Biology of mood & anxiety disorders最新文献

{"title":"Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas.","authors":"Orna Issler, Roderick N Carter, Evan D Paul, Paul At Kelly, Henry J Olverman, Adi Neufeld-Cohen, Yael Kuperman, Christopher A Lowry, Jonathan R Seckl, Alon Chen, Pauline M Jamieson","doi":"10.1186/2045-5380-4-1","DOIUrl":"10.1186/2045-5380-4-1","url":null,"abstract":"<p><strong>Background: </strong>Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice.</p><p><strong>Results: </strong>CRFR2-null mice showed similar anxiety levels to control mice before and immediately after acute restraint stress, and also after cessation of chronic stress. However, they showed increased anxiety by 24 hours after restraint, whether or not they had been chronically stressed.Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were quantified and the level of 5-HIAA in the caudal dorsal raphe nucleus (DRN) was increased under basal conditions in CRFR2-null mice, indicating increased 5-HT turnover. Twenty-four hours following restraint, 5-HIAA was decreased only in CRFR2-null mice, suggesting that they had not fully recovered from the challenge. In efferent limbic structures, CRFR2-null mice showed lower levels of basal 5-HT in the lateral septum and subiculum, and again showed a differential response to restraint stress from controls.Local cerebral glucose utilization (LCMRglu) revealed decreased neuronal activity in the DRN of CRFR2-null mice under basal conditions. Following 5-HT receptor agonist challenge, LCMRglu responses indicated that 5-HT1A receptor responses in the DRN were attenuated in CRFR2-null mice. However, postsynaptic 5-HT receptor responses in forebrain regions were intact.</p><p><strong>Conclusions: </strong>These results suggest that CRFR2 are required for proper functionality of 5-HT1A receptors in the raphe nuclei, and are key to successful recovery from stress. This disrupted serotonergic function in CRFR2-null mice likely contributes to their stress-sensitive phenotype. The 5-HT content in lateral septum and subiculum was notably altered. These areas are important for anxiety, and are also implicated in reward and the pathophysiology of addiction. The role of CRFR2 in stress-related psychopathologies deserves further consideration.</p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"4 1","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2014-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32048456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early handling attenuates enhancement of glucocorticoid receptors in the prefrontal cortex in an animal model of post-traumatic stress disorder.","authors":"Sophie A George, Stephanie A Stout, Melissa Tan, Dayan Knox, Israel Liberzon","doi":"10.1186/2045-5380-3-22","DOIUrl":"10.1186/2045-5380-3-22","url":null,"abstract":"<p><strong>Background: </strong>Changes in glucocorticoid receptors (GRs) have been implicated in the pathogenesis of stress related psychiatric disorders such as depression and post-traumatic stress disorder (PTSD). Abnormal adaptation of the stress-response system following traumatic stress can lead to an altered hypothalamic-pituitary-adrenal axis that may contribute to PTSD development. Indeed, elevated GR expression in the hippocampus and prefrontal cortex linked to PTSD-like characteristics have been reported in the validated animal model of PTSD, single-prolonged stress. These findings implicate increased levels of GRs in the development of post-traumatic psychopathology and suggest that exploration of GR-targeted interventions may have potential for PTSD prevention. Early handling during the neonatal phase alters GR expression and is proposed to confer resilience to stress. We therefore examined the effects of combined early handling and single prolonged stress treatments on GR expression.</p><p><strong>Methods: </strong>Timed pregnant dams gave birth to pups that were subjected to early handling (n = 11) or control (n = 13) procedures during the neonatal phase. At postnatal day 45 animals underwent single prolonged stress or a control procedure. Rats were euthanized one day later and GR levels were assayed using western blot electrophoresis.</p><p><strong>Results: </strong>Single prolonged stress exposure enhanced GR expression in the hippocampus and prefrontal cortex. Early handling treatment protected against single prolonged stress-induced enhancement of GR expression in the prefrontal cortex, but not in the hippocampus.</p><p><strong>Conclusions: </strong>These data are a first step in highlighting the importance of targeting GR systems in prevention/resilience and may suggest that preventive strategies targeting GR upregulation might be particularly effective when prefrontal rather than hippocampal GRs are the target.