Bayesian accounts of perceptual decisions in the nonclinical continuum of psychosis: Greater imprecision in both top-down and bottom-up processes.

Neurocomputational accounts of psychosis propose mechanisms for how information is integrated into a predictive model of the world, in attempts to understand the occurrence of altered perceptual experiences. Conflicting Bayesian theories postulate aberrations in either top-down or bottom-up processing. The top-down theory predicts an overreliance on prior beliefs or expectations resulting in aberrant perceptual experiences, whereas the bottom-up theory predicts an overreliance on current sensory information, as aberrant salience is directed towards objectively uninformative stimuli. This study empirically adjudicates between these models. We use a perceptual decision-making task in a neurotypical population with varying degrees of psychotic-like experiences. Bayesian modelling was used to compute individuals' reliance on prior relative to sensory information. Across two datasets (discovery dataset n = 363; independent replication in validation dataset n = 782) we showed that psychotic-like experiences were associated with an overweighting of sensory information relative to prior expectations, which seem to be driven by decreased precision afforded to prior information. However, when prior information was more uncertain, participants with greater psychotic-like experiences encoded sensory information with greater noise. Greater psychotic-like experiences were associated with aberrant precision in the encoding both prior and likelihood information, which we suggest may be related to generally heightened perceptions of task instability. Our study lends empirical support to notions of both weaker bottom-up and weaker (rather than stronger) top-down perceptual processes, as well as aberrancies in belief updating that extend into the non-clinical continuum of psychosis.

Temporal stability of Bayesian belief updating in perceptual decision-making.

Bayesian inference suggests that perception is inferred from a weighted integration of prior contextual beliefs with current sensory evidence (likelihood) about the world around us. The perceived precision or uncertainty associated with prior and likelihood information is used to guide perceptual decision-making, such that more weight is placed on the source of information with greater precision. This provides a framework for understanding a spectrum of clinical transdiagnostic symptoms associated with aberrant perception, as well as individual differences in the general population. While behavioral paradigms are commonly used to characterize individual differences in perception as a stable characteristic, measurement reliability in these behavioral tasks is rarely assessed. To remedy this gap, we empirically evaluate the reliability of a perceptual decision-making task that quantifies individual differences in Bayesian belief updating in terms of the relative precision weighting afforded to prior and likelihood information (i.e., sensory weight). We analyzed data from participants (n = 37) who performed this task twice. We found that the precision afforded to prior and likelihood information showed high internal consistency and good test-retest reliability (ICC = 0.73, 95% CI [0.53, 0.85]) when averaged across participants, as well as at the individual level using hierarchical modeling. Our results provide support for the assumption that Bayesian belief updating operates as a stable characteristic in perceptual decision-making. We discuss the utility and applicability of reliable perceptual decision-making paradigms as a measure of individual differences in the general population, as well as a diagnostic tool in psychiatric research.

Brain volumes in alcohol use disorder: Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis.

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxel-based, multi-tissue mega-analytic approach, thereby extending our recent surface-based region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller group-by-sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD.

An initial 'snapshot' of sensory information biases the likelihood and speed of subsequent changes of mind.

We often need to rapidly change our mind about perceptual decisions in order to account for new information and correct mistakes. One fundamental, unresolved question is whether information processed prior to a decision being made ('pre-decisional information') has any influence on the likelihood and speed with which that decision is reversed. We investigated this using a luminance discrimination task in which participants indicated which of two flickering greyscale squares was brightest. Following an initial decision, the stimuli briefly remained on screen, and participants could change their response. Using psychophysical reverse correlation, we examined how moment-to-moment fluctuations in stimulus luminance affected participants' decisions. This revealed that the strength of even the very earliest (pre-decisional) evidence was associated with the likelihood and speed of later changes of mind. To account for this effect, we propose an extended diffusion model in which an initial 'snapshot' of sensory information biases ongoing evidence accumulation.

Examining the neural correlates of error awareness in a large fMRI study.

