A Quantitative Phenytoin GC-MS Method and its Validation for Samples from Human ex situ Brain Microdialysis, Blood and Saliva Using Solid-Phase Extraction

This study describes the development and validation of a gas chromatography-mass spectrometry (GC-MS) method to identify and quantitate phenytoin in brain microdialysate, saliva and blood from human samples. A solid-phase extraction (SPE) was performed with a nonpolar C8-SCX column. The eluate was evaporated with nitrogen (50°C) and derivatized with trimethylsulfonium hydroxide before GC-MS analysis. As the internal standard, 5-(p-methylphenyl)-5-phenylhydantoin was used. The MS was run in scan mode and the identification was made with three ion fragment masses. All peaks were identified with MassLib. Spiked phenytoin samples showed recovery after SPE of ≥94%. The calibration curve (phenytoin 50 to 1,200 ng/mL, n = 6, at six concentration levels) showed good linearity and correlation (r2 > 0.998). The limit of detection was 15 ng/mL; the limit of quantification was 50 ng/mL. Dried extracted samples were stable within a 15% deviation range for ≥4 weeks at room temperature. The method met International Organization for Standardization standards and was able to detect and quantify phenytoin in different biological matrices and patient samples. The GC-MS method with SPE is specific, sensitive, robust and well reproducible, and is therefore an appropriate candidate for the pharmacokinetic assessment of phenytoin concentrations in different human biological sample

Comparing adaptive coding of reward in bipolar I disorder and schizophrenia

Deficits in neural processing of reward have been described in both bipolar disorder (BD) and schizophrenia (SZ), but it remains unclear to what extent these deficits are caused by similar mechanisms. Efficient reward processing relies on adaptive coding which allows representing large input spans by limited neuronal encoding ranges. Deficits in adaptive coding of reward have previously been observed across the SZ spectrum and correlated with total symptom severity. In the present work, we sought to establish whether adaptive coding is similarly affected in patients with BD. Twenty-five patients with BD, 27 patients with SZ and 25 healthy controls performed a variant of the Monetary Incentive Delay task during functional magnetic resonance imaging in two reward range conditions. Adaptive coding was impaired in the posterior part of the right caudate in BD and SZ (trend level). In contrast, BD did not show impaired adaptive coding in the anterior caudate and right precentral gyrus/insula, where SZ showed deficits compared to healthy controls. BD patients show adaptive coding deficits that are similar to those observed in SZ in the right posterior caudate. Adaptive coding in BD appeared more preserved as compared to SZ participants especially in the more anterior part of the right caudate and to a lesser extent also in the right precentral gyrus. Thus, dysfunctional adaptive coding could constitute a fundamental deficit in severe mental illnesses that extends beyond the SZ spectrum

Adaptive coding occurs in object categorization and may not be associated with schizotypal personality traits

Processing more likely inputs with higher sensitivity (adaptive coding) enables the brain to represent the large range of inputs coming in from the world. Healthy individuals high in schizotypy show reduced adaptive coding in the reward domain but it is an open question whether these deficits extend to non-motivational domains, such as object categorization. Here, we develop a novel variant of a classic task to test range adaptation for face/house categorization in healthy participants on the psychosis spectrum. In each trial of this task, participants decide whether a presented image is a face or a house. Images vary on a face-house continuum and appear in both wide and narrow range blocks. The wide range block includes most of the face-house continuum (2.50–97.5% face), while the narrow range blocks limit inputs to a smaller section of the continuum (27.5–72.5% face). Adaptive coding corresponds to better performance for the overlapping smaller section of the continuum in the narrow range than in the wide range block. We find that participants show efficient use of the range in this task, with more accurate responses in the overlapping section for the narrow range blocks relative to the wide range blocks. However, we find little evidence that range adaptation in our object categorization task is reduced in healthy individuals scoring high on schizotypy. Thus, reduced range adaptation may not be a domain-general feature of schizotypy

Cerebellar and cortico-striatal-midbrain contributions to reward-cognition processes and apathy within the psychosis continuum

