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1.  Levels-of-processing effect on internal source monitoring in schizophrenia 
Psychological medicine  2006;36(5):641-648.
Recognition can be normalized in schizophrenia by providing patients with semantic organizational strategies through a levels-of-processing (LOP) framework. However, patients may rely primarily on familiarity effects, making recognition less sensitive than source monitoring to the strength of the episodic memory trace. The current study investigates whether providing semantic organizational strategies can also normalize patients’ internal source-monitoring performance.
Sixteen clinically stable medicated patients with schizophrenia and 15 demographically matched healthy controls were asked to identify the source of remembered words following an LOP-encoding paradigm in which they alternated between processing words on a ‘shallow’ perceptual versus a ‘deep’ semantic level. A multinomial analysis provided orthogonal measures of item recognition and source discrimination, and bootstrapping generated variance to allow for parametric analyses. LOP and group effects were tested by contrasting recognition and source-monitoring parameters for words that had been encoded during deep versus shallow processing conditions.
As in a previous study there were no group differences in LOP effects on recognition performance, with patients and controls benefiting equally from deep versus shallow processing. Although there were no group differences in internal source monitoring, only controls had significantly better performance for words processed during the deep encoding condition. Patient performance did not correlate with clinical symptoms or medication dose.
Providing a deep processing semantic encoding strategy significantly improved patients’ recognition performance only. The lack of a significant LOP effect on internal source monitoring in patients may reffect subtle problems in the relational binding of semantic information that are independent of strategic memory processes.
PMCID: PMC4332577  PMID: 16608558
2.  Effect of Schizophrenia on Frontotemporal Activity During Word Encoding and Recognition: A PET Cerebral Blood Flow Study 
The American journal of psychiatry  2001;158(7):1114-1125.
Neuropsychological studies have shown that deficits in verbal episodic memory in schizophrenia occur primarily during encoding and retrieval stages of information processing. The current study used positron emission tomography to examine the effect of schizophrenia on change in cerebral blood flow (CBF) during these memory stages.
CBF was measured in 23 healthy comparison subjects and 23 patients with schizophrenia during four conditions: resting baseline, motor baseline, word encoding, and word recognition. The motor baseline was used as a reference that was subtracted from encoding and recognition conditions by using statistical parametric mapping.
Patients’ performance was similar to that of healthy comparison subjects. During word encoding, patients showed reduced activation of left prefrontal and superior temporal regions. Reduced left prefrontal activation in patients was also seen during word recognition, and additional differences were found in the left anterior cingulate, left mesial temporal lobe, and right thalamus. Although patients’ performance was similar to that of healthy comparison subjects, left inferior prefrontal activation was associated with better performance only in the comparison subjects.
Left frontotemporal activation during episodic encoding and retrieval, which is associated with better recognition in healthy people, is disrupted in schizophrenia despite relatively intact recognition performance and right prefrontal function. This may reflect impaired strategic use of semantic information to organize encoding and facilitate retrieval.
PMCID: PMC4332582  PMID: 11431234
3.  Levels-of-Processing Effect on Frontotemporal Function in Schizophrenia During Word Encoding and Recognition 
The American journal of psychiatry  2005;162(10):1840-1848.
Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function.
Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects.
Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response.
Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.
PMCID: PMC4332803  PMID: 16199830
4.  Event-Related fMRI of Frontotemporal Activity During Word Encoding and Recognition in Schizophrenia 
The American journal of psychiatry  2004;161(6):1004-1015.
Neuropsychological studies have demonstrated verbal episodic memory deficits in schizophrenia during word encoding and retrieval. This study examined neural substrates of memory in an analysis that controlled for successful retrieval.
Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation during word encoding and recognition in 14 patients with schizophrenia and 15 healthy comparison subjects. An unbiased multiple linear regression procedure was used to model the BOLD response, and task effects were detected by contrasting the signal before and after stimulus onset.
Patients attended during encoding and had unimpaired reaction times and normal response biases during recognition, but they had lower recognition discriminability scores, compared with the healthy subjects. Analysis of contrasts was restricted to correct items. Previous findings of a deficit in bilateral prefrontal cortex activation during encoding in patients were reproduced, but patients showed greater parahippocampal activation rather than deficits in temporal lobe activation. During recognition, left dorsolateral pre-frontal cortex activation was lower in the patients and right anterior prefrontal cortex activation was preserved, as in the authors’ previous study using positron emission tomography. Successful retrieval was associated with greater right dorsolateral prefrontal cortex activation in the comparison subjects, whereas orbitofrontal, superior frontal, mesial temporal, middle temporal, and inferior parietal regions were more active in the patients during successful retrieval.
