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1.  Insula–amygdala functional connectivity is correlated with habituation to repeated negative images 
Behavioral habituation during repeated exposure to aversive stimuli is an adaptive process. However, the way in which changes in self-reported emotional experience are related to the neural mechanisms supporting habituation remains unclear. We probed these mechanisms by repeatedly presenting negative images to healthy adult participants and recording behavioral and neural responses using functional magnetic resonance imaging. We were particularly interested in investigating patterns of activity in insula, given its significant role in affective integration, and in amygdala, given its association with appraisal of aversive stimuli and its frequent coactivation with insula. We found significant habituation behaviorally along with decreases in amygdala, occipital cortex and ventral prefrontal cortex (PFC) activity with repeated presentation, whereas bilateral posterior insula, dorsolateral PFC and precuneus showed increased activation. Posterior insula activation during image presentation was correlated with greater negative affect ratings for novel presentations of negative images. Further, repeated negative image presentation was associated with increased functional connectivity between left posterior insula and amygdala, and increasing insula–amygdala functional connectivity was correlated with increasing behavioral habituation. These results suggest that habituation is subserved in part by insula–amygdala connectivity and involves a change in the activity of bottom-up affective networks.
PMCID: PMC4221205  PMID: 24170933
habituation; emotion; functional connectivity; insula; amygdala
2.  The Neural Correlates of Anomalous Habituation to Negative Emotional Pictures in Borderline and Avoidant Personality Disorder Patients 
Extreme emotional reactivity is a defining feature of borderline personality disorder, yet the neural-behavioral mechanisms underlying this affective instability are poorly understood. One possible contributor would be diminished ability to engage the mechanism of emotional habituation. We tested this hypothesis by examining behavioral and neural correlates of habituation in borderline patients, healthy controls, and a psychopathological control group of avoidant personality disorder patients.
During fMRI scan acquisition, borderline patients, healthy controls and avoidant personality disorder patients viewed novel and repeated pictures, providing valence ratings at each presentation. Statistical parametric maps of the contrasts of activation during repeat versus novel negative picture viewing were compared between groups. Psychophysiological interaction analysis was employed to examine functional connectivity differences between groups.
Unlike healthy controls, neither borderline nor avoidant personality disorder participants showed increased activity in dorsal anterior cingulate cortex when viewing repeat versus novel pictures. This failure to increase dorsal anterior cingulate activity was associated with greater affective instability in borderline participants. In addition, borderline and avoidant participants showed smaller insula-amygdala connectivity increases than healthy participants and did not show habituation in ratings of the emotional intensity of the images as did healthy participants. Borderline patients differed from avoidant patients in insula-ventral anterior cingulate connectivity during habituation.
Borderline patients fail to habituate to negative pictures as do healthy participants and differ from both healthy controls and avoidant patients in neural activity during habituation. A failure to effectively engage emotional habituation processes may contribute to affective instability in borderline patients.
PMCID: PMC3947284  PMID: 24275960
borderline personality disorder; avoidant personality disorder; affective instability; fMRI; functional connectivity
3.  White Matter Abnormalities in Schizophrenia and Schizotypal Personality Disorder 
Schizophrenia Bulletin  2014;41(1):300-310.
Prior diffusion tensor imaging (DTI) studies examining schizotypal personality disorder (SPD) and schizophrenia, separately have shown that compared with healthy controls (HCs), patients show frontotemporal white matter (WM) abnormalities. This is the first DTI study to directly compare WM tract coherence with tractography and fractional anisotropy (FA) across the schizophrenia spectrum in a large sample of demographically matched HCs (n = 55), medication-naive SPD patients (n = 49), and unmedicated/never-medicated schizophrenia patients (n = 22) to determine whether (a) frontal-striatal-temporal WM tract abnormalities in schizophrenia are similar to, or distinct from those observed in SPD; and (b) WM tract abnormalities are associated with clinical symptom severity indicating a common underlying pathology across the spectrum. Compared with both the HC and SPD groups, schizophrenia patients showed WM abnormalities, as indexed by lower FA in the temporal lobe (inferior longitudinal fasciculus) and cingulum regions. SPD patients showed lower FA in the corpus callosum genu compared with the HC group, but this regional abnormality was more widespread in schizophrenia patients. Across the schizophrenia spectrum, greater WM disruptions were associated with greater symptom severity. Overall, frontal-striatal-temporal WM dysconnectivity is attenuated in SPD compared with schizophrenia patients and may mitigate the emergence of psychosis.
