Expression of the Rap1 guanine nucleotide exchange factor, MR-GEF, is altered in individuals with bipolar disorder

In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission.

Abnormal functional activation and maturation of fronto-striato-temporal and cerebellar regions during sustained attention in autism spectrum disorder

Objective Sustained attention problems are common in people with autism spectrum disorder (ASD) and may have significant implications for the diagnosis and management of ASD and associated comorbidities. Furthermore, ASD has been associated with atypical structural brain development. The authors used functional MRI to investigate the functional brain maturation of attention between childhood and adulthood in people with ASD. Method Using a parametrically modulated sustained attention/vigilance task, the authors examined brain activation and its linear correlation with age between childhood and adulthood in 46 healthy male adolescents and adults (ages 11–35 years) with ASD and 44 age- and IQ-matched typically developing comparison subjects. Results Relative to the comparison group, the ASD group had significantly poorer task performance and significantly lower activation in inferior prefrontal cortical, medial prefrontal cortical, striato-thalamic, and lateral cerebellar regions. A conjunction analysis of this analysis with group differences in brain-age correlations showed that the comparison group, but not the ASD group, had significantly progressively increased activation with age in these regions between childhood and adulthood, suggesting abnormal functional brain maturation in ASD. Several regions that showed both abnormal activation and functional maturation were associated with poorer task performance and clinical measures of ASD and inattention. Conclusions The results provide first evidence that abnormalities in sustained attention networks in individuals with ASD are associated with underlying abnormalities in the functional brain maturation of these networks between late childhood and adulthood.

Obsessive–compulsive disorder in young people

Obsessive–compulsive disorder (OCD) is one of the most debilitating psychiatric conditions in young people. In DSM-5 it is no longer characterised as an anxiety disorder, but instead is part of a group of ‘obsessive–compulsive and related disorders’. In the past 10 years, cognitive–behavioural therapy (CBT) has become well established as the first-choice treatment. This article explains some of the elements of CBT and describes new directions in research which might improve interventions.

The accuracy of HADS and GHQ-12 in detecting psychiatric morbidity in breast cancer patients

Objective: Psychological problems should be identified in breast cancer patients proactively if doctors and nurses are to help them cope with the challenges imposed by their illness. Screening is one possible way to identify emotional problems proactively. Self-report questionnaires can be useful alternatives to carrying out psychiatric interviews during screening, because interviewing a large number of patients can be impractical due to limited resources. Two such measures are the Hospital Anxiety and Depression Scale (HADS) and the General Health Questionnaire-12 (GHQ-12). Method: The present study aimed to compare the performance of the GHQ-12, and the HADS Unitary Scale and its subscales to that of the Schedule for Affective Disorders and Schizophrenia (SADS) in identifying patients with affective disorders, including DSM major depression and generalized anxiety disorder. The sample consisted of 296 female breast cancer patients who underwent surgery for breast cancer a year previously. Results: A small number of patients (11%) were identified as having DSM major depression or generalized anxiety disorder based on SADS score. The findings indicate that the optimal thresholds in detecting generalized anxiety disorder and DSM major depression with the HADS anxiety and depression subscales were ≥ 8 and ≥ 7, with 93.3% and 77.3% sensitivity, respectively, and 77.9% and 87.1% specificity, respectively. They also had a 21% and 36% positive predictive value, respectively. Using the HADS Unitary Scale the optimal threshold for detecting affective disorders was ≥ 12, with 88.9% sensitivity, 80.7% specificity, and a 35% positive predictive value. In detecting affective disorders, the optimal threshold on the GHQ-12 was ≥ 2, with 77.8% sensitivity and 70.2% specificity. This scale also had a 24% positive predictive value. In detecting generalized anxiety disorder and DSM major depression, the optimal thresholds on the GHQ-12 were ≥ 2 and ≥ 4 with 73.3% and 77.3% sensitivity, respectively, and 67.5% and 82% specificity, respectively. The scale also had 12% and 29% positive predictive values, respectively. Conclusion: The HADS Unitary Scale and its subscales were effective in identifying affective disorders. They can be used as screening measures in breast cancer patients. The GHQ-12 was less accurate in detecting affective disorders than the HADS, but it can also be used as a screening instrument to detect affective disorders, generalized anxiety disorder, and DSM major depression.

