Characterizing Goal-Directed Behavior in Children with Attention-Deficit/Hyperactivity Disorde

Attention-deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, impulsivity and hyperactivity. Children with ADHD show impaired motivational behavior. For example, they tend to select small, immediate over large, delayed rewards. They might be unable to predict the consequences of their actions showing a deficit in action-control strategies. Goals and habits are the two behavioral mechanisms that control actions. Balancing these two behaviors leads to normal action-control. In previous studies, we found that rat models of ADHD demonstrated over-reliance on habits and poor goal-directed actions. This deficit was restored by administering methylphenidate (the most commonly used psychostimulant in ADHD treatment), dopamine D2 receptor agonist or dopamine D1 receptor antagonist. Further, in another pilot study, we found that children with ADHD are less reliant on goal-directed behavior compared to healthy children. In this study, we examined action-control patterns in children with ADHD on- and off- methylphenidate. We hypothesize that on-methylphenidate patients will show different patterns of action-control compared to off-methylphenidate patients. We tested 7 off-medication and 7 on-medication, 6-10 years old children with ADHD, and 13 healthy controls. Participants were 6-10 years old and were group matched for age and sex. We tested patterns of action-control using a computer-based task of the outcome devaluation paradigm that consists of three phases; a training phase, a devaluation phase and a choice test. Children with ADHD were successful at acquiring action-outcome associations as well as showing higher tendency on goal-directed responses. However, throughout the task, on- methylphenidate children showed (1) lower number of errors, (2) higher reaction times and (3) no difference in action-control responses (goals vs. habits). These results indicate that methylphenidate was beneficial in modulating symptoms of ADHD by reducing the number of errors during learning and increasing children’s response times; but it was not effective in improving children’s cognitive profile, reflected by similar action-control patterns in both on and off-medication states

Depression following major life transitions in women: a review and theory

Depression can occur due to common major life transitions, such as giving birth, menopause, retirement, empty-nest transition, and midlife crisis. Although some of these transitions are perceived as positive (e.g., giving birth), they may still lead to depression. We conducted a systematic literature review of the factors underlying the occurrence of depression following major life transition in some individuals. This review shows that major common life transitions can cause depression if they are sudden, major, and lead to loss (or change) of life roles (e.g., no longer doing motherly or fatherly chores after children leave family home). Accordingly, we provide a theoretical framework that explains depression caused by transitions in women. One of the most potential therapeutic methods of ameliorating depression associated with life transitions is either helping individuals accept their new roles (e.g., accepting new role as a mother to ameliorate postpartum depression symptoms) or providing them with novel life roles (e.g., volunteering after retirement or children leave family home) may help them overcome their illness

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Investigating principal working memory features in generalized, panic and social anxiety spectrum disorders

Anxiety spectrum disorders are characterized by excessive and uncontrollable worrying about potential negative events in the short- and long-term future. Various reports linked anxiety spectrum disorders with working memory (WM) deficits despite conflicting results stemming from different study approaches. It remains unclear, however, how different anxiety spectrum disorders such as generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder (PD), differ in WM function. In this study, we utilized verbal, numerical, and sequential evaluations of WM to cover most possible facets of the WM data space. We used principal component analysis to extract the uncorrelated/whitened components of WM based on these measures. We evaluated medication-free patients with GAD, SAD, and PD patients as well as matched healthy individuals using a battery that measures WM duration and load. We found that patients with GAD and SAD, but not PD, exhibited poor performance only in the WM principal component that represents maintenance. There were no other significant differences between the four groups. Further, different WM components significantly predicted the severity of anxiety symptoms in the groups. We explored the clinical utility of WM components for differentiating patients with anxiety spectrum disorders from healthy individuals. By only using the WM components that represent maintenance and encoding, we managed to differentiate patients from controls in 84% of cases. For the first time, we present multiple novel approaches to examine cognitive function and design cognitive screening, and potentially diagnostics, for psychiatric disorders

The influence of trial order on learning from reward versus punishment in a probabilistic categorization task: Experimental and computational analyses