Goal-directed behavior is dependent upon the ability to detect errors and implement appropriate posterror adjustments. Accordingly, several studies have explored the neural activity underlying error-monitoring processes, identifying the insula cortex as crucial for error awareness and reporting mixed findings with respect to the anterior cingulate cortex (ACC). Variable patterns of activation have previously been attributed to insufficient statistical power. We therefore sought to clarify the neural correlates of error awareness in a large event-related functional magnetic resonance imaging (fMRI) study. Four hundred and two healthy participants undertook the error awareness task, a motor Go/No-Go response inhibition paradigm in which participants were required to indicate their awareness of commission errors. Compared to unaware errors, aware errors were accompanied by significantly greater activity in a network of regions, including the insula cortex, supramarginal gyrus (SMG), and midline structures, such as the ACC and supplementary motor area (SMA). Error awareness activity was related to indices of task performance and dimensional measures of psychopathology in selected regions, including the insula, SMG, and SMA. Taken together, we identified a robust and reliable neural network associated with error awareness.

Electrophysiological correlates of confidence differ across correct and erroneous perceptual decisions.

Every decision we make is accompanied by an estimate of the probability that our decision is accurate or appropriate. This probability estimate is termed our degree of decision confidence. Recent work has uncovered event-related potential (ERP) correlates of confidence both during decision formation and after a decision has been made. However, the interpretation of these findings is complicated by methodological issues related to ERP amplitude measurement that are prevalent across existing studies. To more accurately characterise the neural correlates of confidence, we presented participants with a difficult perceptual decision task that elicited a broad range of confidence ratings. We identified a frontal ERP component within an onset prior to the behavioural response, which exhibited more positive-going amplitudes in trials with higher confidence ratings. This frontal effect also biased measures of the centro-parietal positivity (CPP) component at parietal electrodes via volume conduction. Amplitudes of the error positivity (Pe) component that followed each decision were negatively associated with confidence for trials with decision errors, but not for trials with correct decisions, with Bayes factors providing moderate evidence for the null in the latter case. We provide evidence for both pre- and post-decisional neural correlates of decision confidence that are observed in trials with correct and erroneous decisions, respectively. Our findings suggest that certainty in having made a correct response is associated with frontal activity during decision formation, whereas certainty in having committed an error is instead associated with the post-decisional Pe component. These findings also highlight the possibility that some previously reported associations between decision confidence and CPP/Pe component amplitudes may have been a consequence of ERP amplitude measurement-related confounds. Re-analysis of existing datasets may be useful to test this hypothesis more directly.

Predicting alcohol dependence from multi-site brain structural measures.

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.

Addressing methodological issues in a study of impulsivity and vulnerability for transition to alcohol use disorder.

BACKGROUND: Heightened behavioral impulsivity has been advocated as a preexisting risk factor for the development of alcohol use disorder (AUD). Nonetheless, studies investigating impulsivity in adolescent/young adult at-risk drinkers-who are at increased risk of developing AUD-report mixed findings. This may be due to methodological limitations related to definitions of at-risk drinking, the retrospective assessment of alcohol intake, and/or the relatively modest sample size of some studies. METHODS: Healthy individuals (N = 814, Mage  = 22.50) completed online surveys and a measure of choice impulsivity. Of these, a number of participants also undertook an online measure of response inhibition (n = 627, Mage  = 22.66), and a further subgroup submitted real-time alcohol consumption information for a period of 21 days using an app (n = 543, Mage  = 22.96). Differences in behavioral impulsivity were assessed as a function of various at-risk alcohol intake categories. Hierarchical multiple regression was employed to determine whether impulsivity predicted alcohol use in the form of a continuous index comprising variables related to intake and consequences of use. RESULTS: Significantly greater impulsivity was not evident in heavy, standard binge, high binge, harmful, or hazardous alcohol drinkers as compared to controls, regardless of the criteria employed to categorize these at-risk drinkers. Neither choice impulsivity nor reduced response inhibition significantly predicted the alcohol use index. CONCLUSIONS: While results could be attributed to the online nature of this research, it is possible that more sensitive measures of behavioral impulsivity are required when assessing nondependent drinkers.

Error awareness and post-error slowing: The effect of manipulating trial intervals.

