Decision Making and Reward in Frontal Cortex: Complementary Evidence From Neurophysiological and Neuropsychological Studies

Patients with damage to the prefrontal cortex (PFC)—especially the ventral and medial parts of PFC—often show a marked inability to make choices that meet their needs and goals. These decision-making impairments often reflect both a deficit in learning concerning the consequences of a choice, as well as deficits in the ability to adapt future choices based on experienced value of the current choice. Thus, areas of PFC must support some value computations that are necessary for optimal choice. However, recent frameworks of decision making have highlighted that optimal and adaptive decision making does not simply rest on a single computation, but a number of different value computations may be necessary. Using this framework as a guide, we summarize evidence from both lesion studies and single-neuron physiology for the representation of different value computations across PFC areas

Intensive Family Reunification Services: A Conceptual Framework and Case Example

Recent federal mandates require child welfare agencies to make reasonable efforts to reunify families after out-of-home placement. Consistent with those mandates, agencies are increasingly employing techniques from family preservation services intended initially to prevent out-of-home placement. The purpose of this article is to articulate a conceptual framework and practice guidelines for family reunification services and to describe an experimental reunification program based on a family preservation model. A case example illustrates the way in which the services affected one family that participated in the experiment

Further Examination of the Geographic Range of Eriogonum corymbosum var. nilesii (Polygonaceae, Eriogoneae)

The wild buckwheat Eriogonum corymbosum is widely distributed throughout the southwestern United States, forming a complex of eight varieties. E. corymbosum var. nilesii is a predominantly yellow-flowered variant reported primarily from Clark Co., Nevada. A previous genetic study by our research group found that var. nilesii is genetically distinct from other E. corymbosum varieties, based on a limited number of populations. Here, we assess genetic variation in 14 newly sampled yellow-flowered populations from southern Nevada, southern Utah, and northern Arizona, and compare them to genetic variation in six populations of previously determined E. corymbosum varieties. Of the new populations, we identified four as var. nilesii, four as var. aureum, three as var. glutinosum, two as apparent hybrids involving vars. aureum and nilesii, and one as a more distantly related admixture involving E. thompsoniae. Our results extend the range and area of E. corymbosum var. nilesii considerably from that traditionally stated in the literature. However, this extended range is confined to the Mojave Desert region of southern Nevada, and the number of known populations remains limited

One-year outcomes after transcatheter insertion of an interatrial shunt device for the management of heart failure with preserved ejection fraction

Background—Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required. Methods and Results—Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II–IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class (P<0.001), quality of life (Minnesota Living with Heart Failure score, P<0.001), and 6-minute walk distance (P<0.01). Echocardiography showed a small, stable reduction in left ventricular end-diastolic volume index (P<0.001), with a concomitant small stable increase in the right ventricular end-diastolic volume index (P<0.001). Invasive hemodynamic studies performed in a subset of patients demonstrated a sustained reduction in the workload corrected exercise pulmonary capillary wedge pressure (P<0.01). Survival at 1 year was 95%, and there was no evidence of device-related complications. Conclusions—These results provide evidence of safety and sustained clinical benefit in heart failure with preserved ejection fraction patients 1 year after interatrial septal shunt device implantation. Randomized, blinded studies are underway to confirm these observations

Affine su(3) and su(4) fusion multiplicities as polytope volumes

Affine su(3) and su(4) fusion multiplicities are characterised as discretised volumes of certain convex polytopes. The volumes are measured explicitly, resulting in multiple sum formulas. These are the first polytope-volume formulas for higher-rank fusion multiplicities. The associated threshold levels are also discussed. For any simple Lie algebra we derive an upper bound on the threshold levels using a refined version of the Gepner-Witten depth rule.Comment: 16 pages, LaTe

Arbaclofen in fragile X syndrome: results of phase 3 trials

Background: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. Methods: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-C FX ). Secondary outcomes included other ABC-C FX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. Results: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-C FX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-C FX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). Conclusions: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS

Glutamatergic dysfunction leads to a hyper-dopaminergic phenotype through deficits in short-term habituation: a mechanism for aberrant salience

Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1−/−) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1−/− mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1−/− mice. Furthermore, dopamine signals were initially similar in Gria1−/− mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1−/− mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia