[Show abstract][Hide abstract] ABSTRACT: Hippocampal-prefrontal interactions are implicated in working memory (WM) and altered in psychiatric conditions with cognitive impairment such as schizophrenia. While coupling between both structures is crucial for WM performance in rodents, evidence from human studies is conflicting and translation of findings is complicated by the use of differing paradigms across species. We therefore used functional magnetic resonance imaging (fMRI) together with a spatial WM paradigm adapted from rodent research to examine hippocampal-prefrontal coupling in humans. A prefrontal-parietal network was functionally connected to hippocampus (HC) during task stages requiring high levels of executive control but not during a matched control condition. The magnitude of coupling in a network comprising HC, bilateral dorsolateral prefrontal cortex (DLPFC) and right supramarginal gyrus explained one fourth of the variability in an independent spatial WM task but was unrelated to visual WM performance. HC-DLPFC coupling may thus represent a systems-level mechanism specific to spatial WM that is conserved across species, suggesting its utility for modeling cognitive dysfunction in translational neuroscience.Neuropsychopharmacology accepted article preview online, 12 January 2015. doi:10.1038/npp.2015.13.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2015; · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Evidence has emerged indicating that the ε4 allele of APOE and PICALM interact in conferring risk of Alzheimer's disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD.
The aim of this study was to investigate interaction effects of the APOE ε4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia.
There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function.
The data suggest a neural mechanism for APOE–PICALM interactions in patients with manifest AD and indicate that the PICALM genotype modulates both brain atrophy and cognitive performance in APOE ε4 carriers.
Alzheimer's & dementia: the journal of the Alzheimer's Association 10/2014; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity has emerged as a leading health threat but its biological basis remains insufficiently known, hampering the search for novel treatments. Here, we study oleoylethanolamide, a naturally occurring lipid that has been clearly implicated in weight regulation in animals. However, its role for weight regulation and obesity in humans is still unclear.
[Show abstract][Hide abstract] ABSTRACT: Patients suffering from bipolar affective disorder show deficits in working memory functions. In a previous functional magnetic resonance imaging study, we observed an abnormal hyperactivity of the amygdala in bipolar patients during articulatory rehearsal in verbal working memory. In the present study, we investigated the dynamic neurofunctional interactions between the right amygdala and the brain systems that underlie verbal working memory in both bipolar patients and healthy controls. In total, 18 euthymic bipolar patients and 18 healthy controls performed a modified version of the Sternberg item-recognition (working memory) task. We used the psychophysiological interaction approach in order to assess functional connectivity between the right amygdala and the brain regions involved in verbal working memory. In healthy subjects, we found significant negative functional interactions between the right amygdala and multiple cortical brain areas involved in verbal working memory. In comparison with the healthy control subjects, bipolar patients exhibited significantly reduced functional interactions of the right amygdala particularly with the right-hemispheric, i.e., ipsilateral, cortical regions supporting verbal working memory. Together with our previous finding of amygdala hyperactivity in bipolar patients during verbal rehearsal, the present results suggest that a disturbed right-hemispheric "cognitive-emotional" interaction between the amygdala and cortical brain regions underlying working memory may be responsible for amygdala hyperactivation and affects verbal working memory (deficits) in bipolar patients.
European Archives of Psychiatry and Clinical Neuroscience 08/2014; · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functional interactions between the dorsolateral prefrontal cortex and hippocampus during working memory have been studied extensively as an intermediate phenotype for schizophrenia. Coupling abnormalities have been found in patients, their unaffected siblings, and carriers of common genetic variants associated with schizophrenia, but the global genetic architecture of this imaging phenotype is unclear. To achieve genome-wide hypothesis-free identification of genes and pathways associated with prefrontal-hippocampal interactions, we combined gene set enrichment analysis with whole-genome genotyping and functional magnetic resonance imaging data from 269 healthy German volunteers. We found significant enrichment of the synapse organization and biogenesis gene set. This gene set included known schizophrenia risk genes, such as neural cell adhesion molecule (NRCAM) and calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as well as genes with well-defined roles in neurodevelopmental and plasticity processes that are dysfunctional in schizophrenia and have mechanistic links to prefrontal-hippocampal functional interactions. Our results demonstrate a readily generalizable approach that can be used to identify the neurogenetic basis of systems-level phenotypes. Moreover, our findings identify gene sets in which genetic variation may contribute to disease risk through altered prefrontal-hippocampal functional interactions and suggest a link to both ongoing and developmental synaptic plasticity.