PMCID: PMC4266294  PMID: 24962608
DTI; MRI; schizotypal personality disorder; schizophrenia; psychosis; white matter; genu; cingulum; inferior longitudinal fasciculus
4.  Neural Correlates of Using Distancing to Regulate Emotional Responses to Social Situations 
Neuropsychologia  2010;48(6):1813-1822.
Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one’s self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.
PMCID: PMC2905649  PMID: 20226799
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Emotional Distancing; Emotion Regulation; fMRI
5.  Neural Correlates of the Use of Psychological Distancing to Regulate Responses to Negative Social Cues: A Study of Patients with Borderline Personality Disorder 
Biological psychiatry  2009;66(9):854.
Emotional instability is a defining feature of borderline personality disorder (BPD), yet little is understood about its underlying neural correlates. One possible contributing factor to emotional instability is a failure to adequately employ adaptive cognitive regulatory strategies such as psychological distancing.
To determine whether there are differences in neural dynamics underlying this control strategy, between BPD patients and healthy volunteers (HC’s), BOLD fMRI signals were acquired as 18 BPD and 16 HC subjects distanced from or simply looked at negative and neutral pictures depicting social interactions. Contrasts in signal between distance and look condition were compared between groups to identify commonalities and differences in regional activation.
BPD patients show a different pattern of activation compared to HC subjects when looking at negative vs. neutral pictures. When distancing vs. looking at negative pictures, both groups showed decreased negative affect in rating and increased activation of the dorsolateral prefrontal cortex, areas near/along the intraparietal sulcus (IPS), ventrolateral prefrontal cortex and posterior cingulate/precuneus regions. However, the BPD group showed less BOLD signal change in dorsal anterior cingulate cortex and IPS, less deactivation in the amygdala and greater activation in the superior temporal sulcus and superior frontal gyrus.
BPD and HC subjects display different neural dynamics while passively viewing social emotional stimuli. In addition, BPD patients do not engage the cognitive control regions to the extent that HC’s do when employing a distancing strategy to regulate emotional reactions, which may be a factor contributing to the affective instability of BPD.
PMCID: PMC2821188  PMID: 19651401
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Psychological Distancing; Emotion Regulation; fMRI
7.  Neural Correlates of Emotion Processing in Borderline Personality Disorder 
Psychiatry research  2009;172(3):192-199.
Emotional instability is a hallmark feature of borderline personality disorder (BPD), yet its biological underpinnings are poorly understood. We employed functional MRI to compare patterns of regional brain activation in BPD patients and healthy volunteers as they process positive and negative social emotional stimuli. fMRI images were acquired while 19 BPD patients and 17 healthy controls (HC) viewed emotion-inducing pictures from the IAPS set. Activation data were analyzed with SPM5 ANCOVA models to derive the effects of diagnosis and stimulus type. BPD patients demonstrated greater differences in activation than controls, when viewing negative pictures compared to rest, in the amygdala, fusiform gyrus, primary visual areas, superior temporal gyrus (STG), and premotor areas, while healthy controls showed greater differences than BPD’s in the insula, middle temporal gyrus and dorsolateral prefrontal cortex (BA46). When viewing positive pictures compared to rest, BPD patients showed greater differences in the STG, premotor cortex, and ventrolateral prefrontal cortex. These findings suggest that BPD patients show greater amygdala activity and heightened activity of visual processing regions than HC’s, when processing negative social emotional pictures compared to rest. They activate neural networks in emotion processing that are phylogenetically older and more reflexive than healthy controls.