Post-error slowing is often considered to be an error-related process that relies upon conscious error recognition, however evidence regarding this relationship is mixed. These inconsistent findings may be explained by the influence of task demands on post-error slowing. The current set of experiments aimed to investigate the role of error awareness in post-error slowing in an error awareness task with up to three dynamic conditions. In each condition, we manipulated the interval between lure trials (infrequent trials that require a different response to target trials) such that they were presented either randomly (standard condition), closely spaced (proximal condition) or widely spaced (distal condition) among target trials. This design attempted to clarify if the relationship between error awareness and post-error slowing is contingent upon task constraints such as trial timing and whether it persists over several trials. Our experiments demonstrate that under dynamic lure interval conditions, error awareness and post-error slowing are only weakly related. Further, post-error slowing was greatest in the standard condition which randomly presented lure trials, while accuracy was lowest in this condition across both experiments. Exclusion of the first post-error trial from both experiments eliminated all effects, indicating that there were only transient differences in post-error reaction time adjustments that were exclusive to the first post-error trial. Our findings thus align with non-functional accounts of post-error slowing and support the notion that post-error slowing and cognitive control can be separate processes that are largely not dependent on error awareness.

People with tobacco use disorder exhibit more prefrontal activity during preparatory control but reduced anterior cingulate activity during reactive control.

Reduced inhibitory control and a hypersensitivity to reward are key deficits in drug dependents; however, they tend to be studied in isolation. Here, we seek to understand the neural processes underlying control over reward and how this is different in people with a tobacco use disorder (pTUD). A novel variant of the monetary incentive delay task was performed by pTUD (n = 20) and non-smokers (n = 20), where we added a stop-signal component such that participants had to inhibit prepotent responses to earn a larger monetary reward. Brain activity was recorded using functional magnetic resonance imaging (fMRI). We estimated stop signal reaction times (SSRTs), an indicator of impulsivity, and correlated these with brain activity. Inhibitory accuracy scores did not differ between the control group and pTUD. However, pTUD had slower SSRTs, suggesting that they may find it harder to inhibit responses. Brain data revealed that pTUD had greater preparatory control activity in the middle frontal gyrus and inferior frontal gyrus prior to successful inhibitions over reward. In contrast, non-smokers had greater reactive control associated with more activity in the anterior cingulate cortex during these successful inhibitions. SSRT-brain activity correlations revealed that pTUD engaged more control-related prefrontal brain regions when SSRTs are slower. Overall, while the inhibition accuracy scores were similar between groups, differential neural processes and strategies were used to successfully inhibit a prepotent response. The findings suggest that increasing preparatory control in pTUD may be one possible treatment target in order to increase inhibitory control over reward.

Functional connectivity during feedback learning in smokers.

BACKGROUND: Although it has been traditionally assumed that dysregulation of psychological processes in smokers results from activity within specific brain regions, an emerging view regards such dysregulation as attributable to aberrant communication between distinct brain regions. These processes can be measured during appropriate task paradigms such as the learning from errors task. This study aims to elucidate interactions between brain regions underlying the process of learning from errors, punishment and sensitivity to reward in dependent smokers. METHODS: Functional MRI data from 23 age-matched dependent smokers (8 females, mean age = 25.48, SD = 4.46) and 23 controls (13 females, mean age = 24.83, SD = 5.99) were analysed during a feedback-based associative learning task. Functional connectivity between the dorsal anterior cingulate cortex, nucleus accumbens and reward/sensorimotor areas was investigated during a feedback learning task. RESULTS: Behaviourally, smokers exhibited lower error correction rates and were less sensitive to punishment magnitude. Smokers showed increased functional connectivity between dorsal anterior cingulate cortex/nucleus accumbens seed regions and numerous reward-related target regions including the putamen, anterior cingulate and orbitofrontal cortex. CONCLUSIONS: Reduced learning from errors and widespread aberrant functional connectivity contribute to the emerging functional characterisation of dependent smokers and may bear significant implications when considering the efficacy of smoking interventions.

Adaptation following errors: Error awareness predicts future performance.

