Modeling and inference of multisubject fMRI data

Functional magnetic resonance imaging (fMRI) is a rapidly growing technique for studying the brain in action. Since its creation [1], [2], cognitive scientists have been using fMRI to understand how we remember, manipulate, and act on information in our environment. Working with magnetic resonance physicists, statisticians, and engineers, these scientists are pushing the frontiers of knowledge of how the human brain works. The design and analysis of single-subject fMRI studies has been well described. For example, [3], chapters 10 and 11 of [4], and chapters 11 and 14 of [5] all give accessible overviews of fMRI methods for one subject. In contrast, while the appropriate manner to analyze a group of subjects has been the topic of several recent papers, we do not feel it has been covered well in introductory texts and review papers. Therefore, in this article, we bring together old and new work on so-called group modeling of fMRI data using a consistent notation to make the methods more accessible and comparable

Decreasing Ventromedial Prefrontal Cortex Activity During Sequential Risk-Taking: An fMRI Investigation of the Balloon Analog Risk Task

Functional imaging studies examining the neural correlates of risk have mainly relied on paradigms involving exposure to simple chance gambles and an economic definition of risk as variance in the probability distribution over possible outcomes. However, there is little evidence that choices made during gambling tasks predict naturalistic risk-taking behaviors such as drug use, extreme sports, or even equity investing. To better understand the neural basis of naturalistic risk-taking, we scanned participants using fMRI while they completed the Balloon Analog Risk Task, an experimental measure that includes an active decision/choice component and that has been found to correlate with a number of naturalistic risk-taking behaviors. In the task, as in many naturalistic settings, escalating risk-taking occurs under uncertainty and might be experienced either as the accumulation of greater potential rewards, or as exposure to increasing possible losses (and decreasing expected value). We found that areas previously linked to risk and risk-taking (bilateral anterior insula, anterior cingulate cortex, and right dorsolateral prefrontal cortex) were activated as participants continued to inflate balloons. Interestingly, we found that ventromedial prefrontal cortex (vmPFC) activity decreased as participants further expanded balloons. In light of previous findings implicating the vmPFC in value calculation, this result suggests that escalating risk-taking in the task might be perceived as exposure to increasing possible losses (and decreasing expected value) rather than the increasing potential total reward relative to the starting point of the trial. A better understanding of how neural activity changes with risk-taking behavior in the task offers insight into the potential neural mechanisms driving naturalistic risk-taking

Measurement and Reliability of Response Inhibition

Response inhibition plays a critical role in adaptive functioning and can be assessed with the Stop-signal task, which requires participants to suppress prepotent motor responses. Evidence suggests that this ability to inhibit a prepotent motor response (reflected as Stop-signal reaction time (SSRT)) is a quantitative and heritable measure of interindividual variation in brain function. Although attention has been given to the optimal method of SSRT estimation, and initial evidence exists in support of its reliability, there is still variability in how Stop-signal task data are treated across samples. In order to examine this issue, we pooled data across three separate studies and examined the influence of multiple SSRT calculation methods and outlier calling on reliability (using Intra-class correlation). Our results suggest that an approach which uses the average of all available sessions, all trials of each session, and excludes outliers based on predetermined lenient criteria yields reliable SSRT estimates, while not excluding too many participants. Our findings further support the reliability of SSRT, which is commonly used as an index of inhibitory control, and provide support for its continued use as a neurocognitive phenotype

Prognostic Value of Bronchiolitis Obliterans Syndrome Stage 0-p in Single-Lung Transplant Recipients

Rationale: Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV1 and forced expiratory flow, midexpiratory phase (FEF25–75%), has been proposed, there is a paucity of data validating its utility in single-lung transplantation. Objective: The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation. Methods: We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology. Results: BOS 0-p FEV1 was associated with higher sensitivity, specificity, and positive predictive value than the FEF25–75% criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV1 in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV1 in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV1 criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV1 were significantly different between patients with underlying restrictive versus obstructive physiology (p = 0.05 and 0.01, respectively). Conclusion: The FEV1 criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF25–75% criterion.Supported in part by National Institutes of Health grants K23 HL077719 and K24HL04212 and American Lung Association RG-1059-N.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91970/1/2005 AJRCCM - Prognostic Value of Bronchiolitis Obliterans Syndrome Stage 0-p in Single-Lung Transplant Recipients.pd

Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia

Idiopathic interstitial pneumonias are a diverse group of lung diseases with varied prognoses. We hypothesized that changes in physiologic and radiographic parameters would predict survival. We retrospectively examined 80 patients with usual interstitial pneumonia and 29 patients with nonspecific interstitial pneumonia. Baseline characteristics were examined together with 6-month change in forced vital capacity, diffusing capacity for carbon monoxide, and ground glass infiltrate and fibrosis on high resolution computed tomography. Patients with usual interstitial pneumonia were more likely to have a statistically significant or marginally significant decline in lung volume, diffusing capacity for carbon monoxide, and an increase in ground glass infiltrates (p <= 0.08) compared with patients with nonspecific interstitial pneumonia. For patients with usual interstitial pneumonia, change in forced vital capacity was the best physiologic predictor of mortality (p = 0.05). In a multivariate Cox proportional hazards model controlling for histopathologic diagnosis, gender, smoking history, baseline forced vital capacity, and 6-month change in forced vital capacity, a decrease in forced vital capacity remained an independent risk factor for mortality (decrease > 10%; hazard ratio 2.47; 95% confidence interval 1.29, 4.73; p = 0.006). We conclude that a 6-month change in forced vital capacity gives additional prognostic information to baseline features for patients with idiopathic interstitial pneumonia.Supported by National Institutes of Health NHLBI grants P50HL46487, NIH/NCRR 3 MO1 RR00042-33S3, NIH/NIA P60 AG08808-06, NHLBI, 1 K24 HL04212, and 1 K23 HL68713.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91973/1/2003 AJRCCM - Prognostic Implications of Physiologic and Radiographic Changes in Idiopathic Interstitial Pneumonia.pd

Relating psychiatric symptoms and self-regulation during the COVID-19 crisis

Disruptions of self-regulation are a hallmark of numerous psychiatric disorders. Here, we examine the relationship between transdiagnostic dimensions of psychopathology and changes in self-regulation in the early phase of the COVID-19 pandemic. We used a data-driven approach on a large number of cognitive tasks and self-reported surveys in training datasets. Then, we derived measures of self-regulation and psychiatric functioning in an independent population sample (N = 102) tested both before and after the onset of the COVID-19 pandemic, when the restrictions in place represented a threat to mental health and forced people to flexibly adjust to modifications of daily routines. We found independent relationships between transdiagnostic dimensions of psychopathology and longitudinal alterations in specific domains of self-regulation defined using a diffusion decision model. Compared to the period preceding the onset of the pandemic, a symptom dimension related to anxiety and depression was characterized by a more cautious behavior, indexed by the need to accumulate more evidence before making a decision. Instead, social withdrawal related to faster non-decision processes. Self-reported measures of self-regulation predicted variance in psychiatric symptoms both concurrently and prospectively, revealing the psychological dimensions relevant for separate transdiagnostic dimensions of psychiatry, but tasks did not. Taken together, our results are suggestive of potential cognitive vulnerabilities in the domain of self-regulation in people with underlying psychiatric difficulties in face of real-life stressors. More generally, they also suggest that the study of cognition needs to take into account the dynamic nature of real-world events as well as within-subject variability over time

Fibroblastic Foci in Usual Interstitial Pneumonia: Idiopathic versus Collagen Vascular Disease

A histologic feature of usual interstitial pneumonia is the presence of fibroblastic foci. As some patients with usual interstitial pneumonia and an underlying collagen vascular disease have a better prognosis, we hypothesized that they would have fewer fibroblastic foci. Pathologists reviewed surgical lung biopsies from 108 patients with usual interstitial pneumonia (nine with collagen vascular disease) and assigned a score (absent 0, mild 1, moderate 2, and marked 3) for fibroblastic foci. Patients with idiopathic usual interstitial pneumonia had a higher median profusion of fibroblastic foci (1.75 vs. 1.0, p = 0.003). Baseline characteristics were similar, although patients with a collagen vascular disease were younger, had a shorter duration of symptoms, and had a higher percentage of predicted total lung capacity. Profusion of fibroblastic foci was the most discriminative feature for separating idiopathic from collagen vascular disease–associated usual interstitial pneumonia (odds ratio 8.31; 95% confidence interval, 1.98, 59.42; p = 0.002 for a one-unit increase in fibroblastic foci score). No deaths were noted in the collagen vascular disease–associated usual interstitial pneumonia group; 52 deaths occurred in the idiopathic usual interstitial pneumonia group (log rank; p = 0.005). We conclude that patients with collagen vascular disease–associated usual interstitial pneumonia have fewer fibroblastic foci and improved survival.Supported in part by National Institutes of Health National Heart, Lung, and Blood Institute grant #P50HL46487, NIH/NCRR 3 MO1 RR00042–33S3, NIH/NIA P60 AG08808–06, NHLBI 1 K24 HL04212, and 1 K23 HL68713.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91974/1/2003 AJRCCM - Fibroblastic Foci in Usual Interstitial Pneumonia -Idiopathic versus Collagen Vascular Disease.pd

Prognostic Value of Bronchiolitis Obliterans Syndrome Stage 0-p in Single-Lung Transplant Recipients

