Effects of Sleep Deprivation by Olfactorily Induced Sexual Arousal Compared to Immobilization Stress and Manual Sleep Deprivation on Neuromessengers and Time Keeping Genes in the Suprachiasmatic Nuclei and Other Cerebral Entities of Syrian Hamsters-An Immunohistochemical Study.

We investigated the effects of sexual arousal induced by olfactory stimuli on the expression of neuromodulators, neurotransmitters and sexual steroid receptors in the suprachiasmatic nucleus (SCN, the circadian pacemaker of mammals) and other cerebral entities of Syrian hamsters (Mesocricetus auratus) compared to manual sleep deprivation and immobilization stress. The hamsters kept under a 12:12 hours (h) light:dark cycle were deprived of sleep by sexual stimulation, gentle manual handling or immobilization stress for 1 h at the beginning of the light phase and subsequently sacrificed at zeitgeber time 01:00, respectively; for comparison, hamsters were manually sleep deprived for 6 or 20 h or sacrificed after completing a full sleep phase. As demonstrated by immunohistochemistry, apart from various alterations after manual sleep deprivation, sexual stimulation caused down-regulation of arginine-vasopressin (AVP), vasointestinal peptide (VIP), serotonin (5-HT), substance P (SP), and met-enkephalin (ME) in the SCN. Somatostatin (SOM) was diminished in the medial periventricular nucleus (MPVN). In contrast, an increase in AVP was observed in the PVN, that of oxytocin (OXY) in the supraoptic nucleus (SON), of tyrosine-hydroxylase (TH) in the infundibular nucleus (IN), and dopamine beta-hydroxylase (DBH) in the A7 neuron population of the brain stem (A7), respectively. Testosterone in plasma was increased. The results indicate that sexual arousal extensively influences the neuropeptide systems of the SCN, suggesting an involvement of the SCN in reproductive behavior.

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Associative Memory Impairments Are Associated With Functional Alterations Within the Memory Network in Schizophrenia Patients and Their Unaffected First-Degree Relatives: An fMRI Study.

Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.

Visual working memory encoding in schizophrenia and first-degree relatives: neurofunctional abnormalities and impaired consolidation.

BACKGROUND: Working memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation - i.e. the formation of durable WM representations - is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before. METHOD: We examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation. RESULTS: SCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals. CONCLUSIONS: Findings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker.

White Matter Microstructural Changes and Episodic Memory Disturbances in Late-Onset Bipolar Disorder.

Background: Bipolar disorder (BD) has been associated with distributed network disruption, but little is known on how different clinical subtypes, particularly those with an earlier and later onset of disease, are related to connectivity changes in white matter (WM) tracts. Methods: Diffusion tensor imaging (DTI) and volumetric measures were carried out in early-onset bipolar patients [(EOD) (n = 16)], late-onset bipolar disorder [(LOD)(n = 14)] and healthy controls (n = 32). We also computed ROI analysis of gray matter (GM) and white matter (WM) volumes using the regions with significant group differences in the DTI parameters. Cognitive and behavior measurements were analyzed between groups. Results: Lower fraction of anisotropy (FA) in the right hemisphere comprising anterior thalamic radiation, fornix, posterior cingulate, internal capsule, splenium of corpus callosum was observed in the LOD in comparison with EOD; additionally, lower FA was also found in the LOD in comparison with healthy controls, mostly in the right hemisphere and comprising fibers of the splenium of the corpus callosum, cingulum, superior frontal gyrus and posterior thalamic radiation; LOD also showed worse episodic memory performance than EOD; no statistical significant differences between mood symptoms, WM and GM volumes were found between BD groups. Conclusion: Even after correcting for age differences, LOD was associated with more extensive WM microstructural changes and worse episodic memory performance than EOD; these findings suggest that changes in the WM fiber integrity may be associated with a later presentation of BD, possibly due to mechanisms other than neuroprogression. However, these findings deserve replication in larger, prospective, studies.

Altered apolipoprotein C expression in association with cognition impairments and hippocampus volume in schizophrenia and bipolar disorder.

