Effects of scopolamine on matching to sample paradigm and related tests in human subjects

This was a double-blind placebo-controlled study with a cross-over design to examine the effects of scopolamine on cognitive functions in young healthy subjects. Scopolamine hydrobromide was administered subcutaneously to 12 subjects (mean +/- SD age 23.8 +/- 2.2 years) at doses of 0.3 and 0.6 mg in comparison with two placebo conditions. Scopolamine at both doses produced marked sedation as rated by subjects and an observer. In the continuous performance test, vigilance was impaired by both doses of scopolamine. The span of apprehension test showed differing results (only the high dose of scopolamine showed a performance decrement only in the three-character version of the span of apprehension test). Significant impairment by both doses of scopolamine was seen in immediate and delayed free recall, continuous visual recognition, running word recognition and running picture recognition. While scopolamine caused a significant slowing in average reaction times for simultaneous matching as well as for delayed matching, subjects made more errors under scopolamine compared to placebo only in delayed matching, not in simultaneous matching. Also, the main outcome of matching to sample showed significant effects only in delayed matching, not in simultaneous matching. Notable in this study is the incongruity between the simultaneous matching test and the span of apprehension test on the one hand and the other cognitive tests used on the other. These results demonstrated that scopolamine has a greater effect on memory than on attention. Thus, the scopolamine-induced effects in the present study seem to be more relevant to Alzheimer's disease in an advanced phase than to normal aging. Copyright (C) 2003 S. Karger AG, Basel

Conflict monitoring and adaptation as reflected by N2 amplitude in obsessive–compulsive disorder

Background. Feelings of doubt and perseverative behaviours are key symptoms of obsessive–compulsive disorder (OCD) and have been linked to hyperactive error and conflict signals in the brain. While enhanced neural correlates of error monitoring have been robustly shown, far less is known about conflict processing and adaptation in OCD. Method. We examined event-related potentials during conflict processing in 70 patients with OCD and 70 matched healthy comparison participants, focusing on the stimulus-locked N2 elicited in a flanker task. Conflict adaptation was evaluated by analysing sequential adjustments in N2 and behaviour, i.e. current conflict effects as a function of preceding conflict. Results. Patients with OCD showed enhanced N2 amplitudes compared with healthy controls. Further, patients showed stronger conflict adaptation effects on reaction times and N2 amplitude. Thus, the effect of previous compatibility was larger in patients than in healthy participants as indicated by greater N2 adjustments in change trials (i.e. iC, cI). As a result of stronger conflict adaptation in patients, N2 amplitudes were comparable between groups in incompatible trials following incompatible trials. Conclusions. Larger N2 amplitudes and greater conflict adaptation in OCD point to enhanced conflict monitoring leading to increased recruitment of cognitive control in patients. This was most pronounced in change trials and was associated with stronger conflict adjustment in N2 and behaviour. Thus, hyperactive conflict monitoring in OCD may be beneficial in situations that require a high amount of control to resolve conflict, but may also reflect an effortful process that is linked to distress and symptoms of OCD

Modeling subjective relevance in schizophrenia and its relation to aberrant salience

In schizophrenia, increased aberrant salience to irrelevant events and reduced learning of relevant information may relate to an underlying deficit in relevance detection. So far, subjective estimates of relevance have not been probed in schizophrenia patients. The mechanisms underlying belief formation about relevance and their translation into decisions are unclear. Using novel computational methods, we investigated relevance detection during implicit learning in 42 schizophrenia patients and 42 healthy individuals. Participants underwent functional magnetic resonance imaging while detecting the outcomes in a learning task. These were preceded by cues differing in color and shape, which were either relevant or irrelevant for outcome prediction. We provided a novel definition of relevance based on Bayesian precision and modeled reaction times as a function of relevance weighted unsigned prediction errors (UPE). For aberrant salience, we assessed responses to subjectively irrelevant cue manifestations. Participants learned the contingencies and slowed down their responses following unexpected events. Model selection revealed that individuals inferred the relevance of cue features and used it for behavioral adaption to the relevant cue feature. Relevance weighted UPEs correlated with dorsal anterior cingulate cortex activation and hippocampus deactivation. In patients, the aberrant salience bias to subjectively task-irrelevant information was increased and correlated with decreased striatal UPE activation and increased negative symptoms. This study shows that relevance estimates based on Bayesian precision can be inferred from observed behavior. This underscores the importance of relevance detection as an underlying mechanism for behavioral adaptation in complex environments and enhances the understanding of aberrant salience in schizophrenia