PMCID: PMC4153735  PMID: 19394205
Affective Instability; Emotion; fMRI; Social-Emotional Cues; Borderline Personality Disorder
8.  Platelet protein kinase C and brain-derived neurotrophic factor levels in borderline personality disorder patients 
Psychiatry research  2012;199(2):92-97.
Borderline personality disorder (BPD) is a prevalent and difficult to treat psychiatric condition characterized by abrupt mood swings, intense anger and depression, unstable interpersonal relationships, impulsive self-destructive behavior and a suicide rate of approximately 10%. Possible underlying molecular dysregulations in BPD have not been well explored. Protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) have both been implicated in affective disorders, but their role in BPD has not been examined. Platelets were isolated from blood obtained from 24 medication-free BPD patients and 18 healthy control subjects. PKC-α, phosphorylated-PKC-α (p-PKCα), PKC-β II, and BDNF were measured in platelet homogenates by immunoblotting. In the males, platelet BDNF and PKC-α levels were lower in patients than controls. p-PKC-α and PKC-βII were lower at trend levels. In the entire sample, platelet p-PKC α and PKC-α activity were lower, at a trend level, in patients compared to controls. This is the first report to our knowledge of PKC and BDNF activity in BPD and calls for replication. These findings are consistent with altered PKC and BDNF activity in a range of neuropsychiatric conditions including bipolar disorder, depression and suicide.
PMCID: PMC4128317  PMID: 22633012
PKC; BDNF; Neurotrophic Factors; Second Messengers; Personality Disorders; Borderline Personality Disorder
9.  Anterior limb of the internal capsule in schizotypal personality disorder: Fiber-tract counting, volume, and anisotropy 
Schizophrenia research  2012;141(0):119-127.
Mounting evidence suggests that white matter abnormalities and altered subcortical–cortical connectivity may be central to the pathology of schizophrenia (SZ). The anterior limb of the internal capsule (ALIC) is an important thalamo-frontal white-matter tract shown to have volume reductions in SZ and to a lesser degree in schizotypal personality disorder (SPD). While fractional anisotropy (FA) and connectivity abnormalities in the ALIC have been reported in SZ, they have not been examined in SPD. In the current study, magnetic resonance (MRI) and diffusion tensor imaging (DTI) were obtained in age- and sex-matched individuals with SPD (n=33) and healthy controls (HCs; n=38). The ALIC was traced bilaterally on five equally spaced dorsal-to-ventral axial slices from each participant’s MRI scan and co-registered to DTI for the calculation of FA. Tractography was used to examine tracts between the ALIC and two key Brodmann areas (BAs; BA10, BA45) within the dorsolateral prefrontal cortex (DLPFC). Compared with HCs, the SPD participants exhibited (a) smaller relative volume at the mid-ventral ALIC slice level but not the other levels; (b) normal FA within the ALIC; (c) fewer relative number of tracts between the most-dorsal ALIC levels and BA10 but not BA45 and (d) fewer dorsal ALIC–DLPFC tracts were associated with greater symptom severity in SPD. In contrast to prior SZ studies that report lower FA, individuals with SPD show sparing. Our findings are consistent with a pattern of milder thalamo-frontal dysconnectivity in SPD than schizophrenia.
PMCID: PMC3742803  PMID: 22995934
Schizotypal personality disorder; Diffusion tensor imaging; Tractography; Magnetic resonance imaging; Anisotropy; Internal capsule
10.  Striatal Activity in Borderline Personality Disorder with Comorbid Intermittent Explosive Disorder: Sex Differences 
Journal of psychiatric research  2012;46(6):797-804.
