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Genzel L.,Max Planck Institute of Psychiatry | Genzel L.,University of Edinburgh | Dresler M.,Max Planck Institute of Psychiatry | Cornu M.,Max Planck Institute of Psychiatry | And 8 more authors.
Biological Psychiatry | Year: 2015

Background Overnight memory consolidation is disturbed in both depression and schizophrenia, creating an ideal situation to investigate the mechanisms underlying sleep-related consolidation and to distinguish disease-specific processes from common elements in their pathophysiology.Methods We investigated patients with depression and schizophrenia, as well as healthy control subjects (each n = 16), under a motor memory consolidation protocol with functional magnetic resonance imaging and polysomnography.Results In a sequential finger-tapping task associated with the degree of hippocampal-prefrontal cortex functional connectivity during the task, significantly less overnight improvement was identified as a common deficit in both patient groups. A task-related overnight decrease in activation of the basal ganglia was observed in control subjects and schizophrenia patients; in contrast, patients with depression showed an increase. During the task, schizophrenia patients, in comparison with control subjects, additionally recruited adjacent cortical areas, which showed a decrease in functional magnetic resonance imaging activation overnight and were related to disease severity. Effective connectivity analyses revealed that the hippocampus was functionally connected to the motor task network, and the cerebellum decoupled from this network overnight.Conclusions While both patient groups showed similar deficits in consolidation associated with hippocampal-prefrontal cortex connectivity, other activity patterns more specific for disease pathology differed.

Focke N.K.,University Hospital Freiburg | Trost S.,August Research Systems | Paulus W.,University Hospital Freiburg | Falkai P.,Ludwig Maximilians University of Munich | Gruber O.,August Research Systems
Frontiers in Psychiatry | Year: 2014

Voxel-based morphometry (VBM) is a commonly used method to study volumetric variations on a whole brain basis. However, it is often criticized for potential confounds, mainly based on imperfect spatial registration. We therefore aimed to evaluate if VBM and "gold standard" manual volumetry are measuring the same effects with respect to subcortical gray matter volumes. Manual regions-of-interest were drawn in the hippocampus, amygdala, nucleus accumbens, thalamus, putamen, pallidum, and caudate nucleus bilaterally. Resulting volumes were used for a whole brain VBM correlation analysis with Statistical Parametric Mapping (SPM8). The hippocampus, amygdala, putamen, and caudate nucleus were correctly identified by SPM using the contemporary high-dimensional normalization (DARTEL toolbox). This strongly suggests that VBM and manual volumetry both are indeed measuring the same effects with regard to subcortical brain structures. © 2014 Focke, Trost, Paulus, Falkai and Gruber.

Trost S.,August Research Systems | Gruber O.,August Research Systems
Neuropsychobiology | Year: 2012

Objective: Recent functional neuroimaging studies have provided evidence that human verbal working memory is represented by two complementary neural systems, a left lateralized premotor-parietal network implementing articulatory rehearsal and a presumably phylogenetically older bilateral anterior-prefrontal/ inferior-parietal network subserving non-articulatory maintenance of phonological information. In order to corroborate these findings from functional neuroimaging, we performed a targeted behavioural study in patients with very selective and circumscribed brain lesions to key regions suggested to support these different subcomponents of human verbal working memory. Methods: Within a sample of over 500 neurological patients assessed with high-resolution structural magnetic resonance imaging, we identified 2 patients with corresponding brain lesions, one with an isolated lesion to Broca's area and the other with a selective lesion bilaterally to the anterior middle frontal gyrus. These 2 patients as well as groups of age-matched healthy controls performed two circuit-specific verbal working memory tasks. In this way, we systematically assessed the hypothesized selective behavioural effects of these brain lesions on the different subcomponents of verbal working memory in terms of a double dissociation. Results: Confirming prior findings, the lesion to Broca's area led to reduced performance under articulatory rehearsal, whereas the non-articulatory maintenance of phonological information was unimpaired. Conversely, the bifrontopolar brain lesion was associated with impaired non-articulatory phonological working memory, whereas performance under articulatory rehearsal was unaffected. Conclusion: The present experimental neuropsychological study in patients with specific and circumscribed brain lesions confirms the hypothesized double dissociation of two complementary brain systems underlying verbal working memory in humans. In particular, the results demonstrate the functional relevance of the anterior prefrontal cortex for non-articulatory maintenance of phonological information and, in this way, provide further support for the evolutionary-based functional-neuroanatomical model of human working memory. Copyright © 2012 S. Karger AG, Basel.