The pattern of prefrontal cortex underactivation and parahippocampal overactivation in the patients suggests that functional connectivity of dorsolateral prefrontal and temporal-limbic structures is disrupted by schizophrenia. This disruption may be reflected in the memory strategies of patients with schizophrenia, which include reliance on rote rehearsal rather than associative semantic processing.
PMCID: PMC4332807  PMID: 15169688
5.  Meta-Analysis of Olfactory Function in Schizophrenia, First-Degree Family Members, and Youths At-Risk for Psychosis 
Schizophrenia Bulletin  2013;40(1):50-59.
Previous research has provided compelling support for olfactory dysfunction in schizophrenia patients, their first-degree relatives, and youth at-risk for psychosis. A previous meta-analysis revealed large effect sizes across olfactory tasks but was limited to 2 olfactory tasks and did not examine moderator variables. Thus, the current meta-analysis was undertaken to incorporate additional studies, risk cohorts, olfactory test domains, and moderator variable analyses.
A meta-analysis was conducted on 67 publications examining olfactory function in schizophrenia patients and 15 publications examining olfactory functioning in youth at-risk for psychosis, first-degree relatives of schizophrenia patients, and individuals with schizotypy.
Results revealed medium-to-large olfactory deficits in schizophrenia patients though significant heterogeneity was evident. Several variables moderated overall study effects. At-risk youths similarly demonstrated medium-to-large effect sizes, whereas first-degree relatives and individuals with schizotypy showed small effects.
Findings suggest robust olfactory deficits in schizophrenia and at-risk youths. In schizophrenia, several variables had significant impact on these deficits and warrant consideration in prospective studies. Our findings also indicate that olfactory measures may be a useful marker of schizophrenia risk status.
PMCID: PMC3885295  PMID: 23641047
schizophrenia prodrome; smell; olfaction; schizotypy; psychosis
6.  Association of enhanced limbic response to threat with decreased cortical facial recognition memory response in schizophrenia 
The American journal of psychiatry  2010;167(4):418-426.
Recognition memory of faces is impaired in patients with schizophrenia, as is the neural processing of threat-related signals, but how these deficits interact to produce symptoms is unclear. Here we used an affective face recognition paradigm to examine possible interactions between cognitive and affective neural systems in schizophrenia.
fMRI (3T) BOLD response was examined in 21 controls and 16 patients during a two-choice recognition task using images of human faces. Each target face had previously been displayed with a threatening or non-threatening affect, but here were displayed with neutral affect. Responses to successful recognition and for the effect of previously threatening vs. non-threatening affect were evaluated, and correlations with total BPRS examined. Functional connectivity analyses examined the relationship between activation in the amygdala and cortical regions involved in recognition memory.
Patients performed the task more slowly than controls. Controls recruited the expected cortical regions to a greater degree than patients, and patients with more severe symptoms demonstrated proportionally less recruitment. Increased symptoms were also correlated with augmented amygdala and orbitofrontal cortex response to threatening faces. Controls exhibited a negative correlation between activity in the amygdala and cortical regions involved in cognition, while patients showed a weakening of that relationship.
Increased symptoms were related to an enhanced threat response in limbic regions and a diminished recognition memory response in cortical regions, supporting a link between two brain systems often examined in isolation. This finding suggests that abnormal processing of threat-related signals in the environment may exacerbate cognitive impairment in schizophrenia.
PMCID: PMC4243460  PMID: 20194482
7.  More than Just Two Sexes: The Neural Correlates of Voice Gender Perception in Gender Dysphoria 
PLoS ONE  2014;9(11):e111672.
Gender dysphoria (also known as “transsexualism”) is characterized as a discrepancy between anatomical sex and gender identity. Research points towards neurobiological influences. Due to the sexually dimorphic characteristics of the human voice, voice gender perception provides a biologically relevant function, e.g. in the context of mating selection. There is evidence for a better recognition of voices of the opposite sex and a differentiation of the sexes in its underlying functional cerebral correlates, namely the prefrontal and middle temporal areas. This fMRI study investigated the neural correlates of voice gender perception in 32 male-to-female gender dysphoric individuals (MtFs) compared to 20 non-gender dysphoric men and 19 non-gender dysphoric women. Participants indicated the sex of 240 voice stimuli modified in semitone steps in the direction to the other gender. Compared to men and women, MtFs showed differences in a neural network including the medial prefrontal gyrus, the insula, and the precuneus when responding to male vs. female voices. With increased voice morphing men recruited more prefrontal areas compared to women and MtFs, while MtFs revealed a pattern more similar to women. On a behavioral and neuronal level, our results support the feeling of MtFs reporting they cannot identify with their assigned sex.
