Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer’s disease1,2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6,7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).

Background: The few previous studies on resting-state electroencephalography (EEG) microstates in depressive patients suggest altered temporal characteristics of microstates compared to those of healthy subjects. We tested whether resting-state microstate temporal characteristics could capture large-scale brain network dynamic activity relevant to depressive symptomatology. Methods: To evaluate a possible relationship between the resting-state large-scale brain network dynamics and depressive symptoms, we performed EEG microstate analysis in 19 patients with moderate to severe depression in bipolar affective disorder, depressive episode, and recurrent depressive disorder and in 19 healthy controls. Results: Microstate analysis revealed six classes of microstates (A–F) in global clustering across all subjects. There were no between-group differences in the temporal characteristics of microstates. In the patient group, higher depressive symptomatology on the Montgomery–Åsberg Depression Rating Scale correlated with higher occurrence of microstate A (Spearman’s rank correlation, r = 0.70, p < 0.01). Conclusion: Our results suggest that the observed interindividual differences in resting-state EEG microstate parameters could reflect altered large-scale brain network dynamics relevant to depressive symptomatology during depressive episodes. Replication in larger cohort is needed to assess the utility of the microstate analysis approach in an objective depression assessment at the individual level.

SUMMARYWhat is known and Objective: Accurate prediction of actual CYP2D6 metabolic activity may prevent some adverse drug reactions and improve therapeutic response in patients receiving CYP2D6 substrates. Dextromethorphan-to-dextrorphan metabolic ratio (MR DEM WHAT IS KNOWN AND OBJECTIVECYP2D6 plays a pivotal role in the metabolism of many drugs. It is a highly polymorphic enzyme, and to date, more than 80 allelic variants alleles have been identified. 1 The variant alleles may encode proteins with normal (e.g. CYP2D6*2), decreased (e.g. CYP2D6*10) or no (e.g. CYP2D6*4) enzyme activity. As a consequence, there is a wide range of CYP2D6 metabolic activity shows wide inter-subject variability. The CYP2D6 metabolic phenotype can be classified into four groups -poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM). 2 Thus, the same dose of a drug extensively metabolized by CYP2D6 can result in a different clinical response in patients depending on the P450 phenotype. 2 Moreover, CYP2D6-drug interactions may also have clinical consequences. For example, after administration of paroxetine, a CYP2D6 inhibitor, to patients on tamoxifen, a decrease in plasma levels of the active metabolite of tamoxifen was detected. 3 This change may have serious consequences in breast cancer treatment with tamoxifen. CYP2D6 ultrarapid metabolizer phenotype may cause failure of pharmacotherapy because of the very low and thus ineffective drug plasma levels. 4 In antipsychotic treatment, an association has been observed between extrapyramidal adverse effects and the CYP2D6 genotype. 5 Therefore, for drugs with narrow therapeutic indices, it seems to be useful to assess CYP2D6 metabolic activity prior to or during therapy with CYP2D6 substrates and to adjust the individual dosage according to the patient's phenotype. Such personalized pharmacotherapy may prevent adverse effects and improve response. Specific substrates (markers) that are metabolized selectively by CYP2D6 are often used for the assessment of metabolic activity. The concentration of specific substrate and its metabolite in body fluids (a ratio of molar concentrations; metabolic ratio) serves as a measure of the individual CYP activity. Histograms of log-transformed metabolic ratios may show cut-off values of MR which distinguish EM from PM, UM or IM. Suitable substrates for CYP2D6 include debrisoquine, bufuralol, tramadol, dextromethorphan, metoprolol and sparteine. 2,6 Debrisoquine and sparteine are not currently available, and except for dextromethorphan, the other substrates are seldom administered. Dextromethorphan remains the most widely used probe for CYP2D6 metabolic activity

BackgroundImpulsivity is a core symptom of borderline personality disorder (BPD). Impulsivity is a heterogeneous concept, and a comprehensive evaluation of impulsivity dimensions is lacking in the literature. Moreover, it is unclear whether BPD patients manifest impaired cognitive functioning that might be associated with impulsivity in another patient group, such as ADHD, a frequent comorbidity of BPD.MethodsWe tested 39 patients with BPD without major psychiatric comorbidities and ADHD, 25 patients with ADHD, and 55 healthy controls (HC) using a test battery consisting of a self-report measure of impulsivity (UPPS-P questionnaire), behavioral measures of impulsivity – impulsive action (Go/NoGo task, stop signal task) and impulsive choice (delay discounting task, Iowa gambling task), and standardized measures of attention (d2 test), working memory (digit span), and executive functioning (Tower of London).ResultsPatients with BPD and ADHD, as compared with HC, manifested increased self-reported impulsivity except sensation seeking and increased impulsive choice; patients with ADHD but not BPD showed increased impulsive action and deficits in cognitive functioning. Negative urgency was increased in BPD as compared to both HC and ADHD groups and correlated with BPD severity.ConclusionsPatients with BPD without ADHD comorbidity had increased self-reported impulsivity and impulsive choice, but intact impulsive action and cognitive functioning. Controlling for ADHD comorbidity in BPD samples is necessary. Negative urgency is the most diagnostically specific impulsivity dimension in BPD.