</p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"22"},"PeriodicalIF":0.0,"publicationDate":"2013-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31913579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain white matter microstructure alterations in adolescent rhesus monkeys exposed to early life stress: associations with high cortisol during infancy.","authors":"Brittany R Howell,&nbsp;Kai M McCormack,&nbsp;Alison P Grand,&nbsp;Nikki T Sawyer,&nbsp;Xiaodong Zhang,&nbsp;Dario Maestripieri,&nbsp;Xiaoping Hu,&nbsp;Mar M Sanchez","doi":"10.1186/2045-5380-3-21","DOIUrl":"https://doi.org/10.1186/2045-5380-3-21","url":null,"abstract":"<p><strong>Background: </strong>Early adverse experiences, especially those involving disruption of the mother-infant relationship, are detrimental for proper socioemotional development in primates. Humans with histories of childhood maltreatment are at high risk for developing psychopathologies including depression, anxiety, substance abuse, and behavioral disorders. However, the underlying neurodevelopmental alterations are not well understood. Here we used a nonhuman primate animal model of infant maltreatment to study the long-term effects of this early life stress on brain white matter integrity during adolescence, its behavioral correlates, and the relationship with early levels of stress hormones.</p><p><strong>Methods: </strong>Diffusion tensor imaging and tract based spatial statistics were used to investigate white matter integrity in 9 maltreated and 10 control animals during adolescence. Basal plasma cortisol levels collected at one month of age (when abuse rates were highest) were correlated with white matter integrity in regions with group differences. Total aggression was also measured and correlated with white matter integrity.</p><p><strong>Results: </strong>We found significant reductions in white matter structural integrity (measured as fractional anisotropy) in the corpus callosum, occipital white matter, external medullary lamina, as well as in the brainstem of adolescent rhesus monkeys that experienced maternal infant maltreatment. In most regions showing fractional anisotropy reductions, opposite effects were detected in radial diffusivity, without changes in axial diffusivity, suggesting that the alterations in tract integrity likely involve reduced myelin. Moreover, in most regions showing reduced white matter integrity, this was associated with elevated plasma cortisol levels early in life, which was significantly higher in maltreated than in control infants. Reduced fractional anisotropy in occipital white matter was also associated with increased social aggression.</p><p><strong>Conclusions: </strong>These findings highlight the long-term impact of infant maltreatment on brain white matter structural integrity, particularly in tracts involved in visual processing, emotional regulation, and somatosensory and motor integration. They also suggest a relationship between elevations in stress hormones detected in maltreated animals during infancy and long-term brain white matter structural effects.</p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"21"},"PeriodicalIF":0.0,"publicationDate":"2013-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-5380-3-21","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31914758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contextual modulation of medial prefrontal cortex to neutral faces in anxious adolescents.","authors":"Tara S Peris, Adriana Galván","doi":"10.1186/2045-5380-3-18","DOIUrl":"10.1186/2045-5380-3-18","url":null,"abstract":"<p><strong>Background: </strong>Although interpretation biases are well documented among youth with anxiety disorders, understanding of their neural correlates is limited. In particular, there has been little study of how anxious youth neurobiologically represent changing contextual cues that may trigger anxiety. This study examined neural responses during a task in which participants viewed neutral faces paired with experimentally manipulated contextual stimuli.</p><p><strong>Methods: </strong>Participants (16 youth with a primary anxiety disorder diagnosis and 15 age- and gender-matched controls) passively viewed neutral faces that were paired with either neutral descriptive vignettes or with vignettes that were potentially anxiety provoking (for example, those that involved performance/social evaluation).</p><p><strong>Results: </strong>The two groups were differentiated by their medial prefrontal cortex (mPFC) responses, such that context modulated mPFC activation in anxious youth while non-anxious youth demonstrated no such differentiation. Counter to expectations, the performance/evaluation frames were not associated with amygdala reactivity for either group.</p><p><strong>Conclusions: </strong>The present investigation is among the first to identify how context modulates mPFC responding to neutral stimuli among anxious youth. It takes an important step toward understanding the neurobiological correlates underlying interpretation biases of neutral stimuli in this population.</p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"18"},"PeriodicalIF":0.0,"publicationDate":"2013-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31863239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emotion regulation in social anxiety disorder: behavioral and neural responses to three socio-emotional tasks.","authors":"Michal Ziv,&nbsp;Philippe R Goldin,&nbsp;Hooria Jazaieri,&nbsp;Kevin S Hahn,&nbsp;James J Gross","doi":"10.1186/2045-5380-3-20","DOIUrl":"https://doi.org/10.1186/2045-5380-3-20","url":null,"abstract":"<p><strong>Background: </strong>Social anxiety disorder (SAD) is thought to involve deficits in emotion regulation, and more specifically, deficits in cognitive reappraisal. However, evidence for such deficits is mixed.