University of Pittsburgh, Pittsburgh, PA; Department of Bioengineering (HJA), University of Pittsburgh, Pittsburgh, PA. Electronic address:

Introduction: In cognitively healthy older adults, amyloid-beta (Aβ) burden is associated with greater activity on task-based functional magnetic resonance imaging. Higher levels of functional activation are associated with other factors along with amyloid and the authors investigated these relationships as well as how they relate to Aβ in cognitively healthy older adults.

Methods: The authors recruited cognitive healthy older adults (N = 50) from the Pittsburgh community that underwent extensive cognitive batteries, activation during a working memory (digit symbol substitution task, DSST), positron emission tomography scan for Pittsburgh Compound B (PiB, measuring amyloid), and other demographic measures. The authors tested the association between DSST activation and global PiB, neurocognitive batteries, and education.

Results: The authors found that the DSST robustly activated expected structures involved in working memory. The authors found that greater global Aβ deposition was associated with greater DSST activation in the right calcarine, precuneus, middle temporal as well as the left insula and inferior frontal gyrus. The authors also found that greater education was associated with lower DSST activation - however this was not significant after adjusting for Aβ.

Discussion: Greater amyloid was associated with greater activation, which may represent compensatory activation. Greater education was associated with lower activation, which may represent more efficient activation (i.e., less activation for the same task). After adjusting for amyloid, education was not significantly associated with activation suggesting that during the preclinical stage amyloid is the primary determinant of activation. Further, activation was not associated with cognitive function. Compensatory activation in the preclinical stage may help maintain cognitive function.
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http://dx.doi.org/10.1016/j.jagp.2019.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047647PMC
December 2019

Regional Gray Matter Volume Links Rest-Activity Rhythm Fragmentation With Past Cognitive Decline.

Am J Geriatr Psychiatry 2020 02 19;28(2):248-251. Epub 2019 Jul 19.

Department of Epidemiology (AM and CR), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.

Objectives: We examined the extent to which measures of neurodegeneration and cerebrovascular disease explain the rest-activity rhythm (RAR)-cognition link.

Methods: Seventy participants (mean age at MRI = 86, standard deviation (SD) = 2.6; 53% female) had cognitive, MRI, and accelerometer data. The slope of cognitive decline was defined applying a mixed model to 10 repeated Modified Mini Mental Status Test (3MS) measures over 14 years. Regional gray matter volume (GMV), white matter hyperintensities, and RARs were measured around year 12.

Results: Past 3MS decline was related to RAR fragmentation (per SD β = -0.43, 95% confidence interval: -0.73, -0.14) and lower posterior parietal GMV (per standard deviation β = 0.47, 95% confidence interval: 0.14, 0.79). Higher RAR fragmentation was related to lower posterior parietal GMV (Pearson r = -0.39, n = 70, p = 0.0007), which attenuated the association of RAR fragmentation and past cognitive decline by 17%.

Conclusions: Longitudinal studies are warranted to understand the temporal relations and mechanisms linking RAR fragmentation and neurodegeneration.
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http://dx.doi.org/10.1016/j.jagp.2019.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980463PMC
February 2020

Incorporating prior information with fused sparse group lasso: Application to prediction of clinical measures from neuroimages.

Biometrics 2019 12 17;75(4):1299-1309. Epub 2019 Jun 17.

Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.

Predicting clinical variables from whole-brain neuroimages is a high-dimensional problem that can potentially benefit from feature selection or extraction. Penalized regression is a popular embedded feature selection method for high-dimensional data. For neuroimaging applications, spatial regularization using the or norm of the image gradient has shown good performance, yielding smooth solutions in spatially contiguous brain regions. Enormous resources have been devoted to establishing structural and functional brain connectivity networks that can be used to define spatially distributed yet related groups of voxels. We propose using the fused sparse group lasso (FSGL) penalty to encourage structured, sparse, and interpretable solutions by incorporating prior information about spatial and group structure among voxels. We present optimization steps for FSGL penalized regression using the alternating direction method of multipliers algorithm. With simulation studies and in application to real functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange, we demonstrate conditions under which fusion and group penalty terms together outperform either of them alone.
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http://dx.doi.org/10.1111/biom.13075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814453PMC
December 2019

Association Between Amyloid-β, Small-vessel Disease, and Neurodegeneration Biomarker Positivity, and Progression to Mild Cognitive Impairment in Cognitively Normal Individuals.