PMCID: PMC4222943  PMID: 25375171
8.  The Effect of Odor Valence on Olfactory Performance in Schizophrenia Patients, Unaffected Relatives and At-Risk Youth 
Journal of psychiatric research  2013;47(11):1636-1641.
Given the presence of odor identification impairment in individuals with schizophrenia and recent evidence of aberrant odor hedonic processing, the aim of this investigation was to examine the influence of valence and intensity on odor identification in schizophrenia patients, their first-degree family members, and young persons at clinical risk for psychosis. Participants completed the 16-item Sniffin’ Stick Odor Identification Test. A logistic regression was conducted to assess the influence of valence and intensity on odor identification accuracy. Identification performance in the schizophrenia patients and youths at clinical risk for psychosis was significantly influenced by odor valence, but not intensity. Identification accuracy in first-degree family members was not influenced by valence or intensity. These data suggest that abnormalities in odor valence perception may represent an environmentally-mediated marker for hedonic disturbance that could have predictive utility in future conversion to psychosis. Further research examining the utility of odor valence measures as markers for psychosis risk are warranted.
PMCID: PMC4198303  PMID: 23953754
olfaction; anhedonia; emotion; schizophrenia prodrome; smell identification
9.  Olfactory processing in schizophrenia, non-ill first-degree family members, and young people at-risk for psychosis 
While deficits in odor identification and discrimination have been reported in schizophrenia, few studies have examined the relative specificity of these deficits in patients and at-risk youth.
Sniffin’ Sticks odor identification and discrimination were assessed in schizophrenia outpatients and non-ill first-degree relatives (Study One), as well as youth at clinical (CR) or genetic (GR) risk for schizophrenia (Study Two). Scores were z-transformed, using the performance of a demographically-matched adult or adolescent comparison group.
Patients and relatives were impaired on odor identification, but odor discrimination impairment was limited to the patient group. A similar pattern of impairment emerged in at-risk youth. GR youth were impaired on odor identification but not discrimination, while CR youth were impaired on both tasks. In patients, olfactory impairment was correlated with negative symptomatology.
To our knowledge, this is the first study to show that CR youth are impaired on both olfactory tasks, as observed in adult schizophrenia patients. GR youth were impaired only on odor identification like their adult counterparts. These data suggest that odor identification impairment, in isolation, may represent a genetic marker of vulnerability for schizophrenia, while odor discrimination deficits may be a biomarker associated with the development of psychosis.
PMCID: PMC3922881  PMID: 22070564
olfaction; smell; prodrome; negative symptoms; psychosis prone
10.  Mortality and molecular epidemiology associated with extended-spectrum β-lactamase production in Escherichia coli from bloodstream infection 
The rate of infections due to extended-spectrum β-lactamase (ESBL)-producing Escherichia coli is growing worldwide. These infections are suspected to be related to increased mortality. We aimed to estimate the difference in mortality due to bloodstream infections (BSIs) with ESBL-positive and ESBL-negative E. coli isolates and to determine the molecular epidemiology of our ESBL-positive isolates.
Materials and methods
We performed a cohort study on consecutive patients with E. coli BSI between 2008 and 2010 at the Charité University Hospital. Collected data were ESBL production, basic demographic parameters, and underlying diseases by the Charlson comorbidity index (CCI). The presence of ESBL genes was analyzed by polymerase chain reaction (PCR) and sequencing. Phylogenetic groups of ESBL-positive E. coli were determined by PCR. Risk factors for mortality were analyzed by multivariable regression analysis.
We identified 115 patients with BSI due to E. coli with ESBL phenotype and 983 due to ESBL-negative E. coli. Fifty-eight percent (n=67) of the ESBL-positive BSIs were hospital-acquired. Among the 99 isolates that were available for PCR screening and sequencing, we found mainly 87 CTX-M producers, with CTX-M-15 (n=55) and CTX-M-1 (n=21) as the most common types. Parameters significantly associated with mortality were age, CCI, and length of stay before and after onset of BSI.
The most common ESBL genotypes in clinical isolates from E. coli BSIs were CTX-M-15 (58%) and CTX-M-1 (22%). ESBL production in clinical E. coli BSI isolates was not related to increased mortality. However, the common occurrence of hospital-acquired BSI due to ESBL-positive E. coli indicates future challenges for hospitals.