Proceedings of the National Academy of Sciences 06/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Urban upbringing has consistently been associated with schizophrenia, but which specific environmental exposures are reflected by this epidemiological observation and how they impact the developing brain to increase risk is largely unknown. On the basis of prior observations of abnormal functional brain processing of social stress in urban-born humans and preclinical evidence for enduring structural brain effects of early social stress, we investigated a possible morphological correlate of urban upbringing in human brain. In a sample of 110 healthy subjects studied with voxel-based morphometry, we detected a strong inverse correlation between early-life urbanicity and gray matter (GM) volume in the right dorsolateral prefrontal cortex (DLPFC, Brodmann area 9). Furthermore, we detected a negative correlation of early-life urbanicity and GM volumes in the perigenual anterior cingulate cortex (pACC) in men only. Previous work has linked volume reductions in the DLPFC to the exposure to psychosocial stress, including stressful experiences in early life. Besides, anatomical and functional alterations of this region have been identified in schizophrenic patients and high-risk populations. Previous data linking functional hyperactivation of pACC during social stress to urban upbringing suggest that the present interaction effect in brain structure might contribute to an increased risk for schizophrenia in males brought up in cities. Taken together, our results suggest a neural mechanism by which early-life urbanicity could impact brain architecture to increase the risk for schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Relative risk for the brain disorder schizophrenia is more than doubled in ethnic minorities, an effect that is evident across countries and linked to socially relevant cues such as skin color, making ethnic minority status a well-established social environmental risk factor. Pathoepidemiological models propose a role for chronic social stress and perceived discrimination for mental health risk in ethnic minorities, but the neurobiology is unexplored. OBJECTIVE To study neural social stress processing, using functional magnetic resonance imaging, and associations with perceived discrimination in ethnic minority individuals. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional design in a university setting using 3 validated paradigms to challenge neural social stress processing and, to probe for specificity, emotional and cognitive brain functions. Healthy participants included those with German lineage (n = 40) and those of ethnic minority (n = 40) from different ethnic backgrounds matched for sociodemographic, psychological, and task performance characteristics. Control comparisons examined stress processing with matched ethnic background of investigators (23 Turkish vs 23 German participants) and basic emotional and cognitive tasks (24 Turkish vs 24 German participants). MAIN OUTCOMES AND MEASURES Blood oxygenation level-dependent response, functional connectivity, and psychological and physiological measures. RESULTS There were significant increases in heart rate (P < .001), subjective emotional response (self-related emotions, P < .001; subjective anxiety, P = .006), and salivary cortisol level (P = .004) during functional magnetic resonance imaging stress induction. Ethnic minority individuals had significantly higher perceived chronic stress levels (P = .02) as well as increased activation (family-wise error-corrected [FWE] P = .005, region of interest corrected) and increased functional connectivity (PFWE = .01, region of interest corrected) of perigenual anterior cingulate cortex (ACC). The effects were specific to stress and not explained by a social distance effect. Ethnic minority individuals had significant correlations between perceived group discrimination and activation in perigenual ACC (PFWE = .001, region of interest corrected) and ventral striatum (PFWE = .02, whole brain corrected) and mediation of the relationship between perceived discrimination and perigenual ACC-dorsal ACC connectivity by chronic stress (P < .05). CONCLUSIONS AND RELEVANCE Epidemiologists proposed a causal role of social-evaluative stress, but the neural processes that could mediate this susceptibility effect were unknown. Our data demonstrate the potential of investigating associations from epidemiology with neuroimaging, suggest brain effects of social marginalization, and highlight a neural system in which environmental and genetic risk factors for mental illness may converge.
[Show abstract][Hide abstract] ABSTRACT: Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the 'missing heritability' of complex phenotypes.
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a severe and complex brain disorder that usually manifests in early adulthood and disturbs a wide range of human functions. More than 100 years after its initial description, the pathophysiology of the disorder is still incompletely understood. Many epidemiological studies strongly suggest a complex interaction between genetic and environmental risk factors for the development of the disorder. While there is considerable evidence for a social environmental component of this risk, the links between adverse social factors and altered brain function have just come into focus.
In the present review, we first summarize epidemiological evidence for the significance of social environmental risk factors, outline the role of altered social stress processing in mental illness, and review the latest experimental evidence for the neural correlates of social environmental risk for schizophrenia.
The studies we have discussed in this review provide a selection of the current work in the field. We suggest that many of the social environmental risk factors may impact on perceived social stress and engage neural circuits in the brain whose functional and structural architecture undergoes detrimental change in response to prolonged exposure. We conclude that multidisciplinary approaches involving various fields and thoroughly constructed longitudinal designs are necessary to capture complex structure of social environmental risks.
Social Psychiatry 03/2014; 49(4). · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analysed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same systems-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. Schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder. OBJECTIVE To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929). DESIGN, SETTING, AND PARTICIPANTS Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied. MAIN OUTCOMES AND MEASURES Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype. RESULTS Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P < .03 for multiple comparisons across the whole brain). Supplemental analyses confirmed that the identified systems-level functional phenotype is reliable (with intraclass correlation coefficients of 0.59-0.73), independent of local gray matter volume (with no corresponding group differences and no correlation to function, and with all uncorrected P values >.05), and affected by the NRG1 genotype (higher striatal responses in controls with the protective rs10503929 C allele; familywise error-corrected P < .03 for ventral striatal response). CONCLUSIONS AND RELEVANCE Healthy first-degree relatives of schizophrenic patients show altered striatal activation during reward anticipation in a directionality and localization consistent with prior patient findings. This provides evidence for a functional neural system mechanism related to familial risk. The phenotype can be assessed reliably, is independent of alterations in striatal structure, and is influenced by a schizophrenia candidate gene variant in NRG1. These data encourage us to further investigate the genetic and molecular contributions to this phenotype.
[Show abstract][Hide abstract] ABSTRACT: The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved.
Journal of Neuroscience 01/2014; 34(3):1051-6. · 6.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Although a heritable contribution to risk for Major Depressive Disorder (MDD) has been established and neural alterations in patients have been identified through neuroimaging, it is unclear which brain abnormalities are related to genetic risk. Studies on brain structure of high-risk subjects – such as individuals carrying a familial liability for the development of MDD – can provide information on the potential usefulness of these measures as intermediate phenotypes of MDD.
63 healthy first-degree relatives of patients with MDD and 63 healthy controls underwent structural magnetic resonance imaging. Regional gray matter volumes were analyzed via voxel-based morphometry (VBM).
Whole-brain analysis revealed significantly larger gray matter volume in the bilateral amygdala in first-degree relatives of patients with MDD. Furthermore, relatives showed significantly larger gray matter volume in anatomical structures found relevant to MDD in previous literature, specifically in bilateral hippocampus and amygdala as well as left dorsolateral prefrontal cortex (DLPFC). Bilateral DLPFC volume correlated positively with the experience of negative affect.
Larger gray matter volume in healthy relatives of MDD patients point to a possible vulnerability mechanism in MDD etiology and therefore extend knowledge in the field of high-risk approaches in MDD.
[Show abstract][Hide abstract] ABSTRACT: In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.
[Show abstract][Hide abstract] ABSTRACT: Variation in CACNA1C has consistently been associated with psychiatric disease in genome-wide association studies. We have previously shown that healthy carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate (pgACC) dysfunction during episodic memory recall. To test whether this brain systems-level abnormality is a potential intermediate phenotype for psychiatric disorder, we studied unaffected relatives of patients with bipolar disorder, major depression, and schizophrenia.
The study population comprised 188 healthy first-degree relatives of patients with bipolar disorder (n = 59), major depression (n = 73), and schizophrenia (n = 56) and 110 comparison subjects from our discovery study who were genotyped for rs1006737 and underwent functional magnetic resonance imaging while performing an episodic memory task and psychological testing. Group comparisons were analyzed using SPM8 and PASW Statistics 20.
Similar to risk allele carriers in the discovery sample, relatives of index patients exhibited hippocampal and pgACC dysfunction as well as increased scores in depression and anxiety measures, correlating negatively with hippocampal activation. Carrying the rs1006737 risk variant resulted in a stronger decrease of hippocampal and pgACC activation in relatives, indicating an additive effect of CACNA1C variation on familial risk.
Our findings implicate abnormal perigenual and hippocampal activation as a promising intermediate phenotype for psychiatric disease and suggest a pathophysiologic mechanism conferred by a CACNA1C variant being implicated in risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: The investigation of the brain connectome with functional magnetic resonance imaging (fMRI) and graph theory analyses has recently gained much popularity, but little is known about the robustness of these properties, in particular those derived from active fMRI tasks. Here, we studied the test-retest reliability of brain graphs calculated from 26 healthy participants with three established fMRI experiments (n-back working memory, emotional face-matching, resting state) and two parcellation schemes for node definition (AAL atlas, functional atlas proposed by Power et al.). We compared the intra-class correlation coefficients (ICCs) of five different data processing strategies and demonstrated a superior reliability of task-regression methods with condition-specific regressors. The between-task comparison revealed significantly higher ICCs for resting state relative to the active tasks, and a superiority of the n-back task relative to the face-matching task for global and local network properties. While the mean ICCs were typically lower for the active tasks, overall fair to good reliabilities were detected for global and local connectivity properties, and for the n-back task with both atlases, smallworldness. For all three tasks and atlases, low mean ICCs were seen for the local network properties. However, node-specific good reliabilities were detected for node degree in regions known to be critical for the challenged functions (resting-state: default-mode network nodes, n-back: fronto-parietal nodes, face-matching: limbic nodes). Between-atlas comparison demonstrated significantly higher reliabilities for the functional parcellations for global and local network properties. Our findings can inform the choice of processing strategies, brain atlases and outcome properties for fMRI studies using active tasks, graph theory methods, and within-subject designs, in particular future pharmaco-fMRI studies.
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a frequent and highly heritable brain disorder that typically manifests around or after puberty and has a fluctuating course. Multiple lines of evidence point to a neurodevelopmental origin of the illness and suggest that its (post) pubertal manifestation is related to genetic and environmental risk factors that interfere with the structural and functional reorganization of neural networks at this time. Longitudinal structural neuroimaging studies point to a progressive reduction in gray matter volume in many brain regions in schizophrenia. It has been proposed that these neuroimaging observations reflect an enduring disturbance of experience-dependent synaptic plasticity arising from developmental abnormalities in key neural circuits implicated in schizophrenia, including dorsolateral prefrontal cortex and hippocampal formation. Recent work has identified genetic variants linked to neural plasticity that are associated with changes in these circuits. Furthermore, non-invasive interventions such as transcranial magnetic stimulation have been shown to impact some of these systems-level intermediate phenotypes, suggesting a modifiability of these core pathophysiological processes of schizophrenia that may be exploited by therapy.