Proteomic analyses facilitate the interpretation of molecular biomarker probes which are very helpful in diagnosing schizophrenia (SZ). In the current study, we attempt to test whether potential differences in plasma protein expressions in SZ and bipolar disorder (BD) are associated with cognitive deficits and their underlying brain structures. Forty-two plasma proteins of 29 SZ patients, 25 BD patients and 93 non-clinical controls were quantified and analysed using multiple reaction monitoring-based triple quadrupole mass spectrometry approach. We also computed group comparisons of protein expressions between patients and controls, and between SZ and BD patients, as well. Potential associations of protein levels with cognitive functioning (psychomotor speed, executive functioning, crystallised intelligence) as well as underlying brain volume in the hippocampus were explored, using bivariate correlation analyses. The main finding of this study was that apolipoprotein expression differed between patients and controls and that these alterations in both disease groups were putatively related to cognitive impairments as well as to hippocampus volumes. However, none of the protein level differences were related to clinical symptom severity. In summary, altered apolipoprotein expression in BD and SZ was linked to cognitive decline and underlying morphological changes in both disorders. Our results suggest that the detection of molecular patterns in association with cognitive performance and its underlying brain morphology is of great importance for understanding of the pathological mechanisms of SZ and BD, as well as for supporting the diagnosis and treatment of both disorders.

Omega-3 Fatty Acids: Repurposing Opportunities for Cognition and Biobehavioral Disturbances in MCI and Dementia.

Neurodegenerative diseases may directly affect memory performance, thus leading to functional impairments. An increasing body of evidence suggests an association between dietary intake of omega-3 fatty acids and memory functioning in animal models as well as in human studies. Recent evidence supports a potential beneficial role of omega-3 fatty acid supplementation on psychopathological and cognitive symptoms, beside their established positive effects on cardiovascular health. OBJECTIVE: We summarize relevant and recent evidence from epidemiological, interventional and experimental studies investigating dietary consumption of omega-3 fatty acids and emphazing mechanisms of memory disorders, with a focus on mild cognitive impairment (MCI) and dementia. Omega-3 fatty acid could represent an affordable and accessible adjunctive treatment option to improve cognitive and non-cognitive function with a focus on MCI or dementia. However, apart from its translational promise, which is based on mechanistic models and evidence from animal studies, evidence for clinical benefits in humans is lacking. METHOD: To follow this research question, a search through electronic databases for the following search terms to identify relevant studies was conducted: 'omega 3 fatty acids', 'cognition', 'memory', ´Alzheimer´s Disease ´, ´dementia´, ´MCI`. Studies were included if they presented original data and were published in English between 1990 and 2015. RESULTS: To our the best of our knowledge, there are only 8 interventional studies that investigated the effects of n3-PUFAs in dementia patients, while 6 studies were conducted in healthy individuals, which in combination show equivocal results. CONCLUSION: This verifies the need for larger and (more) well designed clinical trials.

Integrated Biomarkers for Depression in Alzheimer's Disease: A Critical Review.

Depression is a common neuropsychiatric manifestation among Alzheimer's disease (AD) patients. It may compromise everyday activities and lead to a faster cognitive decline as well as worse quality of life. The identification of promising biomarkers may therefore help to timely initiate and improve the treatment of preclinical and clinical states of AD, and to improve the long-term functional outcome. In this narrative review, we report studies that investigated biomarkers for AD-related depression. Genetic findings state AD-related depression as a rather complex, multifactorial trait with relevant environmental and inherited contributors. However, one specific set of genes, the brain derived neurotrophic factor (BDNF), specifically the Val66Met polymorphism, may play a crucial role in AD-related depression. Regarding neuroimaging markers, the most promising findings reveal structural impairments in the cortico-subcortical networks that are related to affect regulation and reward / aversion control. Functional imaging studies reveal abnormalities in predominantly frontal and temporal regions. Furthermore, CSF based biomarkers are seen as potentially promising for the diagnostic process showing abnormalities in metabolic pathways that contribute to AD-related depression. However, there is a need for standardization of methodological issues and for replication of current evidence with larger cohorts and prospective studies.

Neuroimaging Findings Related to Behavioral Disturbances in Alzheimer's Disease: A Systematic Review.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) associated with Alzheimer's Disease (AD) have been linked to structural and functional alterations in fronto-temporal circuits and cortical abnormalities. However, little is known on how specific volumetric and functional brain changes may be associated with the frequency, severity and pattern of BPSD. METHODS: A systematic review of the literature regarding neuroimaging and BPSD changes in AD was performed through Pubmed/Medline, ISI, and EMBASE electronic databases from January 2000 to May 2015. Eligible references (n=40) included clinical studies in which structural or functional neuroimaging assessment was performed in AD subjects presenting BPSD features. RESULTS: BPSD symptoms, particularly apathy and psychosis have been associated in most of studies with either volume reductions or decreased metabolism in the prefrontal cortex (orbital and dorsolateral portions), anterior cingulate, insula and temporal lobes (middle portion). WM lacunes associated with AD progression have been associated with depressive symptoms. CONCLUSION: The sum of evidence highlights the importance of BPSD-related imaging findings for the understanding of the non-cognitive symptom spectrum in AD. Results suggest that structural and functional changes in fronto-limbic areas may lead to emotional deregulation and symptom unawareness. As these findings may be present early on the AD clinical course, they may have a relevance for the development of imaging markers that could be used in diagnosis, disease monitoring and prediction of therapeutic response.