Negative symptoms in the psychosis continuum are linked to impairments in reward processing and cognitive function. Processes at the interface of reward processing and cognition and their relation to negative symptoms remain little studied, despite evidence suggestive of integration in mechanisms and neural circuitry. Here, we investigated brain activation during reward-dependent modulation of working memory (WM) and their relationship to negative symptoms in subclinical and early stages of the psychosis continuum. We included 27 persons with high schizotypal personality traits and 23 patients with first episode psychosis as well as 27 healthy controls. Participants underwent functional magnetic resonance imaging while performing an established 2-back WM task with two reward levels (5 CHF vs. no reward), which allowed us to assess common reward-cognition regions through whole-brain conjunction analyses and to investigate relations with clinical scores of negative symptoms. As expected for behavior, reward facilitated performance while cognitive load diminished it. At the neural level, the conjunction of high reward and high cognitive load contrasts across the psychosis continuum showed increased hemodynamic activity in the thalamus and the cerebellar vermis. During high cognitive load, more severe apathy but not diminished expression in the psychosis continuum was associated with reduced activity in right lateral orbitofrontal cortex, midbrain, posterior vermal cerebellum, caudate and lateral parietal cortex. Our results suggest that hypoactivity in the cerebellar vermis and the cortical-striatal-midbrain-circuitry in the psychosis continuum relates to apathy possibly via impaired flexible cognitive resource allocation for effective goal pursuit

Apathy But Not Diminished Expression in Schizophrenia Is Associated With Discounting of Monetary Rewards by Physical Effort

Negative symptoms in schizophrenia have been grouped into the 2 factors of apathy and diminished expression, which might be caused by separable pathophysiological mechanisms. Recently, it has been proposed that apathy could be due to dysfunctional integration of reward and effort during decision making. We asked whether apathy in particular is associated with stronger devaluation ("discounting”) of monetary rewards that require physical effort. Thirty-one patients with schizophrenia and 20 healthy control participants performed a computerized effort discounting task in which they could choose to exert physical effort on a handgrip to obtain monetary rewards. This procedure yields an individual measure for the strength of effort discounting. The degree of effort discounting was strongly correlated with apathy, but not with diminished expression. Importantly, the association between apathy and effort discounting was not driven by cognitive ability, antipsychotic medication, or other clinical and demographic variables. This study provides the first evidence for a highly specific association of apathy with effort-based decision making in patients with schizophrenia. Within a translational framework, the present effort discounting task could provide a bridge between apathy as a psychopathological phenomenon and established behavioral tasks to address similar states in animal

The cognitive and neural basis of option generation and subsequent choice

Decision-making research has thoroughly investigated how people choose from a set of externally provided options. However, in ill-structured real-world environments, possible options for action are not defined by the situation but have to be generated by the agent. Here, we apply behavioral analysis (Study 1) and functional magnetic resonance imaging (Study 2) to investigate option generation and subsequent choice. For this purpose, we employ a new experimental task that requires participants to generate options for simple real-world scenarios and to subsequently decide among the generated options. Correlational analysis with a cognitive test battery suggests that retrieval of options from long-term memory is a relevant process during option generation. The results of the fMRI study demonstrate that option generation in simple real-world scenarios recruits the anterior prefrontal cortex. Furthermore, we show that choice behavior and its neural correlates differ between self-generated and externally provided options. Specifically, choice between self-generated options is associated with stronger recruitment of the dorsal anterior cingulate cortex. This impact of option generation on subsequent choice underlines the need for an expanded model of decision making to accommodate choice between self-generated option

Case Report Mayer-Rokitansky-Kuster-Hauser Syndrome Associated with Severe Inferior Vena Cava Stenosis

Precis. The postoperative course of a neovagina creation procedure in a young woman with Meyer-Rokitansky-Kuster-Hauser syndrome was complicated, despite prophylaxis, by extensive pelvic deep venous thrombosis secondary to unsuspected severe inferior vena cava stenosis. Background. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by congenital vaginal agenesis and an absent or rudimentary uterus in genotypical females. Malformations of the inferior vena cava (IVC) are not commonly associated with MRKH syndrome. We report a case of a patient with MRKH syndrome with severe IVC stenosis that was diagnosed when the patient presented with extensive pelvic deep venous thrombosis (DVT) during the postoperative course of a neovagina creation. Case. A 19-year-old female underwent a McIndoe procedure. Despite DVT prophylaxis, extensive pelvic DVT of the femoral vein was diagnosed on postoperative day 7. Therapeutic anticoagulation was initiated, and pharmacological and mechanical thrombolysis were performed. During these procedures, a hypoplastic IVC was noted. Conclusion. MRKH syndrome can be associated with IVC malformations, which constitute an anatomical risk factor for postoperative DVT