Intergenerational Effect of Maternal Exposure to Childhood Maltreatment on Newborn Brain Anatomy

Background Childhood maltreatment (CM) confers deleterious long-term consequences, and growing evidence suggests some of these effects may be transmitted across generations. We examined the intergenerational effect of maternal CM exposure on child brain structure and also addressed the hypothesis that this effect may start during the child's intrauterine period of life. Methods A prospective longitudinal study was conducted in a clinical convenience sample of 80 mother-child dyads. Maternal CM exposure was assessed using the Childhood Trauma Questionnaire. Structural magnetic resonance imaging was employed to characterize newborn global and regional brain (tissue) volumes near the time of birth. Results CM exposure was reported by 35% of the women. Maternal CM exposure was associated with lower child intracranial volume (F1,70 = 6.84, p =.011), which was primarily due to a global difference in cortical gray matter (F1,70 = 9.10, p =.004). The effect was independent of potential confounding variables, including maternal socioeconomic status, obstetric complications, obesity, recent interpersonal violence, pre- and early postpartum stress, gestational age at birth, infant sex, and postnatal age at magnetic resonance imaging scan. The observed group difference between offspring of CM-exposed mothers versus nonexposed mothers was 6%. Conclusions These findings represent the first report to date associating maternal CM exposure with variation in newborn brain structure. These observations support our hypothesis of intergenerational transmission of the effects of maternal CM exposure on child brain development and suggest this effect may originate during the child's intrauterine period of life, which may have downstream neurodevelopmental consequences

Saccadic eye velocity after selective GABAergic treatment with tiagabine in healthy volunteers

Background: Saccadic eye velocity (SEV) has been shown to be a reliable neurophysiological tool for the assessment of gamma-aminobutyric acid GABA(A) receptor sensitivity. Administration of benzodiazepines targeting the GABA(A) receptor decreases SEV in healthy volunteers. Tiagabine is a new antiepileptic drug which acts via selective blockade of GABA reuptake. Therefore, we examined the effects of tiagabine on saccade parameters. Methods: SEV was analyzed in 8 healthy volunteers before and after 7 days of tiagabine treatment. Subjects received tiagabine in a daily dose of 15 mg. Saccades were measured using a noninvasive infrared oculographic device. Amplitude, latency, and SEV were analyzed as a function of treatment and target eccentricity. Results: SEV and saccade latency increased with target amplitude. Treatment with tiagabine had no significant effect on SEV and saccade amplitude. A trend was found for increased latencies after tiagabine. Conclusion: In contrast to findings with benzodiazepines, tiagabine treatment had no impact on SEV in healthy volunteers. The subchronic tolerance effects or the different site of action on the GABA(A)/BZD receptor complex may account for this deviating profile. Copyright (C) 2005 S. Karger AG, Basel

Implementation of Dynamical Nucleation Theory Effective Fragment Potentials Method for Modeling Aerosol Chemistry

In this work, the dynamical nucleation theory (DNT) model using the ab initio based effective fragment potential (EFP) is implemented for evaluating the evaporation rate constant and molecular properties of molecular clusters. Predicting the nucleation rates of aerosol particles in different chemical environments is a key step toward understanding the dynamics of complex aerosol chemistry. Therefore, molecular scale models of nanoclusters are required to understand the macroscopic nucleation process. On the basis of variational transition state theory, DNT provides an efficient approach to predict nucleation kinetics. While most DNT Monte Carlo simulations use analytic potentials to model critical sized clusters, or use ab initio potentials to model very small clusters, the DNTEFP Monte Carlo method presented here can treat up to critical sized clusters using the effective fragment potential (EFP), a rigorous nonempirical intermolecular model potential based on ab initio electronic structure theory calculations, improvable in a systematic manner. The DNTEFP method is applied to study the evaporation rates, energetics, and structure factors of multicomponent clusters containing water and isoprene. The most probable topology of the transition state characterizing the evaporation of one water molecule from a water hexamer at 243 K is predicted to be a conformer that contains six hydrogen bonds, with a topology that corresponds to two water molecules stacked on top of a quadrangular (H2O)4 cluster. For the water hexamer in the presence of isoprene, an increase in the cluster size and a 3-fold increase in the evaporation rate are predicted relative to the reaction in which one water molecule evaporates from a water hexamer cluster