Neuropsychiatric Disturbances in Mild Cognitive Impairment (MCI): A Systematic Review of Population-Based Studies.

Mild cognitive impairment (MCI) is a nosological entity associated with a higher risk of developing dementia. Previous evidence indicates that behavioral and psychological symptoms of dementia (BPSDs) frequently occur in individuals of MCI. These neuropsychiatric manifestations may predict conversion to dementia. However, no updated systematic review has been conducted aiming to investigate the prevalence of BPSDs in MCI in general population samples. We conducted a systematic review to summarize research results regarding the prevalence of any or specific BPSDs in MCI subjects out of the clinical setting, compared to subjects who are either cognitively intact and/or demented. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from January 1st, 1990 to January 3rd, 2015 for general population studies in which the prevalence of BPSDs in individuals with MCI was estimated. Twenty-one studies met inclusion criteria. Studies varied in overall methodological quality as evaluated with a modified version of the New Castle-Ottawa Scale for cross-sectional studies. Depression (median prevalence: 29.8%; range: 6.8-63.3%), sleep disturbances (median prevalence: 18.3%; range: 7.9-49.0%), and apathy (median prevalence: 15.2%; range: 2.3-18.5%) were the more frequent BPSDs across studies. The prevalence range for any BPSD was 12.8-66.0%. No consistent pattern for differences in the prevalence of BPSDs according to MCI subtype emerged. Studies considered different diagnostic criteria for MCI and used different instruments to assess BPSDs in this population. In conclusion, BPSDs are prevalent among communitydwelling individuals with MCI. However, consistent socio-demographic and clinical correlates for BPSDs in this population remains to be established.

White matter abnormalities in the fornix are linked to cognitive performance in SZ but not in BD disorder: An exploratory analysis with DTI deterministic tractography.

BACKGROUND: In psychosis, white matter (WM) microstructural changes have been detected previously; however, direct comparisons of findings between bipolar (BD) and schizophrenia (SZ) patients are scarce. In this study, we employed deterministic tractography to reconstruct WM tracts in BD and SZ patients. METHODS: Diffusion tensor imaging (DTI) data was carried out with n=32 euthymic BD type I patients, n=26 SZ patients and 30 matched healthy controls. Deterministic tractography using multiple indices of diffusion (fractional anisotropy (FA), tract volume (Vol), tract length (Le) and number of tracts (NofT)) were obtained from the fornix, the cingulum, the anterior thalamic radiation, and the corpus callosum bilaterally. RESULTS: We showed widespread WM microstructural changes in SZ, and changes in the corpus callosum, the left cingulum and the fornix in BD. Fornix fiber tracking scores were associated with cognitive performance in SZ, and with age and age at disease onset in the BD patient group. LIMITATIONS: Although the influence of psychopharmacological drugs as biasing variables on morphological alterations has been discussed for SZ and BD, we did not observe a clear influence of drug exposure on our findings. CONCLUSIONS: These results confirm the assumption that SZ patients have more severe WM changes than BD patients. The findings also suggest a major role of WM changes in the fornix as important fronto-limbic connections in the etiology of cognitive symptoms in SZ, but not in BD.

Age-Related Effects of the Apolipoprotein E Gene on Brain Function.

The apolipoprotein E (ApoE) ɛ4 allele is a well-established genetic risk factor for sporadic Alzheimer's disease. Some evidence suggests a negative role of the ApoE ɛ4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n = 50; age 26.4±4.6 years, 25 ɛ4 carriers) and old (n = 40; age 66.1±7.0 years, 20 ɛ4 carriers) participants. A cross-sectional factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ɛ4 carriers. The increased BOLD response in old ɛ4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ɛ4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ɛ4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age.

Shared and distinct gray matter abnormalities in schizophrenia, schizophrenia relatives and bipolar disorder in association with cognitive impairment.