Borderline Personality Disorder (BPD) is associated with behavioral and emotional dysregulation, particularly in social contexts; however, the underlying pathophysiology at the level of brain function is not well understood. Previous studies found abnormalities in frontal cortical and limbic areas suggestive of poor frontal regulation of downstream brain regions. However, the striatum, which is closely connected with the medial frontal cortices and plays an important role in motivated behaviors and processing of rewarding stimuli, has been understudied in BPD. Here we hypothesized that, in addition to frontal dysfunction, BPD patients may show abnormal striatal function. In this study, 38 BPD patients with intermittent explosive disorder (BPD-IED) and 36 healthy controls (HC) participated in the Point Subtraction Aggression Paradigm (PSAP), a computer game played with a fictitious other player. 18Fluoro-deoxyglucose positron emission tomography (FDG-PET) measured relative glucose metabolism (rGMR) within caudate and putamen in response to aggression-provoking and non-provoking versions of the PSAP. Male BPD-IED patients had significantly lower striatal rGMR than all other groups during both conditions, although male and female BPD-IED patients did not differ in clinical or behavioral measures. These sex differences suggest differential involvement of frontal-striatal circuits in BPD-IED, and are discussed in relation to striatal involvement in affective learning and social decision-making.
PMCID: PMC3645307  PMID: 22464337
Borderline personality disorder; intermittent explosive disorder; striatum; aggression; positron emission tomography
11.  Dorso- and Ventro-lateral Prefrontal Volume and Spatial Working Memory in Schizotypal Personality Disorder 
Behavioural brain research  2010;218(2):335-340.
Schizotypal personality disorder (SPD) individuals and borderline personality disorder (BPD) individuals have been reported to show neuropsychological impairments and abnormalities in brain structure. However, relationships between neuropsychological function and brain structure in these groups are not well understood. This study compared visual-spatial working memory (SWM) and its associations with dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) gray matter volume in 18 unmedicated SPD patients with no BPD traits, 18 unmedicated BPD patients with no SPD traits, and 16 healthy controls (HC). Results showed impaired SWM in SPD but not BPD, compared with HC. Moreover, among the HC group, but not SPD patients, better SWM performance was associated with larger VLPFC (BA44/45) gray matter volume (Fisher's Z p-values<0.05). Findings suggest spatial working memory impairments may be a core neuropsychological deficit specific to SPD patients and highlight the role of VLPFC subcomponents in normal and dysfunctional memory performance.
PMCID: PMC3049905  PMID: 21115066
working memory; borderline personality disorder; schizotypal personality disorder; dorsolateral prefrontal cortex; ventrolateral prefrontal cortex; MRI
12.  Cingulate and Temporal Lobe Fractional Anisotropy in Schizotypal Personality Disorder 
Neuroimage  2011;55(3):900-908.
Consistent with the clinical picture of milder symptomatology in schizotypal personality disorder (SPD) than schizophrenia, morphological studies indicate SPD abnormalities in temporal lobe regions but to a much lesser extent in prefrontal regions implicated in schizophrenia. Lower fractional anisotropy (FA), a measure of white-matter integrity within prefrontal, temporal, and cingulate regions has been reported in schizophrenia but has been little studied in SPD.
To examine temporal and prefrontal FA in 30 neuroleptic-naïve SPD patients and 35 matched healthy controls. We hypothesized that compared with healthy controls (HCs), SPD patients would exhibit lower FA in temporal and anterior cingulum regions but relative sparing in prefrontal regions.
We acquired diffusion tensor imaging (DTI) in all participants and examined FA in the white matter underlying Brodmann areas (BAs) in dorsolateral prefrontal (BA44,45,46), temporal (BA22,21,20), and cingulum (BA25,24,31,23,29) regions using multivariate-ANOVAs.
Compared with healthy controls, the SPD group had significantly lower FA in left temporal but not prefrontal regions. In the cingulum, FA was lower in the SPD group in posterior regions (BA31 and 23), higher in anterior (BA25) regions and lower overall in the right but not left cingulum. Among the SPD group, lower FA in the cingulum was associated with more severe negative symptoms (e.g., odd speech).
Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms.
PMCID: PMC3262398  PMID: 21223999
Diffusion tensor imaging; schizotypal personality disorder; dorsolateral prefrontal cortex; temporal lobe; cingulum; fractional anisotropy
13.  Tryptophan Hydroxylase 2 haplotype association with borderline personality disorder and aggression in a sample of patients with personality disorders and healthy controls 
Journal of psychiatric research  2010;44(15):1075-1081.
There is decreased serotonergic function in impulsive aggression and borderline personality disorder (BPD), and genetic association studies suggest a role of serotonergic genes in impulsive aggression and BPD. Only one study has analyzed the association between the tryptophan-hydroxylase 2 (TPH2) gene and BPD. A TPH2 “risk” haplotype has been described that is associated with anxiety, depression and suicidal behavior.
We assessed the relationship between the previously identified “risk” haplotype at the TPH2 locus and BPD diagnosis, impulsive aggression, affective lability, and suicidal/parasuicidal behaviors, in a well-characterized clinical sample of 103 healthy controls (HCs) and 251 patients with personality disorders (109 with BPD). A logistic regression including measures of depression, affective lability and aggression scores in predicting “risk” haplotype was conducted.
The prevalence of the “risk” haplotype was significantly higher in patients with BPD compared to HCs. Those with the “risk” haplotype have higher aggression and affect lability scores and more suicidal/parasuicidal behaviors than those without it. In the logistic regression model, affect lability was the only significant predictor and it correctly classified 83.1% of the subjects as “risk” or “non-risk” haplotype carriers.
We found an association between the previously described TPH2 “risk” haplotype and BPD diagnosis, affective lability, suicidal/parasuicidal behavior, and aggression scores.
PMCID: PMC2955771  PMID: 20451217
Borderline personality disorder; TPH2; suicidal behavior; affective instability; impulsive aggression
14.  Pergolide Treatment of Cognitive Deficits Associated with Schizotypal Personality Disorder: Continued Evidence of the Importance of the Dopamine System in the Schizophrenia Spectrum 
Neuropsychopharmacology  2010;35(6):1356-1362.
Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD). Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders. In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D1 and D2 receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance. We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory. These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.
PMCID: PMC3055340  PMID: 20130535
schizotypal personality; schizotypy; schizophrenia spectrum; cognition; pergolide; dopamine; Schizophrenia/Antipsychotics; Dopamine; Cognition; Clinical Pharmacology/Trials; schizotypal personality; pergolide
15.  Laboratory Induced Aggression: A PET Study of Aggressive Individuals with Borderline Personality Disorder 
Biological psychiatry  2009;66(12):1107-1114.
Borderline personality disorder (BPD) is often associated with symptoms of impulsive aggression, which pose a threat to patients themselves and to others. Preclinical studies show that orbital frontal cortex (OFC) plays a role in regulating impulsive aggression. Prior work has found OFC dysfunction in BPD.
We employed a task to provoke aggressive behavior, the Point Subtraction Aggression Paradigm (PSAP), which has never previously been used during functional brain imaging. Thirty-eight BPD patients with impulsive aggression (BPD-IED) and 36 age-matched healthy controls (HC) received 18FDG-PET on two occasions with a provocation and non-provocation version of the PSAP. For each participant, we measured mean relative glucose metabolism in cortical Brodmann areas (BAs) in each hemisphere; difference scores (Provoked–Non-provoked) were calculated. A whole brain exploratory analysis for the double difference of BPD-IED–HC for Provoked–Non-provoked was also conducted.
BPD-IED patients were significantly more aggressive than HC on the PSAP. BPD-IED patients also increased relative glucose metabolic rate (rGMR) in OFC and amygdala when provoked, while HC decreased rGMR in these areas. However, HC increased rGMR in anterior, medial, and dorsolateral prefrontal regions during provocation more than BPD-IED patients.