Anger, preoccupied attachment and domain disorganisation in borderline personality disorder

Emotional dysregulation and attachment insecurity have been reported in borderline personality disorder (BPD). Domain disorganization, evidenced in poor regulation of emotions and behaviors in relation to the demands of different social domains, may be a distinguishing feature of BPD. Understanding the interplay between these factors may be critical for identifying interacting processes in BPD and potential subtypes of BPD. Therefore, we examined the joint and interactive effects of anger, preoccupied attachment, and domain disorganization on BPD traits in a clinical sample of 128 psychiatric patients. The results suggest that these factors contribute to BPD both independently and in interaction, even when controlling for other personality disorder traits and Axis I symptoms. In regression analyses, the interaction between anger and domain disorganization predicted BPD traits. In recursive partitioning analyses, two possible paths to BPD were identified: high anger combined with high domain disorganization and low anger combined with preoccupied attachment. These results may suggest possible subtypes of BPD or possible mechanisms by which BPD traits are established and maintained.

A Functional Magnetic Resonance Imaging Predictor of Treatment Response to Venlafaxine in Generalized Anxiety Disorder

Background: Functional magnetic resonance imaging (fMRI) holds promise as a noninvasive means of identifying neural responses that can be used to predict treatment response before beginning a drug trial. Imaging paradigms employing facial expressions as presented stimuli have been shown to activate the amygdala and anterior cingulate cortex (ACC). Here, we sought to determine whether pretreatment amygdala and rostral ACC (rACC) reactivity to facial expressions could predict treatment outcomes in patients with generalized anxiety disorder (GAD).Methods: Fifteen subjects (12 female subjects) with GAD participated in an open-label venlafaxine treatment trial. Functional magnetic resonance imaging responses to facial expressions of emotion collected before subjects began treatment were compared with changes in anxiety following 8 weeks of venlafaxine administration. In addition, the magnitude of fMRI responses of subjects with GAD were compared with that of 15 control subjects (12 female subjects) who did not have GAD and did not receive venlafaxine treatment.Results The magnitude of treatment response was predicted by greater pretreatment reactivity to fearful faces in rACC and lesser reactivity in the amygdala. These individual differences in pretreatment rACC and amygdala reactivity within the GAD group were observed despite the fact that 1) the overall magnitude of pretreatment rACC and amygdala reactivity did not differ between subjects with GAD and control subjects and 2) there was no main effect of treatment on rACC-amygdala reactivity in the GAD group.Conclusions: These findings show that this pattern of rACC-amygdala responsivity could prove useful as a predictor of venlafaxine treatment response in patients with GAD.

Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate.

We argue that impulsiveness is characterized by compromised timing functions such as premature motor timing, decreased tolerance to delays, poor temporal foresight and steeper temporal discounting. A model illustration for the association between impulsiveness and timing deficits is the impulsiveness disorder of attention-deficit hyperactivity disorder (ADHD). Children with ADHD have deficits in timing processes of several temporal domains and the neural substrates of these compromised timing functions are strikingly similar to the neuropathology of ADHD. We review our published and present novel functional magnetic resonance imaging data to demonstrate that ADHD children show dysfunctions in key timing regions of prefrontal, cingulate, striatal and cerebellar location during temporal processes of several time domains including time discrimination of milliseconds, motor timing to seconds and temporal discounting of longer time intervals. Given that impulsiveness, timing abnormalities and more specifically ADHD have been related to dopamine dysregulation, we tested for and demonstrated a normalization effect of all brain dysfunctions in ADHD children during time discrimination with the dopamine agonist and treatment of choice, methylphenidate. This review together with the new empirical findings demonstrates that neurocognitive dysfunctions in temporal processes are crucial to the impulsiveness disorder of ADHD and provides first evidence for normalization with a dopamine reuptake inhibitor.