Wolf C.,August Research Systems | Linden D.E.J.,University of Cardiff
Genes, Brain and Behavior | Year: 2012

Because living systems depend on their environment, the evolution of environmental adaptability is inseparable from the evolution of life itself. In animals and humans, environmental adaptability extends further to adaptive behavior. It has recently emerged that individual adaptability depends on the interaction of adaptation mechanisms at diverse functional levels. This interaction enables the integration of genetic, epigenetic and environmental factors for coordinated regulation of adaptations. In this review, we first present the basis for the regulation of adaptation mechanisms across functional levels. We then focus on neuronal activity-regulated adaptation mechanisms that involve the regulation of genes, noncoding DNA (ncDNA), ncRNAs and proteins to change the structural and functional properties of neurons. Finally, we discuss a selection of these important neuronal activity-regulated molecules and their effects on brain structure and function and on behavior. Most of the evidence so far is based on sampling of animal tissue or post-mortem studies in humans. However, we also present techniques that combine genetic with behavioral and neurophysiological measures in humans (e.g. genetic imaging) and discuss their potential and limitations. We argue that we need to understand how neuronal activity-dependent adaptation mechanisms integrate genetic, epigenetic and experience-dependent signals in order to explain individual variations in behavior and cognitive performance. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Diekhof E.K.,August Research Systems | Diekhof E.K.,University of Hamburg | Nerenberg L.,August Research Systems | Falkai P.,August Research Systems | And 3 more authors.
Human Brain Mapping | Year: 2012

The ability to resist immediate rewards is crucial for lifetime success and individual well-being. Using functional magnetic resonance imaging, we assessed the association between trait impulsivity and the neural underpinnings of the ability to control immediate reward desiring. Low and high extreme impulsivity groups were compared with regard to their behavioral performance and brain activation in situations, in which they had to forego immediate rewards with varying value to achieve a superordinate long-term goal. We found that highly impulsive (HI) individuals, who successfully compensated for their lack in behavioral self-control, engaged two complementary brain mechanisms when choosing actions in favor of a long-term goal, but at the expense of an immediate reward. First, self-controlled decisions led to a general attenuation of reward-related activation in the nucleus accumbens, which was accompanied by an increased inverse connectivity with the anteroventral prefrontal cortex. Second, HI subjects controlled their desire for increasingly valuable, but suboptimal rewards through a linear reduction of activation in the ventromedial prefrontal cortex (VMPFC). This was achieved by an increased inverse coupling between the VMPFC and the ventral striatum. Importantly, the neural mechanisms observed in the HI group differed from those in extremely controlled individuals, despite similar behavioral performance. Collectively, these results suggest trait-specific neural mechanisms that allow HI individuals to control their desire for immediate reward. © 2011 Wiley Periodicals, Inc.

Henseler I.,August Research Systems | Falkai P.,August Research Systems | Gruber O.,August Research Systems
Journal of Psychiatric Research | Year: 2010

Introduction: Disturbed interregional functional connectivity has been hypothesized to be a promising marker of schizophrenia. The relationship between working memory (WM) impairment, disturbed functional connectivity, and the characteristic symptoms of schizophrenia, however, remains elusive. Methods: We used functional MRI (fMRI) to investigate in patients with schizophrenia and matched controls the patterns of functional connectivity during the performance of different tasks selectively engaging subcomponent processes of working memory. Results: Compared with controls, patients showed reduced connectivity of the prefrontal cortex with the intraparietal cortex and the hippocampus and abnormal negative interactions between the ventrolateral and dorsolateral prefrontal cortex during the non-articulatory maintenance of phonological information. During the maintenance of visuospatial information, patients presented reduced connectivity between regions in the superior parietal and occipital cortex, as well as enhanced positive connectivity of the frontal eye field with visual processing areas. Discussion: Our findings suggest complex dysregulations within the networks supporting working memory functions in schizophrenia, which manifest as decreased positive and abnormal negative interactions. Correlations between the connection strength and WM performance suggest that these dysregulations may be neurofunctional correlates of the WM deficits seen in schizophrenia. Altered prefronto-hippocampal and parieto-occipital connectivity was further found to be associated with higher positive symptoms, providing a possible explanation for the development of delusions and disorganization symptoms. Conclusion: The present findings can help to better understand the relationship between altered patterns of synchronized brain activity and the cognitive and clinical symptoms of schizophrenia. © 2009 Elsevier Ltd.