the cortico-striatal-pallidal-thalamic and limbic circuits are suggested to play a crucial role in the pathophysiology of depression. Stimulation of deep brain targets might improve symptoms in treatment-resistant depression. However, a better understanding of connectivity properties of deep brain structures potentially implicated in deep brain stimulation (DBS) treatment is needed. Using highdensity EEG, we explored the directed functional connectivity at rest in 25 healthy subjects and 26 patients with moderate to severe depression within the bipolar affective disorder, depressive episode, and recurrent depressive disorder. We computed the Partial Directed Coherence on the source EEG signals focusing on the amygdala, anterior cingulate, putamen, pallidum, caudate, and thalamus. The global efficiency for the whole brain and the local efficiency, clustering coefficient, outflow, and strength for the selected structures were calculated. In the right amygdala, all the network metrics were significantly higher (p < 0.001) in patients than in controls. The global efficiency was significantly higher (p < 0.05) in patients than in controls, showed no correlation with status of depression, but decreased with increasing medication intake (-=. =. R 0 59 and p 1 52e 05 2). the amygdala seems to play an important role in neurobiology of depression. Practical treatment studies would be necessary to assess the amygdala as a potential future DBS target for treating depression. Affective disorders belong to the most common and most serious psychiatric disorders 1. A crucial role of the cortico-striatal-pallidal-thalamic and limbic circuits in the neurobiology of depression was repeatedly reported 2-4. Magnetic resonance imaging, functional magnetic resonance imaging (fMRI), magnetoencephalographic, and electroencephalographic (EEG) studies have confirmed that depressive patients show structural impairments and functional dysbalances of brain networks that involve structures engaged in (a) emotions, i.e. amygdala, subgenual anterior cingulate, caudate, putamen and pallidum 3,5-12 ; (b) self-referential processes, i.e. medial prefrontal cortex, precuneus, and posterior cingulate cortex 13,14 ; (c) memory, i.e. hippocampus, parahippocampal cortex 15 ; (d) visual processing, i.e. fusiform gyrus, lingual gyrus, and lateral temporal cortex 16 ; and (e) attention, i.e. dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), thalamus, and insula 10-12,17. Moreover, post-mortem morphometric measurements revealed smaller volumes of the hypothalamus, pallidum, putamen and thalamus in patients with affective disorders 18. Many depressive patients fail to respond to pharmacological therapy resulting in 1-3% prevalence of treatment-resistant depression (TRD) 19. One of the newest therapeutic approaches for TRD is an invasive direct electrical stimulation of relevant deep brain structures 20. Both unipolar and bipolar depression patients might benefit from deep brain stimulation (DBS) treatment 21 , although an optimal approach, incl...

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Objective: Impulsivity, observed in patients with various psychiatric disorders, is a heterogeneous construct with different behavioral manifestations. Through confirmatory factor analysis (CFA), this study tests hypotheses about relationships between dimensions of impulsivity measured using personality questionnaires and behavioral tests. Method: The study included 200 healthy people, 40 patients with borderline personality disorder, and 26 patients with attention-deficit/hyperactivity disorder (ADHD) who underwent a comprehensive impulsivity test battery including the Barratt Impulsiveness Scale (BIS), UPPS-P Impulsive Behavior Scale, a Go-NoGo task, a stop-signal task, and a delay discounting task. Results: A CFA model comprising three self-reported and three behavioral latent variables reached a good fit. Both patient groups scored higher in the self-reported dimensions and impulsive choice; only the ADHD patients displayed impaired waiting and stopping impulsivity. Conclusions: Using the developed CFA model, it is possible to describe relations between impulsivity dimensions and show different impulsivity patterns in patient populations.

In this study, task-related stress induction through Stroop task and social stress induction protocol based on elements of Trier Social Stress Test are examined. The aim of the paper is to find the optimal combination of social and task-related stress to be used to consistently and reliably induce a stressful reaction. In total 16 healthy subjects participated in this study that seeks to find and compare the different stressors and their relation to physiological reactivity. Our findings show that electrodermal activity measurements are suitable when using a combination of stressors while heart rate and Root Mean Square of the Successive Differences highlight a greater reactivity to task-stress.