The cognitive and neural basis of option generation and subsequent choice

Decision-making research has thoroughly investigated how people choose from a set of externally provided options. However, in ill-structured real-world environments, possible options for action are not defined by the situation but have to be generated by the agent. Here, we apply behavioral analysis (Study 1) and functional magnetic resonance imaging (Study 2) to investigate option generation and subsequent choice. For this purpose, we employ a new experimental task that requires participants to generate options for simple real-world scenarios and to subsequently decide among the generated options. Correlational analysis with a cognitive test battery suggests that retrieval of options from long-term memory is a relevant process during option generation. The results of the fMRI study demonstrate that option generation in simple real-world scenarios recruits the anterior prefrontal cortex. Furthermore, we show that choice behavior and its neural correlates differ between self-generated and externally provided options. Specifically, choice between self-generated options is associated with stronger recruitment of the dorsal anterior cingulate cortex. This impact of option generation on subsequent choice underlines the need for an expanded model of decision making to accommodate choice between self-generated options

Investigating the association of ventral and dorsal striatal dysfunction during reward anticipation with negative symptoms in patients with schizophrenia and healthy individuals

Background Negative symptoms are a core feature of schizophrenia and also found in healthy individuals in subclinical forms. According to the current literature the two negative symptom domains, apathy and diminished expression may have different underlying neural mechanisms. Previous observations suggest that striatal dysfunction is associated with apathy in schizophrenia. However, it is unclear whether apathy is specifically related to ventral or dorsal striatal alterations. Here, we investigated striatal dysfunction during reward anticipation in patients with schizophrenia and a non-clinical population, to determine whether it is associated with apathy. Methods Chronic schizophrenia patients (n = 16) and healthy controls (n = 23) underwent an event- related functional MRI, while performing a variant of the Monetary Incentive Delay Task. The two negative symptom domains were assessed in both groups using the Brief Negative Symptoms Scale. Results In schizophrenia patients, we saw a strong negative correlation between apathy and ventral and dorsal striatal activation during reward anticipation. In contrast, there was no correlation with diminished expression. In healthy controls, apathy was not correlated with ventral or dorsal striatal activation during reward anticipation. Conclusion This study replicates our previous findings of a correlation between ventral striatal activity and apathy but not diminished expression in chronic schizophrenia patients. The association between apathy and reduced dorsal striatal activity during reward anticipation suggests that impaired action-outcome selection is involved in the pathophysiology of motivational deficits in schizophrenia

Predator-induced changes of female mating preferences: innate and experiential effects

Background: In many species males face a higher predation risk than females because males display elaborate traits that evolved under sexual selection, which may attract not only females but also predators. Females are, therefore, predicted to avoid such conspicuous males under predation risk. The present study was designed to investigate predator-induced changes of female mating preferences in Atlantic mollies (Poecilia mexicana). Males of this species show a pronounced polymorphism in body size and coloration, and females prefer large, colorful males in the absence of predators. Results: In dichotomous choice tests predator-naïve (lab-reared) females altered their initial preference for larger males in the presence of the cichlid Cichlasoma salvini, a natural predator of P. mexicana, and preferred small males instead. This effect was considerably weaker when females were confronted visually with the non-piscivorous cichlid Vieja bifasciata or the introduced non-piscivorous Nile tilapia (Oreochromis niloticus). In contrast, predator experienced (wild-caught) females did not respond to the same extent to the presence of a predator, most likely due to a learned ability to evaluate their predators' motivation to prey. Conclusions: Our study highlights that (a) predatory fish can have a profound influence on the expression of mating preferences of their prey (thus potentially affecting the strength of sexual selection), and females may alter their mate choice behavior strategically to reduce their own exposure to predators. (b) Prey species can evolve visual predator recognition mechanisms and alter their mate choice only when a natural predator is present. (c) Finally, experiential effects can play an important role, and prey species may learn to evaluate the motivational state of their predators. Keywords: Sexual selection; female choice; non-independent mate choice; predator recognition; Poecilia mexican