Previous research has shown that trial ordering affects cognitive performance, but this has not been not tested using category-learning tasks that differentiate learning from reward and punishment. Here, we tested two groups of healthy young adults using a probabilistic category learning task of reward and punishment in which there are two types of trials (reward, punishment) and three possible outcomes: (1) positive feedback for correct responses in reward trials, (2) negative feedback for incorrect responses in punishment trials, and (3) no feedback for incorrect answers in reward trials and correct answers in punishment trials. Hence, trials without feedback are ambiguous, and may represent either successful avoidance of punishment or failure to obtain reward. In Experiment 1, the first group of subjects received an intermixed task in which reward and punishment trials were presented in the same block, as a standard baseline task. In Experiment 2, a second group completed the separated task, in which reward and punishment trials were presented in separate blocks. Additionally, in order to understand the mechanisms underlying performance in the experimental conditions, we fit individual data using a Q-learning model. Results from Experiment 1 show that subjects who completed the intermixed task paradoxically valued the no-feedback outcome as a reinforcer when it occurred on reinforcement-based trials, and as a punisher when it occurred on punishment-based trials. This is supported by patterns of empirical responding, where subjects showed more win-stay behavior following an explicit reward than following an omission of punishment, and more lose-shift behavior following an explicit punisher than following an omission of reward. In Experiment 2, results showed similar performance whether subjects received reward-based or punishment-based trials first. However, when the Q-learning model was applied to these data, there were differences between subjects in the re

A model of reversal learning and working memory in medicated and unmedicated patients with Parkinson's disease

We present a neural network model of cognition in medicated and unmedicated patients with Parkinson's disease (PD) in various learning and memory tasks. The model extends our prior models of the basal ganglia and PD with further modeling of the role of prefrontal cortex (PFC) dopamine in stimulus-response learning, reversal, and working memory. In our model, PD is associated with decreased dopamine levels in the basal ganglia and PFC, whereas dopamine medications increase dopamine levels in both brain structures. Simulation results suggest that dopamine medications impair stimulus-response learning in agreement with experimental data ( Breitenstein etal., 2006; Gotham, Brown, & Marsden, 1988). We show how decreased dopamine levels in the PFC in unmedicated PD patients are associated with impaired working memory performance, as seen experimentally ( Costa etal., 2003; Lange etal., 1992; Moustafa, Sherman, & Frank, 2008; Owen, Sahakian, Hodges, Summers, & Polkey, 1995). Further, our model simulations illustrate how increases in tonic dopamine levels in the PFC due to dopamine medications will enhance working memory, in accord with previous modeling and experimental results ( Cohen, Braver, & Brown, 2002; Durstewitz, Seamans, & Sejnowski, 2000; Wang, Vijayraghavan, & Goldman-Rakic, 2004). The model is also consistent with data reported in Cools, Barker, Sahakian, and Robbins (2001), who showed that dopamine medications impair reversal learning. In addition, our model shows that extended training of the reversal phase leads to enhanced reversal performance in medicated PD patients, which is a new, and as yet untested, prediction of the model. Overall, our model provides a unified account for performance in various behavioral tasks using common computational principles

Dissociating the cognitive effects of levodopa versus dopamine agonists in a neurocomputational model of learning in Parkinson's Disease

Background/Aims: Levodopa and dopamine agonists have different effects on the motor, cognitive, and psychiatric aspects of Parkinson’s disease (PD). Methods: Using a computational model of basal ganglia (BG) and prefrontal cortex (PFC) dopamine, we provide a theoretical synthesis of the dissociable effects of these dopaminergic medications on brain and cognition. Our model incorporates the findings that levodopa is converted by dopamine cells into dopamine, and thus activates prefrontal and striatal D1 and D2 dopamine receptors, whereas antiparkinsonian dopamine agonists directly stimulate D2 receptors in the BG and PFC (although some have weak affinity to D1 receptors). Results: In agreement with prior neuropsychological studies, our model explains how levodopa enhances, but dopamine agonists impair or have no effect on, stimulus-response learning and working memory. Conclusion: Our model explains how levodopa and dopamine agonists have differential effects on motor and cognitive processes in PD

The influence of trial order on learning from reward vs. punishment in a probabilistic categorization task : experimental and computational analyses