J Gerontol A Biol Sci Med Sci 2019 10;74(11):1753-1760

Department of Neurology, University of Pittsburgh, Pennsylvania.

Background: We estimated the prevalence and incidence of amyloid-β deposition (A), small-vessel disease (V), and neurodegeneration (N) biomarker positivity in community-dwelling cognitively normal individuals (CN). We determined the longitudinal association between the respective biomarker indices with progression to all-cause mild cognitive impairment (MCI) and its amnestic and nonamnestic subtypes.

Methods: CN participants, recruited by advertising, underwent brain [C-11]Pittsburgh Compound-B (PiB)-positron emission tomography (PET), magnetic resonance imaging, and [F-18]fluoro-2-deoxy-glucose (FDG)-PET, and were designated as having high or low amyloid-β (A+/A-), greater or lower white matter hyperintensities burden (V+/V-) and diminished or normal cortical glucose metabolism (N+/N-). MCI was adjudicated using clinical assessments. We examined the association between A, V, and N biomarker positivity at study baseline and endpoint, with progression to MCI using linear regression, Cox proportional hazards and Kaplan-Meier analyses adjusted for age and APOE-ε4 carrier status.

Results: In 98 CN individuals (average age 74 years, 65% female), A+, V+, and N+ prevalence was 26%, 33%, and 8%, respectively. At study endpoint (median: 5.5 years), an A+, but not a V+ or N+ scan, was associated with higher odds of all-cause MCI (Chi-square = 3.9, p = .048, odds ratio, 95% confidence interval = 2.6 [1.01-6.8]). Baseline A+, V+, or N+ were not associated with all-cause MCI, however, baseline A+ (p = .018) and A+N+ (p = .049), and endpoint A+N+ (p = .025) were associated with time to progression to amnestic, not nonamnestic, MCI.

Conclusion: Longitudinal assessments clarify the association between amyloid-β and progression to all-cause MCI in CN individuals. The association between biomarker positivity indices of amyloid-β and neurodegeneration, and amnestic MCI reflects the underlying pathology involved in the progression to prodromal Alzheimer's disease.
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http://dx.doi.org/10.1093/gerona/glz088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777090PMC
October 2019

Training the Next Generation of Geriatric-Focused Clinical Neuroscientists.

Am J Geriatr Psychiatry 2019 07 13;27(7):720-727. Epub 2019 Mar 13.

Department of Psychiatry (KJM, DCS), University of Connecticut Health Center, Farmington, CT.

It remains challenging to integrate clinical neuroscience into clinical practice. Hindrances at the training level (e.g., lack of qualified faculty and curriculum) contribute to this impasse. To help address this, we present a model of training in clinical neuroscience. We expand on a growing literature on incorporating neuroscience into psychiatry training by emphasizing two points. That is, 1) we propose a training model designed for the geriatric-minded clinician; and 2) that extends across several phases of education and career development. Considering the relevance of dementia to our population of interest, and the potential impact expertise in clinical neuroscience can have in elders with cognitive impairment, we provide relevant curriculum examples at various training stages. Clinical research, both as a practitioner and consumer, figures prominently into our training model. We discuss two mentoring programs, T32 fellowships and Research Career Institute in the Mental Health of Aging, as ways to engage geriatric psychiatrists early in their training and transition them successfully to post-residency clinical investigator positions. Although there is increasing opportunity for geriatric psychiatrists and other clinicians to become leaders in the field of neuroscience, this remains a work in progress; ours and others' training programs continue to evolve based on input from trainers and trainees alike, as well as from the increasing literature on this important topic.
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http://dx.doi.org/10.1016/j.jagp.2019.03.006DOI Listing
July 2019

Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women.

Neurobiol Aging 2019 04 1;76:141-150. Epub 2018 Dec 1.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (Aβ)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65-93 years old). We found that men and women showed different associations between Aβ load and hippocampal functional connectivity. During associative memory encoding, in men greater Aβ burden was accompanied by greater hippocampus-prefrontal connectivity (i.e., more synchronized activities), whereas in women hippocampal connectivity did not vary by Aβ burden. For resting-state data, the interaction of gender × Aβ on hippocampal connectivity did not survive multiple comparison in the whole-brain analyses. In the region of interest-based analyses, resting-state hippocampal-prefrontal connectivity was positively correlated with Aβ load in men and was negatively correlated with Aβ load in women. The observed Aβ-related neural differences may explain the accelerated trajectory of cognitive decline and AD progression in women.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584958PMC
April 2019

Low-dose augmentation with buprenorphine increases emotional reactivity but not reward activity in treatment resistant mid- and late-life depression.