</p><p><strong>Methods: </strong>Using functional magnetic resonance imaging (fMRI) of blood oxygen-level dependent (BOLD) signal, we examined reappraisal-related behavioral and neural responses in 27 participants with generalized SAD and 27 healthy controls (HC) during three socio-emotional tasks: (1) looming harsh faces (Faces); (2) videotaped actors delivering social criticism (Criticism); and (3) written autobiographical negative self-beliefs (Beliefs).</p><p><strong>Results: </strong>Behaviorally, compared to HC, participants with SAD had lesser reappraisal-related reduction in negative emotion in the Beliefs task. Neurally, compared to HC, participants with SAD had lesser BOLD responses in reappraisal-related brain regions when reappraising faces, in visual and attention related regions when reappraising criticism, and in the left superior temporal gyrus when reappraising beliefs. Examination of the temporal dynamics of BOLD responses revealed late reappraisal-related increased responses in HC, compared to SAD. In addition, the dorsomedial prefrontal cortex (DMPFC), which showed reappraisal-related increased activity in both groups, had similar temporal dynamics in SAD and HC during the Faces and Criticism tasks, but greater late response increases in HC, compared to SAD, during the Beliefs task. Reappraisal-related greater late DMPFC responses were associated with greater percent reduction in negative emotion ratings in SAD patients.</p><p><strong>Conclusions: </strong>These results suggest a dysfunction of cognitive reappraisal in SAD patients, with overall reduced late brain responses in prefrontal regions, particularly when reappraising faces. Decreased late activity in the DMPFC might be associated with deficient reappraisal and greater negative reactivity.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT00380731.</p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"20"},"PeriodicalIF":0.0,"publicationDate":"2013-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-5380-3-20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32107364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational evidence for the involvement of the endocannabinoid system in stress-related psychiatric illnesses.","authors":"Matthew N Hill,&nbsp;Sachin Patel","doi":"10.1186/2045-5380-3-19","DOIUrl":"https://doi.org/10.1186/2045-5380-3-19","url":null,"abstract":"<p><p>Accumulating evidence over the past decade has highlighted an important role of the endocannabinoid (eCB) system in the regulation of stress and emotional behavior across divergent species, from rodents to humans. The general findings from this work indicate that the eCB system plays an important role in gating and buffering the stress response, dampening anxiety and regulating mood. Work in rodents has allowed researchers to determine the neural mechanisms mediating this relationship while work in human populations has demonstrated the possible importance of this system in stress-related psychiatric diseases, such as post-traumatic stress disorder, generalized anxiety and major depression. These stress-protective effects of eCB signaling appear to be primarily mediated by their actions within corticolimbic structures, particularly the amygdala and the prefrontal cortex. The aim of this review is to provide an up-to-date discussion of the current level of knowledge in this field, as well as address the current gaps in knowledge and specific areas of research that require attention. </p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"19"},"PeriodicalIF":0.0,"publicationDate":"2013-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-5380-3-19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31911333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational neuroscience measures of fear conditioning across development: applications to high-risk children and adolescents.","authors":"Tanja Jovanovic, Karin Maria Nylocks, Kaitlyn L Gamwell","doi":"10.1186/2045-5380-3-17","DOIUrl":"10.1186/2045-5380-3-17","url":null,"abstract":"<p><p>Several mental illnesses, including anxiety, can manifest during development, with onsets in late childhood. Understanding the neurobiological underpinnings of risk for anxiety is of crucial importance for early prevention and intervention approaches. Translational neuroscience offers tools to investigate such mechanisms in human and animal models. The current review describes paradigms derived from neuroscience, such as fear conditioning and extinction and overviews studies that have used these paradigms in animals and humans across development. The review also briefly discusses developmental trajectories of the relevant neural circuits and the emergence of clinical anxiety. Future studies should focus on developmental changes in these paradigms, paying close attention to neurobiological and hormonal changes associated with childhood and adolescence. </p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"17"},"PeriodicalIF":0.0,"publicationDate":"2013-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31706630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual differences in cognitive reappraisal usage modulate the time course of brain activation during symptom provocation in specific phobia.","authors":"Andrea Hermann,&nbsp;Verena Leutgeb,&nbsp;Wilfried Scharmüller,&nbsp;Dieter Vaitl,&nbsp;Anne Schienle,&nbsp;Rudolf Stark","doi":"10.1186/2045-5380-3-16","DOIUrl":"https://doi.org/10.1186/2045-5380-3-16","url":null,"abstract":"<p><strong>Background: </strong>Extinction learning is proposed to be one key mechanism of action underlying exposure-based cognitive-behavioral therapy (CBT) in specific phobia. Beyond that, cognitive reappraisal, one important strategy to regulate negative emotions, is a crucial component of CBT interventions, but has been disregarded in previous studies investigating neural change processes in specific phobia. The aim of this study was to investigate the association of individual differences in habitual/dispositional cognitive reappraisal usage and the time course of brain activation during phobic stimulation in specific phobia.