The ability to detect an error in performance is critical to ongoing and future goal-directed behaviour. Diminished awareness of errors has been associated with a loss of insight and poor functional recovery in several clinical disorders (e.g., attention-deficit/hyperactivity disorder, addiction, schizophrenia). Despite the clear imperative to understand and remediate such deficits, error awareness and its instantiation in corrective behaviour remains to be fully elucidated. The present study investigated the relationship between error awareness and future performance in order to determine whether conscious recognition of errors facilitates adaptive behaviour. Fifty-one healthy participants completed a motor Go/No-Go error awareness task that afforded the opportunity to learn from errors. A mixed-effects model was specified wherein awareness of an error was used to predict inhibitory performance on the following No-Go trial. The model revealed a significant predictive effect of error awareness on future performance, such that aware errors were more frequently followed by correct inhibitory performance. Notably, improvement in performance accuracy was not due to a temporary increase in conservatism of responding, but appeared to be a context-specific adaptation. These results highlight the adaptive role of error awareness and the relationship between error awareness and learning from errors that has the potential to contribute to clinical symptomatology.

Web-Based Independent Versus Laboratory-Based Stop-Signal Task Performance: Within-Subjects Counterbalanced Comparison Study.

BACKGROUND: Considered a facet of behavioral impulsivity, response inhibition facilitates adaptive and goal-directed behavior. It is often assessed using the Stop-Signal Task (SST), which is presented on stand-alone computers under controlled laboratory conditions. Sample size may consequently be a function of cost or time and sample diversity constrained to those willing or able to attend the laboratory. Statistical power and generalizability of results might, in turn, be impacted. Such limitations may potentially be overcome via the implementation of web-based testing. OBJECTIVE: The aim of this study was to investigate if there were differences between variables derived from a web-based SST when it was undertaken independently-that is, outside the laboratory, on any computer, and in the absence of researchers-versus when it was performed under laboratory conditions. METHODS: We programmed a web-based SST in HTML and JavaScript and employed a counterbalanced design. A total of 166 individuals (mean age 19.72, SD 1.85, range 18-36 years; 146/166, 88% female) were recruited. Of them, 79 undertook the independent task prior to visiting the laboratory and 78 completed the independent task following their laboratory visit. The average time between SST testing was 3.72 (SD 2.86) days. Dependent samples and Bayesian paired samples t tests were used to examine differences between laboratory-based and independent SST variables. Correlational analyses were conducted on stop-signal reaction times (SSRT). RESULTS: After exclusions, 123 participants (mean age 19.73, SD 1.97 years) completed the SST both in the laboratory and independently. While participants were less accurate on go trials and exhibited reduced inhibitory control when undertaking the independent-compared to the laboratory-based-SST, there was a positive association between the SSRT of each condition (r=.48; P<.001; 95% CI 0.33-0.61). CONCLUSIONS: Findings suggest a web-based SST, which participants undertake on any computer, at any location, and in the absence of the researcher, is a suitable measure of response inhibition.

Tracking dynamic adjustments to decision making and performance monitoring processes in conflict tasks.

How we exert control over our decision-making has been investigated using conflict tasks, which involve stimuli containing elements that are either congruent or incongruent. In these tasks, participants adapt their decision-making strategies following exposure to incongruent stimuli. According to conflict monitoring accounts, conflicting stimulus features are detected in medial frontal cortex, and the extent of experienced conflict scales with response time (RT) and frontal theta-band activity in the Electroencephalogram (EEG). However, the consequent adjustments to decision processes following response conflict are not well-specified. To characterise these adjustments and their neural implementation we recorded EEG during a modified Flanker task. We traced the time-courses of performance monitoring processes (frontal theta) and multiple processes related to perceptual decision-making. In each trial participants judged which of two overlaid gratings forming a plaid stimulus (termed the S1 target) was of higher contrast. The stimulus was divided into two sections, which each contained higher contrast gratings in either congruent or incongruent directions. Shortly after responding to the S1 target, an additional S2 target was presented, which was always congruent. Our EEG results suggest enhanced sensory evidence representations in visual cortex and reduced evidence accumulation rates for S2 targets following incongruent S1 stimuli. Results of a follow-up behavioural experiment indicated that the accumulation of sensory evidence from the incongruent (i.e. distracting) stimulus element was adjusted following response conflict. Frontal theta amplitudes positively correlated with RT following S1 targets (in line with conflict monitoring accounts). Following S2 targets there was no such correlation, and theta amplitude profiles instead resembled decision evidence accumulation trajectories. Our findings provide novel insights into how cognitive control is implemented following exposure to conflicting information, which is critical for extending conflict monitoring accounts.