PMCID: PMC3958498  PMID: 24648746
BSI; mortality; ESBL-genotype; sepsis
11.  Dimensional Information-Theoretic Measurement of Facial Emotion Expressions in Schizophrenia 
Altered facial expressions of emotions are characteristic impairments in schizophrenia. Ratings of affect have traditionally been limited to clinical rating scales and facial muscle movement analysis, which require extensive training and have limitations based on methodology and ecological validity. To improve reliable assessment of dynamic facial expression changes, we have developed automated measurements of facial emotion expressions based on information-theoretic measures of expressivity of ambiguity and distinctiveness of facial expressions. These measures were examined in matched groups of persons with schizophrenia (n = 28) and healthy controls (n = 26) who underwent video acquisition to assess expressivity of basic emotions (happiness, sadness, anger, fear, and disgust) in evoked conditions. Persons with schizophrenia scored higher on ambiguity, the measure of conditional entropy within the expression of a single emotion, and they scored lower on distinctiveness, the measure of mutual information across expressions of different emotions. The automated measures compared favorably with observer-based ratings. This method can be applied for delineating dynamic emotional expressivity in healthy and clinical populations.
PMCID: PMC3956414  PMID: 24724025
12.  Odor Hedonic Capacity and Anhedonia in Schizophrenia and Unaffected First-Degree Relatives of Schizophrenia Patients 
Schizophrenia Bulletin  2011;39(1):59-67.
Objective: There is increasing evidence that schizophrenia patients have difficulties in the hedonic appraisal of odors. In a prior study, we assessed olfactory hedonic perception birhinally and found that males with schizophrenia failed to attach the appropriate hedonic valence to a pleasant odor, despite correctly perceiving changes in odor intensity. Female patients, in contrast, exhibited normal responses. The current study extends this work by examining odor valence processing in unaffected first-degree relatives of schizophrenia patients, to determine the extent to which this abnormality may be genetically mediated. We also examine odor valence processing unirhinally, rather than birhinally, to probe possible lateralized differences in patients’ hedonic processing deficits. Method: Individuals with schizophrenia (n = 54), first-degree unaffected family members (n = 22), and demographically matched controls (n = 45) were administered the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test. Results: In contrast to family members and controls, both male and female schizophrenia probands underevaluated the hedonic characteristics of amyl acetate at lower concentrations and overevaluated its pleasantness at concentrations perceived as unpleasant by both controls and relatives. These patient-specific differences could not be explained by differences in smoking habit, medication use, or subjective ratings of odor intensity. However, they were associated with increased levels of anhedonia/asociality and negative symptomatology. Conclusions: Our findings suggest that both male and female schizophrenia patients have difficulties in the unirhinal appraisal of hedonic valence. Normal responses in unaffected first-degree relatives suggest that this is an environmentally, rather than genetically, mediated abnormality denoting negative symptomatology.
PMCID: PMC3523921  PMID: 21616912
smell; olfactory; valence processing; pleasantness; emotion; olfaction
13.  Different Patterns of Epstein-Barr Virus Latency in Endemic Burkitt Lymphoma (BL) Lead to Distinct Variants within the BL-Associated Gene Expression Signature 
Journal of Virology  2013;87(5):2882-2894.
Epstein-Barr virus (EBV) is present in all cases of endemic Burkitt lymphoma (BL) but in few European/North American sporadic BLs. Gene expression arrays of sporadic tumors have defined a consensus BL profile within which tumors are classifiable as “molecular BL” (mBL). Where endemic BLs fall relative to this profile remains unclear, since they not only carry EBV but also display one of two different forms of virus latency. Here, we use early-passage BL cell lines from different tumors, and BL subclones from a single tumor, to compare EBV-negative cells with EBV-positive cells displaying either classical latency I EBV infection (where EBNA1 is the only EBV antigen expressed from the wild-type EBV genome) or Wp-restricted latency (where an EBNA2 gene-deleted virus genome broadens antigen expression to include the EBNA3A, -3B, and -3C proteins and BHRF1). Expression arrays show that both types of endemic BL fall within the mBL classification. However, while EBV-negative and latency I BLs show overlapping profiles, Wp-restricted BLs form a distinct subgroup, characterized by a detectable downregulation of the germinal center (GC)-associated marker Bcl6 and upregulation of genes marking early plasmacytoid differentiation, notably IRF4 and BLIMP1. Importantly, these same changes can be induced in EBV-negative or latency I BL cells by infection with an EBNA2-knockout virus. Thus, we infer that the distinct gene profile of Wp-restricted BLs does not reflect differences in the identity of the tumor progenitor cell per se but differences imposed on a common progenitor by broadened EBV gene expression.
PMCID: PMC3571367  PMID: 23269792
14.  An odor-specific threshold deficit implicates abnormal cAMP signaling in youths at clinical risk for psychosis 
Schizophrenia Research  2012;138(2-3):280-284.