Rationale: Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV 1 and forced expiratory flow, midexpiratory phase (FEF 25-75% ), has been proposed, there is a paucity of data validating its utility in single-lung transplantation. Objective: The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation. Methods: We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology. Results: BOS 0-p FEV 1 was associated with higher sensitivity, specificity, and positive predictive value than the FEF 25-75% criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV 1 in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV 1 in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV 1 criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV 1 were significantly different between patients with underlying restrictive versus obstructive physiology (p ϭ 0.05 and 0.01, respectively). Conclusion: The FEV 1 criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF 25-75% criterion. Keywords: bronchiolitis obliterans syndrome; diagnosis; lung transplantation; staging Bronchiolitis obliterans is the major complication limiting outcomes in lung transplantation (1-3). Its clinical correlate, bronchiolitis obliterans syndrome (BOS), is defined as a fall in FEV 1 of greater than 20% from baseline determined by the average of two measurements made at least 3 weeks apart (4). Development of BOS is associated with progressive irreversible decline in lung function with a poor response to therapeutic interventions (1, 2). This feature, and the knowledge that pathogenesis of BO involves progressive fibroproliferation (2, 5), underscores the need for early intervention and the need to develop predictors of this disease. Implementation of increasingly sensitive criteria for identifying early decline in pulmonary function may allow the prediction of BOS. As such, a potential-BOS stage (BOS 0-p), defined by a 10 to 19% decrease in FEV 1 and/or by a 25% or greater decrease in forced expiratory flow, midexpiratory phase (FEF 25-75% ), from baseline was added to the original staging system in 2001 (4). In bilateral lung transplant recipients, the FEV 1 but not the FEF 25-75% criterion for BOS 0-p was shown to be a reasonable predictor of BOS (6). However, the role of various criteria of BOS 0-p in predicting recipients with BOS remains to be established in single-lung transplant (SLT) recipients. This population is of particular interest because spirometric criteria, such as FEV 1 and FEF 25-75% , are influenced by degree and nature of native lung pathology This study provides novel data defining the ability of both FEV 1 and FEF 25-75% criteria for BOS 0-p to predict development of BOS in a large cohort of SLT recipients. Some of these results have been previously reported in the form of an abstract (8). METHODS Patients The study group comprised 197 consecutive SLT recipients who were alive 3 months post-transplantation and had post-transplant pulmonary functions available. The study was approved by the University of Michigan Institutional Review Board. All patients were followed by a standardized protocol as previously described (9). Pulmonary function testing was performed following standards established by the American Thoracic Society at each clinic visit (10). Definition of BOS Baseline FEV 1 and FEF 25-75% were determined according to the published guidelines (4). The criterion for BOS was met when two consecutive FEV 1 values at least 3 weeks apart fell below 80% of baseline FEV 1 . Therefore, BOS diagnosis included stages 1, 2, and 3. Medical records of the patients during this time period were reviewed to exclude confounding variables, including infection, acute rejection, bronchial stenosis, and recurrence of primary disease or any other factors that might explain this decline in lung function. The date of onset of BOS was defined as the date of the first of the two FEV 1 measurements used to establish the diagnosis. Definition of BOS 0-p BOS 0-p was determined by the FEV 1 and the FEF 25-75% criteria, as defined by the new guidelines (4), using a similar method as described above. A modified FEF 25-75% criterion for stage 0-p as defined by Hachem and others (6) in the bilateral lung transplant population was also analyzed. This modified FEF 25-75% redefines the baseline FEF 25-75% as the average of the two FEF 25-75% measurements obtained with the two highest FEV 1 measurements (6). Data Analysis Correlated times to event were analyzed using years-of-life-saved statistics (11). Kaplan-Meier methodology was used to estimate sensitivity, specificity, and positive predictive value (PPV) curves for relating the diagnosis of BOS 0-p by various criteria to development of BOS. These diagnostic curves are functions of the time between meeting, or not meeting, the BOS 0-p and BOS criteria as well as the available follow-up window. The appropriate patient population, event time scale, and follow-up time scale used to construct sensitivity, specificity, and PP

Sex Differences in Severe Pulmonary Emphysema

Rationale: Limited data on sex differences in advanced COPD are available. Objectives: To compare male and female emphysema patients with severe disease. Methods: One thousand fifty-three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National Emphysema Treatment Trial were analyzed. Measurements and Main Results: Detailed clinical, physiological, and radiological assessment, including quantitation of emphysema severity and distribution from helical chest computed tomography, was completed. In a subgroup (n = 101), airway size and thickness was determined by histological analyses of resected tissue. Women were younger and exhibited a lower bodymass index (BMI), shorter smoking history, less severe airflow obstruction, lower DLCO and arterial PO2, higher arterial PCO2, shorter six-minute walk distance, and lower maximal wattage during oxygen-supplemented cycle ergometry. For a given FEV1% predicted, age, number of packyears, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE, more depression, lower SF-36 mental component score, and lower quality of well-being. Overall emphysema was less severe in women, with the difference from men most evident in the outer peel of the lung. Females had thicker small airway walls relative to luminal perimeters. Conclusions: In patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.The National Emphysema Treatment Trial (NETT) was supported by contracts with the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119); the Centers for Medicare and Medicaid Services (CMS; formerly the Health Care Financing Administration); and the Agency for Healthcare Research and Quality (AHRQ). J.L.C. is supported by funding from a Research Enhancement Award Program (REAP) from the Biomedical Laboratory Research & Development Service, Department of Veterans Affairs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91968/1/2007 Martinez AJRCCM Sex Differences in Empy.pd