Patients responded aggressively and showed heightened rGMR in emotional brain areas, including amygdala and OFC in response to provocation, but not in more dorsal brain regions associated with cognitive control of aggression. In contrast, HC increased rGMR in dorsal regions of PFC during aggression provocation, brain regions involved in top-down cognitive control of aggression and, more broadly, of emotion.
PMCID: PMC2788117  PMID: 19748078
brain imaging; Point Subtraction Aggression Paradigm; PSAP; emotion
16.  Evaluation of behavioral impulsivity and aggression tasks as endophenotypes for borderline personality disorder 
Journal of psychiatric research  2009;43(12):1036-1048.
Borderline personality disorder (BPD) is marked by aggression and impulsive, often self-destructive behavior. Despite the severe risks associated with BPD, relatively little is known about the disorder’s etiology. Identification of genetic correlates (endophenotypes) of BPD would improve the prospects of targeted interventions for more homogeneous subsets of borderline patients characterized by specific genetic vulnerabilities. The current study evaluated behavioral measures of aggression and impulsivity as potential endophenotypes for BPD. Subjects with BPD (N = 127), a non cluster B personality disorder (OPD N = 122), or healthy volunteers (HV N = 112) completed self report and behavioral measures of aggression, motor impulsivity and cognitive impulsivity. Results showed that BPD subjects demonstrated more aggression and motor impulsivity than HV (but not OPD) subjects on behavioral tasks. In contrast, BPD subjects self-reported more impulsivity and aggression than either comparison group. Subsequent analyses showed that among BPD subjects behavioral aggression was associated with self-reported aggression, while behavioral and self-report impulsivity measures were more modestly associated. Overall, the results provide partial support for the use of behavioral measures of aggression and motor impulsivity as endophenotypes for BPD, with stronger support for behavioral aggression measures as an endophenotype for aggression within BPD samples.
PMCID: PMC2853811  PMID: 19232640
Borderline personality disorder; Endophenotype; Aggression; Impulsivity
17.  Predictors of Dropout in Psychodynamic Psychotherapy of Borderline Personality Disorder 
This study aimed to identify patient factors that predict early dropout from psychodynamic psychotherapy for borderline personality disorder (BPD). Thirty-six BPD patients began an open-ended course of twice per week psychodynamic psychotherapy that was defined in a treatment manual and supervised. Dropout rates were 31% and 36% at 3 and 6 months of therapy, respectively. Survival analysis techniques demonstrated that age and hostility ratings predicted early dropout, with continuers more likely to be older and expressing lower levels of hostility than dropouts. Many variables hypothesized to predict dropout failed to do so. Both the positive and negative findings are discussed relative to the literature.
PMCID: PMC3330395  PMID: 22700251
18.  The Combination of Psychotherapy and Pharmacotherapy in the Treatment of Borderline Patients 
The combination of psychotherapy and pharmacotherapy may offer some borderline patients a more effective treatment than either modality alone. The author reviews evidence from recent studies demonstrating the strengths and weaknesses of each modality separately; discusses the indications and contraindications for combined treatment; considers the special complications introduced in conducting such a combined treatment with borderline patients; and presents some strategies for addressing these complications.
PMCID: PMC3330364  PMID: 22700184
19.  A Method for Analyzing Therapist Interventions in the Psychotherapy of Borderline Patients 
The authors developed a method for studying the therapist’s use of technique in responding to specific patient themes during treatment of patients with borderline personality disorder. This method can monitor the use of expressive and supportive techniques as well as the congruence between patients’ theme categories and the direction of the therapist’s interventions. The method was developed to monitor adherence to an operationally defined treatment approach for psychodynamic psychotherapy of borderline patients. Data are presented on interrater agreement obtained with this method and on its application to 12 psychotherapy sessions.
PMCID: PMC3330333  PMID: 22700136

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