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Patients suffering from bipolar disorder often report negative thoughts and a bias towards negative environmental stimuli. Previous studies show that this mood-congruent attentional bias could mediated by dysfunctions in anterior limbic regions. The Error-Related Negativity (ERN), which originates in the anterior cingulate cortex (ACC), has been used to research this negativity bias in depressed patients, and could also help to better understand the underlying mechanisms causing the negativity bias in bipolar patients. In this study we investigated error processing in patients with bipolar disorder. Acute depressive bipolar patients (n = 20) and age-matched healthy controls (n = 20) underwent a modified Eriksen Flanker Task to assess test performance and two error-related event-related potentials (ERPs), i.e., the ERN and Error Positivity (Pe) were measured by EEG. Half of the patients were measured again in a euthymic state. We found similar ERN amplitudes in bipolar patients as compared to healthy controls, but significantly reduced Pe amplitudes. Moreover, acutely depressed bipolar patients displayed an ERN and Pe even if they responded accurately or too slow, which indicates that correct responses are processed in a way similar to wrong responses. This can be interpreted as a psychophysiological correlate of typical cognitive distortions in depression, i.e., an erroneous perception of personal failures. This biased error perception partially remained when patients were in a euthymic state. Together, our data indicate that aberrant error processing of bipolar patients may be regarded a trait marker possibly reflecting a risk factor for depressive relapses in bipolar disorder.

Background: A recent study suggested that progranulin (encoded by the fronto-temporal dementia risk gene GRN) plasma levels are decreased in bipolar disorder (BD). Replication of this finding is however lacking. Methods: Progranulin plasma levels of bipolar patients (n¼104) and healthy controls (n¼80) were measured by enzyme-linked immunosorbent assay (ELISA). Participants were also genotyped for three single nucleotide polymorphisms (SNPs) in the GRN gene (rs2879096, rs4792938 and rs5848), and the effect of genetic variation on progranulin levels was examined. Results: Plasma progranulin levels were decreased in BD (ANCOVA, p¼0.001). Furthermore, age was significantly and positively correlated with plasma progranulin (Pearson's correlation, r¼0.269, po0.001). Also, lithium treatment but no other medication had a significant effect on progranulin plasma levels (ANCOVA, p¼0.007). Specifically in BD, the GRN SNP rs5848 was associated with progranulin plasma levels (Kruskal–Wallis test, po0.005). Limitations: Subgroup analysis regarding bipolar I vs. bipolar II subtype and polarity of the episode at sampling (manic vs. depressed vs. mixed vs. rapid cycling vs. euthymic) could only be performed with limited validity due to the relatively small sample size. The suitability of peripheral progranulin as a biomarker for BD is limited due to the overlap between patients and controls. Conclusion: The findings strengthen the evidence for progranulin being involved in pathomechanisms of bipolar disorder, and suggest a genetic determinant of progranulin concentrations that is relevant specifically in bipolar patients.

NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. ? 2013 Published by Elsevier B.V. and ECNP.

Introduction Impulsivity is one of the core symptoms of Attention-Deficit-Hyperactivity-Disorder (ADHD). However, the neural mechanisms underlying impulsivity remain poorly understood. Recent studies from our own lab have shown altered cortico-striatal functionality in healthy controls carrying long or short alleles of the NOS1ex1f-VNTR, a polymorphism associated with heightened impulsivity and ADHD. The study used a switching task to examine striatal functioning of the prefrontal cortex in those controls, which presumably is modulated by differential functionality of NOS1ex1f-VNTR, which in humans is mainly expressed in the striatum. The short allele of this polymorphism leads to a decrease in the expression of NO-Synthase. This switching task is known to be disturbed in Parkinson’s patients, a disorder affecting the striatum. Other studies also suggest a link between ADHD and altered cortico-striatal pathways, presuming that this dysfunctional cortico-striatal connection may be responsible for many of the symptoms of ADHD. Methods 19 patients with ADHD with no medication or a medication washout of at least 24 h and 20 healthy controls were given a set switching task. While performing that task, prefrontal brain activity was measured using near-infrared spectroscopy. Results Behavioral results showed a heightened error rate and reaction time for the ADHD group, as compared with the control group. However, this effect was not modulated by a varying difficulty for the switching tasks. Brain activation show a robust dorsolateral prefrontal activation pattern for the control group, switch trials activated the dorsolateral prefrontal cortex (dlPFC) more than the no-switch trials. ADHD subjects activated the dlPFC significantly less than did the control group, surprisingly, no modulation by the switching task could be found. Our hypothesis that the activation pattern of the ADHD group could hint at a dysfunctional mechanism in the fronto-striatal-frontal loop, hypothesized to be active in switching set, could not be validated. Whats more, an overall hypoactivation of the prefrontal cortex could be observed in patients with ADHD. Apparently their disease load is so high that patients were slower than controls even in the easy no switch condition. It is possible that the dysfunction in the striatum is so severe that patients overall prefrontal activation is suffering. However, with fNIRS it is not possible to disentangle the underlying mechanisms in subcortical areas, not even by means of measuring related prefrontal activity. Further studies using other imaging methods are needed to research the question of dysfunctional cortico-striatal loops in ADHD patients.