Previous research has shown that trial ordering affects cognitive performance, but this has not been tested using category-learning tasks that differentiate learning from reward and punishment. Here, we tested two groups of healthy young adults using a probabilistic category learning task of reward and punishment in which there are two types of trials (reward, punishment) and three possible outcomes: (1) positive feedback for correct responses in reward trials; (2) negative feedback for incorrect responses in punishment trials; and (3) no feedback for incorrect answers in reward trials and correct answers in punishment trials. Hence, trials without feedback are ambiguous, and may represent either successful avoidance of punishment or failure to obtain reward. In Experiment 1, the first group of subjects received an intermixed task in which reward and punishment trials were presented in the same block, as a standard baseline task. In Experiment 2, a second group completed the separated task, in which reward and punishment trials were presented in separate blocks. Additionally, in order to understand the mechanisms underlying performance in the experimental conditions, we fit individual data using a Q-learning model. Results from Experiment 1 show that subjects who completed the intermixed task paradoxically valued the no-feedback outcome as a reinforcer when it occurred on reinforcement-based trials, and as a punisher when it occurred on punishment-based trials. This is supported by patterns of empirical responding, where subjects showed more win-stay behavior following an explicit reward than following an omission of punishment, and more lose-shift behavior following an explicit punisher than following an omission of reward. In Experiment 2, results showed similar performance whether subjects received reward-based or punishment-based trials first. However, when the Q-learning model was applied to these data, there were differences between subjects in the reward-first and punishment-first conditions on the relative weighting of neutral feedback. Specifically, early training on reward-based trials led to omission of reward being treated as similar to punishment, but prior training on punishment-based trials led to omission of reward being treated more neutrally. This suggests that early training on one type of trials, specifically reward-based trials, can create a bias in how neutral feedback is processed, relative to those receiving early punishment-based training or training that mixes positive and negative outcomes

Behavioral/Cognitive Amygdala Signaling during Foraging in a Hazardous Environment

We recorded basolateral amygdala (BL) neurons in a seminaturalistic foraging task. Rats had to leave their nest to retrieve food in an elongated arena inhabited by a mechanical predator. There were marked trial-to-trial variations in behavior. After poking their head into the foraging arena and waiting there for a while, rats either retreated to their nest or initiated foraging. Before initiating foraging, rats waited longer on trials that followed failed than successful trials indicating that prior experience influenced behavior. Upon foraging initiation, most principal cells (Type-1) reduced their firing rate, while in a minority (Type-2) it increased. When rats aborted foraging, Type-1 cells increased their firing rates, whereas in Type-2 cells it did not change. Surprisingly, the opposite activity profiles of Type-1 and Type-2 units were also seen in control tasks devoid of explicit threats or rewards. The common correlate of BL activity across these tasks was movement velocity, although an influence of position was also observed. Thus depending on whether rats initiated movement or not, the activity of BL neurons decreased or increased, regardless of whether threat or rewards were present. Therefore, BL activity not only encodes threats or rewards, but is closely related to behavioral output. We propose that higher order cortical areas determine task-related changes in BL activity as a function of reward/threat expectations and internal states. Because Type-1 and Type-2 cells likely form differential connections with the central amygdala (controlling freezing), this process would determine whether movement aimed at attaining food or exploration is suppressed or facilitated

A neural model of hippocampal-striatal interactions in associative learning and transfer generalization in various neurological and psychiatric patients

Building on our previous neurocomputational models of basal ganglia and hippocampal region function (and their modulation by dopamine and acetylcholine, respectively), we show here how an integration of these models can inform our understanding of the interaction between the basal ganglia and hippocampal region in associative learning and transfer generalization across various patient populations. As a common test bed for exploring interactions between these brain regions and neuromodulators, we focus on the acquired equivalence task, an associative learning paradigm in which stimuli that have been associated with the same outcome acquire a functional similarity such that subsequent generalization between these stimuli increases. This task has been used to test cognitive dysfunction in various patient populations with damages to the hippocampal region and basal ganglia, including studies of patients with Parkinson's disease (PD), schizophrenia, basal forebrain amnesia, and hippocampal atrophy. Simulation results show that damage to the hippocampal region-as in patients with hippocampal atrophy (HA), hypoxia, mild Alzheimer's (AD), or schizophrenia-leads to intact associative learning but impaired transfer generalization performance. Moreover, the model demonstrates how PD and anterior communicating artery (ACoA) aneurysm-two very different brain disorders that affect different neural mechanisms-can have similar effects on acquired equivalence performance. In particular, the model shows that simulating a loss of dopamine function in the basal ganglia module (as in PD) leads to slow acquisition learning but intact transfer generalization. Similarly, the model shows that simulating the loss of acetylcholine in the hippocampal region (as in ACoA aneurysm) also results in slower acquisition learning. We argue from this that changes in associative learning of stimulus-action pathways (in the basal ganglia) or changes in the learning of stimulus representations (in the hippocampal region) can have similar functional effects