Neuroimage Clin 2019 22;21:101679. Epub 2019 Jan 22.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Buprenorphine is currently being studied for treatment-resistant depression because of its rapid effect, relative safety, and unique pharmacodynamics. To understand the neural impact of buprenorphine in depression, we examined acute limbic and reward circuit changes during an intervention with low-dose buprenorphine augmentation pharmacotherapy. Mid and late-life adults with major depression (N = 31) who did not completely respond to an adequate trial of venlafaxine were randomized to augmentation with low-dose buprenorphine or matching placebo. We investigated early neural changes using functional magnetic resonance imaging (fMRI) from pre-randomization to 3 weeks using both an emotional reactivity task and a gambling task. We tested if: 1) there were significant neural changes acutely per intervention group, and 2) if acute neural changes were associated with depressive symptom change over 8 weeks using both the total score and the dysphoria subscale of the Montgomery Asberg Depression Rating Scale. Participants in both the buprenorphine and placebo groups showed similar changes in depressive symptoms. Neither the emotional reactivity nor gambling task resulted in significant neural activation changes from pre-randomization to 3-weeks. In both groups, increases in rostral anterior cingulate (rACC) and ventromedial prefrontal cortex (vmPFC) activation during the emotional reactivity task were associated with overall symptom improvement. In the buprenorphine but not the placebo group, increased activation in left anterior insula (aINS) and bilateral middle frontal gyrus (MFG) was associated with improvement on the dysphoria subscale. Activation changes in the reward task were not associated with buprenorphine. This is the first study to show an association between acute neural changes during emotion reactivity and changes in depression severity with buprenorphine treatment.
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http://dx.doi.org/10.1016/j.nicl.2019.101679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356006PMC
January 2020

Computational and experimental evaluation of the Tic-Tac-Toe RF coil for 7 Tesla MRI.

PLoS One 2019 10;14(1):e0209663. Epub 2019 Jan 10.

University of Pittsburgh, Department of Bioengineering, Pittsburgh, PA, United States of America.

A variety of 7 Tesla RF coil systems have been proposed to produce spin excitation (B1+ field) and MR image acquisition. Different groups have attempted to mitigate the challenges at high and ultra-high field MRI by proposing novel hardware and software solutions to obtain uniformly high spin excitation at acceptable RF absorption levels. In this study, we extensively compare the designs of two distributed-circuit based RF coils: the Tic-Tac-Toe (TTT) head coil and TEM head coil on multiple anatomically detailed head models and in-vivo. Bench measurements of s-parameters and experimental B1+ field distribution were obtained in volunteers and compared with numerical simulations. RF absorption, quantified by both average and peak SAR, and B1+ field intensity and homogeneity, calculated/measured in terms of maximum over minimum and coefficient of variation (CV) in the region of interest (ROI), are presented for both coils. A study of the RF consistency of both coils across multiple head models for different RF excitation strategies is also presented.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209663PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328242PMC
September 2019

A Homeostatic Model of Subjective Cognitive Decline.

Brain Sci 2018 Dec 19;8(12). Epub 2018 Dec 19.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Subjective Cognitive Decline (SCD) is possibly one of the earliest detectable signs of dementia, but we do not know which mental processes lead to elevated concern. In this narrative review, we will summarize the previous literature on the biomarkers and functional neuroanatomy of SCD. In order to extend upon the prevailing theory of SCD, compensatory hyperactivation, we will introduce a new model: the breakdown of homeostasis in the prediction error minimization system. A cognitive prediction error is a discrepancy between an implicit cognitive prediction and the corresponding outcome. Experiencing frequent prediction errors may be a primary source of elevated subjective concern. Our homeostasis breakdown model provides an explanation for the progression from both normal cognition to SCD and from SCD to advanced dementia stages.
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http://dx.doi.org/10.3390/brainsci8120228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316074PMC
December 2018