Intrinsic disorder prediction from the analysis of multiple protein fold recognition models

Motivation: Intrinsic protein disorder is functionally implicated in numerous biological roles and is, therefore, ubiquitous in proteins from all three kingdoms of life. Determining the disordered regions in proteins presents a challenge for experimental methods and so recently there has been much focus on the development of improved predictive methods. In this article, a novel technique for disorder prediction, called DISOclust, is described, which is based on the analysis of multiple protein fold recognition models. The DISOclust method is rigorously benchmarked against the top.ve methods from the CASP7 experiment. In addition, the optimal consensus of the tested methods is determined and the added value from each method is quantified. Results: The DISOclust method is shown to add the most value to a simple consensus of methods, even in the absence of target sequence homology to known structures. A simple consensus of methods that includes DISOclust can significantly outperform all of the previous individual methods tested.

Disorder and dissolution enhancement: Deposition of ibuprofen on to insoluble polymers

Microcrystalline cellulose (MCC) and cross-linked polyvinylpyrrolidone (PVP-CL) were examined as polymeric carriers to support amorphous ibuprofen (IB). Drug/cartier systems were prepared as physical mixes, and drug was loaded onto the polymers by hot mix and solvent deposition methods. The systems were examined using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRD) and by dissolution testing. PVP-CL reduced drug crystallinity more than MCC and, surprisingly, even very simple mixing of ibuprofen with PVP-CL induced disordering of the drug. Increased ibuprofen dissolution rates were achieved with both polymers, in the order of solvent deposition > hot mixes > physical mixes. The increased dissolution rates could be attributed to a combination of faster dissolution from amorphous ibuprofen, microcrystalline drug deposition on carrier surfaces and polymer swelling. However, no clear relationship was observed between ibuprofen dissolution rates (using first order, Higuchi or Hixson-Crowell relationships) and drug crystallinity. (C) 2005 Elsevier B.V. All rights reserved.

Learning and memory in holocaust survivors with posttraumatic stress disorder

Background: Impairments in explicit memory have been observed in Holocaust survivors with posttraumatic stress disorder. Methods: To evaluate which memory components are preferentially affected, the California Verbal Learning Test was administered to Holocaust survivors with (n = 36) and without (n = 26) posttraumatic stress disorder, and subjects not exposed to the Holocaust (n = 40). Results: Posttraumatic stress disorder subjects showed impairments in learning and short-term and delayed retention compared to nonexposed subjects; survivors without posttraumatic stress disorder did not. Impairments in learning, but not retention, were retained after controlling fir intelligence quotient. Older age was associated with poorer learning and memory performance in the posttraumatic stress disorder group only. Conclusions: The most robust impairment observed in posttraumatic stress disorder was in verbal learning, which may be a risk factor for or consequence of chronic posttraumatic stress disorder. The negative association between performance and age may reflect accelerated cognitive decline in posttraumatic stress disorder.

Problems in the coupling of eye and hand in the sequential movements of children with developmental coordination disorder

Background: Shifting gaze and attention ahead of the hand is a natural component in the performance of skilled manual actions. Very few studies have examined the precise co-ordination between the eye and hand in children with Developmental Coordination Disorder (DCD). Methods This study directly assessed the maturity of eye-hand co-ordination in children with DCD. A double-step pointing task was used to investigate the coupling of the eye and hand in 7-year-old children with and without DCD. Sequential targets were presented on a computer screen, and eye and hand movements were recorded simultaneously. Results There were no differences between typically developing (TD) and DCD groups when completing fast single-target tasks. There were very few differences in the completion of the first movement in the double-step tasks, but differences did occur during the second sequential movement. One factor appeared to be the propensity for the DCD children to delay their hand movement until some period after the eye had landed on the target. This resulted in a marked increase in eye-hand lead during the second movement, disrupting the close coupling and leading to a slower and less accurate hand movement among children with DCD. Conclusions In contrast to skilled adults, both groups of children preferred to foveate the target prior to initiating a hand movement if time allowed. The TD children, however, were more able to reduce this foveation period and shift towards a feedforward mode of control for hand movements. The children with DCD persevered with a look-then-move strategy, which led to an increase in error. For the group of DCD children in this study, there was no evidence of a problem in speed or accuracy of simple movements, but there was a difficulty in concatenating the sequential shifts of gaze and hand required for the completion of everyday tasks or typical assessment items.