</p><p><strong>Methods: </strong>Dental phobic patients and healthy control subjects participated in a functional magnetic resonance imaging (fMRI) study whilst being confronted with phobic, disgust, fear and neutral pictures. Individual differences in cognitive reappraisal usage were assessed via a self-report questionnaire and correlated with activation decreases over the course of time.</p><p><strong>Results: </strong>Phobic individuals with higher dispositional cognitive reappraisal scores showed a more pronounced activation decline in the right dorsomedial prefrontal cortex (dmPFC) which might be associated with a diminution of explicit cognitive emotion regulation over the course of time. Less decrease of activation in the right ventromedial prefrontal cortex (vmPFC) and the lateral orbitofrontal cortex (lOFC) over time in subjects with higher cognitive reappraisal scores might be related to a stronger automatic regulation of emotions or even emotional relearning. Additionally, phobic subjects compared with healthy controls showed a stronger habituation of the left dmPFC over the course of symptom provocation.</p><p><strong>Conclusions: </strong>The results of this study show for the first time that individual differences in cognitive reappraisal usage are associated with the time course of brain activation during symptom provocation in specific phobia. Additionally, the present study gives first indications for the importance of considering individual differences in cognitive reappraisal usage in the treatment of specific phobia.</p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2013-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-5380-3-16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31650785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroimaging predictors of treatment response in anxiety disorders.","authors":"Lisa M Shin,&nbsp;F Caroline Davis,&nbsp;Michael B Vanelzakker,&nbsp;Mary K Dahlgren,&nbsp;Stacey J Dubois","doi":"10.1186/2045-5380-3-15","DOIUrl":"https://doi.org/10.1186/2045-5380-3-15","url":null,"abstract":"<p><p>Although several psychological and pharmacological treatment options are available for anxiety disorders, not all patients respond well to each option. Furthermore, given the relatively long duration of adequate treatment trials, finding a good treatment fit can take many months or longer. Thus, both clinicians and patients would benefit from the identification of objective pre-treatment measures that predict which patients will best respond to a given treatment. Recent studies have begun to use biological measures to help predict symptomatic change after treatment in anxiety disorders. In this review, we summarize studies that have used structural and functional neuroimaging measures to predict treatment response in obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD). We note the limitations of the current studies and offer suggestions for future research. Although the literature is currently small, we conclude that pre-treatment neuroimaging measures do appear to predict treatment response in anxiety disorders, and future research will be needed to determine the relative predictive power of neuroimaging measures as compared to clinical and demographic measures. </p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 1","pages":"15"},"PeriodicalIF":0.0,"publicationDate":"2013-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-5380-3-15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31632914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroimaging studies of pediatric social anxiety: paradigms, pitfalls and a new direction for investigating the neural mechanisms.","authors":"Johanna M Jarcho, Ellen Leibenluft, Olga Lydia Walker, Nathan A Fox, Daniel S Pine, Eric E Nelson","doi":"10.1186/2045-5380-3-14","DOIUrl":"10.1186/2045-5380-3-14","url":null,"abstract":"<p><p>Social Anxiety Disorder (SAD) is a common and debilitating condition that typically manifests in adolescence. Here we describe cognitive factors engaged by brain-imaging tasks, which model the peer-based social interactions that evoke symptoms of SAD. We then present preliminary results from the Virtual School paradigm, a novel peer-based social interaction task. This paradigm is designed to investigate the neural mechanisms mediating individual differences in social response flexibility and in participants' responses to uncertainty in social contexts. We discuss the utility of this new paradigm for research on brain function and developmental psychopathology. </p>","PeriodicalId":89532,"journal":{"name":"Biology of mood & anxiety disorders","volume":"3 ","pages":"14"},"PeriodicalIF":0.0,"publicationDate":"2013-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31577064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}