Cognitive impairments have been linked to structural and functional alterations in frontal and subcortical brain regions, ultimately leading to fronto-thalamic connectivity disturbances. We hypothesized that such neuronal disruptions in frontal and subcortical structures may account for neuropsychological deficits in schizophrenia (SZ), schizophrenia relatives and bipolar disorder (BD). We acquired T1-weighted anatomical MRI sequences in 209 participants: 57 SZ patients, 47 first-degree relatives of SZ patients, 48 BD I patients and 57 healthy controls. We computed group comparisons of gray matter (GM) volume in frontal and basal ganglia regions-of-interest, followed by correlation analysis between psychomotor speed, executive functioning and learning and GM volumes in candidate regions. Several frontal GM volume reductions as well as GM increases in the thalamus and the putamen were exhibited in SZ patients as compared to controls. The same finding was observed - less pronounced - when comparing SZ relatives and controls. BD patients presented GM volume increases in the basal ganglia in comparison to controls. In SZ patients, increases in bilateral thalamus GM volume and decreases in left middle and superior frontal gyrus volume were significantly associated with worse cognitive performance. In summary, our results indicate distinct imbalances across frontal-subcortical circuits in BD, SZ relatives and SZ. The functional relevance of the findings were mainly limited to the SZ patients group: in this group, abnormalities were directly associated with cognitive performance. This result is in line with the finding that the volume alterations were strongest in SZ patients and followed by BD patients and SZ relatives.

Cortical thinning in bipolar disorder and schizophrenia.

Although schizophrenia (SZ) and bipolar disorder (BD) share some clinical features such as psychotic symptoms and cognitive dysfunctions, little is known about possible pathophysiological similarities between both diseases. Therefore, we investigated the potential topographical overlap and segregation of cortical thickness abnormalities in SZ and BD patients. We analyzed 3D-anatomical magnetic resonance imaging datasets with the FreeSurfer 5.1.0 software to examine cortical thickness and volumes in three groups of participants: n=34 BD patients, n=32 SZ patients and n=38 healthy controls. We observed similar bilateral cortical thickness reductions in BD and SZ patients predominantly in the pars opercularis of the inferior frontal gyrus and in the anterior and posterior cingulate. We also found disease-specific cortical reductions in the orbitofrontal cortex for BD patients and in dorsal frontal and temporal areas for SZ. Furthermore, inferior frontal gyrus cortical thinning was associated with deficits in psychomotor speed and executive functioning in SZ patients and with age at onset in both groups. Our findings support the hypothesis that thinning of the frontal cortex may represent a biological feature shared by both disease groups. The associations between cognitive deficits and the reported findings in SZ and to a lesser degree in BD patients add to the functional relevance of our results. However, further studies are needed to corroborate a model of shared pathophysiological disease features across BD and SZ.

Impaired working memory for visual motion direction in schizophrenia: Absence of recency effects and association with psychopathology.

OBJECTIVE: Working memory (WM) impairments are a prominent neurocognitive symptom in schizophrenia (SZ) and include deficits in memory for serial order and abnormalities in serial position effects (i.e., primacy and recency effects). Former studies predominantly focused on investigating these deficits applying verbal or static visual stimuli, but little is known about WM processes that involve dynamic visual movements. We examined WM for visual motion directions, its susceptibility to distraction and the effect of serial positioning. METHOD: Twenty-three patients with paranoid SZ and 23 healthy control subjects (HC) took part in the study. We conducted an adapted Sternberg-type recognition paradigm: three random dot kinematograms (RDKs) that depicted coherent visual motion were used as stimuli and a distractor stimulus was incorporated into the task. RESULTS: SZ patients performed significantly worse in the WM visual motion task, when a distractor stimulus was presented. While HC showed a recency effect for later RDKs, the effect was absent in SZ patients. WM deficits were associated with more severe psychopathological symptoms, poor visual and verbal learning, and a longer duration of illness. Furthermore, SZ patients showed impairments in several other neurocognitive domains. CONCLUSIONS: Findings suggest that early WM processing of visual motion is susceptible to interruption and that WM impairments are associated with clinical symptoms in SZ. The absence of a recency effect is discussed in respect of 3 theoretical approaches-impaired WM for serial order information, abnormalities in early visual representations (i.e., masking effects), and deficits in later visual processing (i.e., attentional blink effect). (PsycINFO Database Record

Treatment-resistant Late-life Depression: Challenges and Perspectives.

The current Review article provides a narrative review about the neurobiological underpinnings and treatment of treatment resistant late-life depression (TRLLD). The manuscript focuses on therapeutic targets of late-life depression, which include pharmacological, psychological, biophysical and exercise treatment approaches. Therefore, we summarize available evidences on that kind of therapies for patients suffering from late-life depression. The search for evidences of therapeutic options of late-life depression were done using searching websites as "pubmed", and using the searching terms "depression", "late-life depression", "treatment", "biophysical therapy", "exercise therapy", "pharmacological therapy" and "psychological therapy". To the end, we summarize and discuss current data, providing some directions for further research. Treatment recommendations for elderly depressive patients favour a multimodal approach, containing psychological, pharmacological and secondary biophysical therapeutic options. Particularly, a combination of psychotherapy and antidepressant medication reflects the best therapeutic option. However, mostly accepted and used is the pharmacological treatment although evidence suggests that the drug therapy is not as effective as it is in younger depressive patients. Further studies employing larger samples and longer follow-up periods are necessary and may focus on comparability of study designs and involve novel approaches to establish the validity and reliability of multimodal treatment programs.