Attention disengagement in children with developmental coordination disorder

Purpose. Previous research has shown that children with Developmental Coordination Disorder (DCD) have poorly developed strategies for allocating attention. This study examines the allocation of attention and integration of visuo-spatial and motor systems in children with DCD in a motor (look+hit condition) and a motor-free (look condition) task. Method. Three groups of control children were used to compare the performance of a group of children with DCD. Children were seated in front of a central fixation point and six peripheral targets, and were asked to look at or hit targets when illuminated. Saccade/hand movement latencies were measured on gap trials (gap between fixation offset and target onset) and overlap trials (fixation offset and target onset overlapped). Results. DCD children were not slower than controls to disengage attention during the look condition. However, during the look+hit condition the DCD children showed a prolonged disengagement period, which was also seen in younger control children. Conclusions. The results suggest that DCD children may have deficits in the allocation of attention for action, in both the speed of onset of a movement and the accuracy of the movement. It is concluded that attention disengagement may contribute to problems of visuo-motor integration in DCD.

Self-esteem and coping in children with developmental coordination disorder

This study investigated self-esteem in children with developmental coordination disorder (DCD). Fifteen children between the ages of 8 and 12 years diagnosed with DCD were compared with a typically developing group comprising 30 children with average and good motor abilities, using measures of perceived competence, social support and self-esteem. The types of coping strategy generated in response to example vignettes were also compared. There was no significant difference between the groups in global self-esteem, but the children with DCD reported lower athletic and scholastic competence than their typically developing peers. No difference was found between the groups in level of perceived social support. The DCD group generated fewer coping strategies overall, but more passive and avoidant strategies than the typically developing children. The implications of the study are discussed with regard to future research directions, such as the investigation of the effects of motor skill intervention on self-esteem and the development of strategies to protect children's self-esteem.

Self-, parent-report and interview measures of obsessive-compulsive disorder in children and adolescents

Self-report measures of obsessive-compulsive disorder (OCD) in children and adolescents are needed for practical evaluation of severity and treatment response. We compared the self- and parent-report Obsessional Compulsive Inventory Revised (CHOCI-R) to the interview-based Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) in a clinical sample of 285 children and adolescents with OCD. Classical test theory and item-response theory were applied to compare the instruments. The self- and parent-report CHOCI-R had good internal consistency and were strongly related to each other. The self- and parent-report CHOCI-R severity scores correlated with the CY-BOCS (Pearson's r 0.55 and 0.45 respectively). The CY-BOCS discriminated better at the severe end of the spectrum. The CHOCI-R provided better discrimination in the mild to moderate range. The time-efficient self- and parent-report alternatives will enable routine measurement of OCD severity in clinical practice. Estimates of equivalent summed scores are provided to facilitate comparison. (c) 2007 Elsevier Ltd. All rights reserved.

Expressive versus receptive language skills in specific reading disorder

Despite ample research into the language skills of children with specific reading disorder no studies so far have investigated whether there may be a difference between expressive and receptive language skills in this population. Yet, neuro-anatomical models would predict that children who have specific reading disorder which is not associated with movement or attention difficulties, would have lower receptive language skills than expressive. This study investigates the difference between expressive and receptive language skills in a sample of 17 children with specific reading difficulty aged between 7 and 12 years. They were administered a battery of two receptive and two expressive language measures. The results showed that as the neuro-anatomical model would predict, the children scored significantly lower on tests of receptive than on tests of expressive language skills.