Physiological Modeling and Simulation-Validation, Credibility, and Application.

In this review, we discuss the science of model validation as it applies to physiological modeling. There is widespread disagreement and ambiguity about what constitutes model validity. In areas in which models affect real-world decision-making, including within the clinic, in regulatory science, or in the design and engineering of novel therapeutics, this question is of critical importance. Without an answer, it impairs the usefulness of models and casts a shadow over model credibility in all domains. To address this question, we examine the use of nonmathematical models in physiological research, in medical practice, and in engineering to see how models in other domains are used and accepted. We reflect on historic physiological models and how they have been presented to the scientific community. Finally, we look at various validation frameworks that have been proposed as potential solutions during the past decade.

Inflammatory breast cancer: early recognition and diagnosis is critical.

Inflammatory breast cancer is a rare and aggressive malignancy that is often initially misdiagnosed because of its similar presentation to more benign breast pathologies such as mastitis, resulting in treatment delays. Presenting symptoms of inflammatory breast cancer include erythema, skin changes such as peau d' orange or nipple inversion, edema, and warmth of the affected breast. The average age at diagnosis is younger than in noninflammatory breast cancer cases. Known risk factors include African American race and obesity. Diagnostic criteria include erythema occupying at least one-third of the breast, edema, peau d' orange, and/or warmth, with or without an underlying mass; a rapid onset of <3 months; and pathologic confirmation of invasive carcinoma. Treatment of inflammatory breast cancer includes trimodal therapy with chemotherapy, surgery, and radiation. An aggressive surgical approach that includes a modified radical mastectomy enhances survival outcomes. Although the outcomes for patients with inflammatory breast cancer are poor compared with those of patients with noninflammatory breast cancer, patients with inflammatory breast cancer who complete trimodal therapy have a favorable locoregional control rate, underscoring the importance of a prompt diagnosis of this serious but treatable disease. Obstetrician-gynecologists and other primary care providers must recognize the signs and symptoms of inflammatory breast cancer to make a timely diagnosis and referral for specialized care.

Perceptual change-of-mind decisions are sensitive to absolute evidence magnitude.

To navigate the world safely, we often need to rapidly 'change our mind' about decisions. Current models assume that initial decisions and change-of-mind decisions draw upon common sources of sensory evidence. In two-choice scenarios, this evidence may be 'relative' or 'absolute'. For example, when judging which of two objects is the brightest, the luminance difference and luminance ratio between the two objects are sources of 'relative' evidence, which are invariant across additive and multiplicative luminance changes. Conversely, the overall luminance of the two objects combined is a source of 'absolute' evidence, which necessarily varies across symmetric luminance manipulations. Previous studies have shown that initial decisions are sensitive to both relative and absolute evidence; however, it is unknown whether change-of-mind decisions are sensitive to absolute evidence. Here, we investigated this question across two experiments. In each experiment participants indicated which of two flickering greyscale squares was brightest. Following an initial decision, the stimuli remained on screen for a brief period and participants could change their response. To investigate the effect of absolute evidence, the overall luminance of the two squares was varied whilst either the luminance difference (Experiment 1) or luminance ratio (Experiment 2) was held constant. In both experiments we found that increases in absolute evidence led to faster, less accurate initial responses and slower changes of mind. Change-of-mind accuracy decreased when the luminance difference was held constant, but remained unchanged when the luminance ratio was fixed. We show that the three existing change-of-mind models cannot account for our findings. We then fit three alternative models, previously used to account for the effect of absolute evidence on one-off decisions, to the data. A leaky competing accumulator model best accounted for the changes in behaviour across absolute evidence conditions - suggesting an important role for input-dependent leak in explaining perceptual changes of mind.

Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.