Omega 3 Fatty Acids: Novel Neurotherapeutic Targets for Cognitive Dysfunction in Mood Disorders and Schizophrenia?

An increasing body of evidences from preclinical as well as epidemiological and clinical studies suggest a potential beneficial role of dietary intake of omega-3 fatty acids for cognitive functioning. In this narrative review, we will summarize and discuss recent findings from epidemiological, interventional and experimental studies linking dietary consumption of omega-3 fatty acids to cognitive function in healthy adults. Furthermore, affective disorders and schizophrenia (SZ) are characterized by cognitive dysfunction encompassing several domains. Cognitive dysfunction is closely related to impaired functioning and quality of life across these conditions. Therefore, the current review focues on the potential influence of omega-3 fatty acids on cognition in SZ and affective disorders. In sum, current data predominantly from mechanistic models and animal studies suggest that adjunctive omega-3 fatty acid supplementation could lead to improved cognitive functioning in SZ and affective disorders. However, besides its translational promise, evidence for clinical benefits in humans has been mixed. Notwithstanding evidences indicate that adjunctive omega-3 fatty acids may have benefit for affective symptoms in both unipolar and bipolar depression, to date no randomized controlled trial had evaluated omega-3 as cognitive enhancer for mood disorders, while a single published controlled trial suggested no therapeutic benefit for cognitive improvement in SZ. Considering the pleiotropic mechanisms of action of omega-3 fatty acids, the design of well-designed controlled trials of omega-3 supplementation as a novel, domain-specific, target for cognitive impairment in SZ and affective disorders is warranted.

Peripheral vascular endothelial growth factor as a novel depression biomarker: A meta-analysis.

BACKGROUND: The neurotrophic hypothesis of major depressive disorder (MDD) postulates that the pathology of this illness incorporates a down-regulation of neurotrophin signaling. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic mediator regarding the neurobiology of MDD. Nevertheless, emerging evidence has implicated the multi-competent angiogenic and neurogenic molecule - vascular endothelial growth factor (VEGF) - in hippocampal neurogenesis and depression pathophysiology. OBJECTIVE: To compare peripheral levels of VEGF between individuals with MDD and healthy controls. METHODS: We performed a systematic review and meta-analysis of original studies measuring peripheral levels of VEGF in participants with MDD compared to healthy controls. We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases for studies published in any language through December 16th, 2014. RESULTS: Fourteen studies met eligibility criteria (N=1633). VEGF levels were significantly elevated in individuals with MDD when compared to healthy controls (Hedges's g=0.343; 95% CI: 0.146-0.540; P<0.01). Funnel plot inspection and the Egger's test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P<0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, sample for assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender emerged as significant sources of heterogeneity. CONCLUSIONS: Taken together, extant data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD.

Schizophrenia risk variants modulate white matter volume across the psychosis spectrum: evidence from two independent cohorts.

Polygenic risk scores, based on risk variants identified in genome-wide-association-studies (GWAS), explain a considerable portion of the heritability for schizophrenia (SZ) and bipolar disorder (BD). However, little is known about the combined effects of these variants, although polygenic neuroimaging has developed into a powerful tool of translational neuroscience. In this study, we used genome wide significant SZ risk variants to test the predictive capacity of the polygenic model and explored potential associations with white matter volume, a key candidate in imaging phenotype for psychotic disorders. By calculating the combined additive schizophrenia risk of seven SNPs (significant hits from a recent schizophrenia GWAS study), we show that increased additive genetic risk for SZ was associated with reduced white matter volume in a group of participants (n = 94) consisting of healthy individuals, SZ first-degree relatives, SZ patients and BD patients. This effect was also seen in a second independent sample of healthy individuals (n = 89). We suggest that a moderate portion of variance (~4%) of white matter volume can be explained by the seven hits from the recent schizophrenia GWAS. These results provide evidence for associations between cumulative genetic risk for schizophrenia and intermediate neuroimaging phenotypes in models of psychosis. Our work contributes to a growing body of literature suggesting that polygenic risk may help to explain white matter alterations associated with familial risk for psychosis.