Trost S.,August Research Systems | Diekhof E.K.,August Research Systems | Diekhof E.K.,University of Hamburg | Zvonik K.,August Research Systems | And 7 more authors.
Neuropsychopharmacology | Year: 2014

Bipolar disorder (BD) is characterized by recurrent mood episodes ranging from severe depression to acute full-blown mania. Both states of this severe psychiatric disorder have been associated with alterations of reward processing in the brain. Here, we present results of a functional magnetic resonance imaging (fMRI) study on the neural correlates and functional interactions underlying reward gain processing and reward dismissal in favor of a long-term goal in bipolar patients. Sixteen medicated patients diagnosed with bipolar I disorder, euthymic to mildly depressed, and sixteen matched healthy controls performed the 'desire-reason dilemma' (DRD) paradigm demanding rejection of priorly conditioned reward stimuli to successfully pursue a superordinate goal. Both groups exhibited significant activations in reward-related brain regions, particularly in the mesolimbic reward system. However, bipolar patients showed reduced neural responses of the ventral striatum (vStr) when exploiting a reward stimulus, and exhibited a decreased suppression of the reward-related activation of the mesolimbic reward system while having to reject immediate reward in favor of the long-term goal. Further, functional interaction between the anteroventral prefrontal cortex and the vStr in the 'DRD' was significantly impaired in the bipolar group. These findings provide evidence for a reduced responsivity of the vStr to reward stimuli in BD, possibly related to clinical features like anhedonia. The disturbed top-down control of mesolimbic reward signals by prefrontal brain regions in BD can be interpreted in terms of a disease-related enhanced impulsivity, a trait marker of BD. © 2014 American College of Neuropsychopharmacology. All rights reserved.

Zilles D.,August Research Systems | Meyer J.,University of Trier | Schneider-Axmann T.,August Research Systems | Ekawardhani S.,University of Trier | And 3 more authors.
European Archives of Psychiatry and Clinical Neuroscience | Year: 2012

Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-Omethyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit-specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches. © The Author(s) 2012.

Recent genome-wide association studies have identified MAD1L1 (mitotic arrest deficient-like 1) as a susceptibility gene for bipolar disorder and schizophrenia. The minor allele of the single-nucleotide polymorphism (SNP) rs11764590 in MAD1L1 was associated with bipolar disorder. Both diseases, bipolar disorder and schizophrenia, are linked to functional alterations in the reward system. We aimed at investigating possible effects of the MAD1L1 rs11764590 risk allele on reward systems functioning in healthy adults. A large homogenous sample of 224 young (aged 18–31 years) participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All participants performed the ‘Desire-Reason Dilemma’ paradigm investigating the neural correlates that underlie reward processing and active reward dismissal in favor of a long-term goal. We found significant hypoactivations of the ventral tegmental area (VTA), the bilateral striatum and bilateral frontal and parietal cortices in response to conditioned reward stimuli in the risk allele carriers compared with major allele carriers. In the dilemma situation, functional connectivity between prefrontal brain regions and the ventral striatum was significantly diminished in the risk allele carriers. Healthy risk allele carriers showed a significant deficit of their bottom-up response to conditioned reward stimuli in the bilateral VTA and striatum. Furthermore, functional connectivity between the ventral striatum and prefrontal areas exerting top-down control on the mesolimbic reward system was reduced in this group. Similar alterations in reward processing and disturbances of prefrontal control mechanisms on mesolimbic brain circuits have also been reported in bipolar disorder and schizophrenia. Together, these findings suggest the existence of an intermediate phenotype associated with MAD1L1.Neuropsychopharmacology advance online publication, 8 June 2016; doi:10.1038/npp.2016.70. © 2016 American College of Neuropsychopharmacology

Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase I | Award Amount: 69.18K | Year: 2010

August Research Systems, Inc. proposes to establish the feasibility of rapidly deployable, thin-film camouflage coatings for on ground vehicles. The film-based coatings will leverage the robust and expanding vehicle wraps industry, which provides full-vehicle appliqué systems that are digitally printed, self-adhesive, vinyl films that serve as a medium for vivid vehicle graphics, while the underlying vehicle paint is protected. Vehicle wraps offer potential advantages in military use among which are: enabling color-rich, digitally optimized camouflage patterns without the need for paint; the circumvention of a paint operation for refreshing or changing vehicle appearance; a deployable and field-installable coating system that is 0-VOC and free of hazardous air pollutants; protection and life extension of underlying CARC paint; and rapid, cost-effective repair or replacement. However, wrap technology does not address several important military requirements such as non-slip properties, specific camouflage color and gloss characteristics, and near infrared reflectance spectral requirements. This Phase I effort will, through testing and evaluation, quantify the shortcomings of current wrap material and manufacturing technology per military requirements and define innovative approaches for the engineering and production of militarily useful wrap materials for vehicle applications.

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