While olfactory deficits have been reported in schizophrenia and youths at-risk for psychosis, few studies have linked these deficits to current pathophysiological models of the illness. There is evidence that disrupted cyclic adenosine 3’,5’-monophosphate (cAMP) signaling may contribute to schizophrenia pathology. As cAMP mediates olfactory signal transduction, the degree to which this disruption could manifest in olfactory impairment was ascertained. Odor-detection thresholds to two odorants that differ in the degree to which they activate intracellular cAMP were assessed in clinical risk and low-risk participants.
Birhinal assessments of odor-detection threshold sensitivity to lyral and citralva were acquired in youths experiencing prodromal symptoms (n = 17) and controls at low risk for developing psychosis (n = 15). Citralva and lyral are odorants that differ in cAMP activation; citralva is a strong cAMP activator and lyral is a weak cAMP activator.
The overall group-by-odor interaction was statistically significant. At-risk youths showed significantly reduced odor detection thresholds for lyral, but showed intact detection thresholds for citralva. This odor-specific threshold deficit was uncorrelated with deficits in odor identification or discrimination, which were also present. ROC curve analysis revealed that olfactory performance correctly classified at-risk and low-risk youths with greater than 97% accuracy.
This study extends prior findings of an odor-specific hyposmia implicating cAMP-mediated signal transduction in schizophrenia and unaffected first-degree relatives to include youths at clinical risk for developing the disorder. These results suggest that dysregulation of cAMP signaling may be present during the psychosis prodrome.
PMCID: PMC3372687  PMID: 22537567
schizophrenia prodrome; ultra high risk; cAMP; adenosine cyclase; DISC1
15.  A Meta-Analysis of Emotion Perception and Functional Outcomes in Schizophrenia 
Schizophrenia Research  2012;137(1-3):203-211.
Emotion perception (EP) is impaired in schizophrenia, is stable across clinical state, resistant to antipsychotic treatment and linked to symptom severity. Given its pervasive nature, there is a need to quantitatively examine whether this dysfunction impacts functional outcomes. We used a meta-analytic strategy to combine results from several studies and examine synthesized effect sizes.
A Meta-analysis Of Observational Studies in Epidemiology standard was used to extract data following a PubMed and PsychInfo search. Studies reporting correlations between measures of EP and functional outcomes in schizophrenia spectrum disorders were selected. The impact of potential methodological (task type), demographic (sex, age, race, education, marital status) and clinical (age of onset, duration of illness, setting, symptoms, anti-psychotic medication) moderators on effect sizes were examined.
Twenty-five studies met inclusion criteria and included 1306 patients who were 37 years old, with 12 years of education, 64% male and 63% Caucasian. There was a significant relationship between EP and functional outcomes in individuals with schizophrenia or schizoaffective disorder, with effect sizes in the medium range. Medium to large range positive correlations were observed between emotion identification and functional outcome domains involving social problem solving, social skills and community functioning. Significant moderators included task type (emotion identification tasks), sex (% male in sample), race (% Caucasian in sample) and clinical symptoms (negative and positive).
Emotion identification deficits are associated with functional impairments in schizophrenia and moderated by sex, race and symptoms. This has implications for treatment efforts to improve outcomes.
PMCID: PMC3351501  PMID: 22341200
emotion perception; social cognition; schizophrenia; functional outcome; quality of life; meta-analysis
16.  Evaluation and Treatment of Children and Adolescents with Psychotic Symptoms 
Current psychiatry reports  2012;14(2):101-110.
In recent years, there have been increasing efforts to develop early detection and prevention strategies for patients at risk of the development of psychotic disorders. These efforts have led to improved recognition and characterization of psychotic symptoms in youth. This review focuses on the evaluation of children and adolescents with psychotic symptoms who are experiencing functional impairment but who do not meet current criteria for schizophrenia. For this article, emphasis is placed on the evaluation of symptoms, differential diagnosis, and consideration of potential interventions.
PMCID: PMC3500659  PMID: 22350543
Ultra high risk (UHR); Prodrome; At-risk; Psychosis; Psychotic symptoms; Children; Adolescents; Schizophrenia; Youth
19.  Computerized Neurocognitive Profile in Young People with 22q11.2 Deletion Syndrome Compared to Youths with Schizophrenia and At-risk for Psychosis 
Adults with 22q11.2 Deletion Syndrome (22q11DS) have increased prevalence of schizophrenia features. Our goal is to compare the neurocognitive profile in 22q11DS, schizophrenia and individuals at risk for schizophrenia.
Twenty-one 22q11DS patients (8y-32y, mean 14.9y, 15M 6F) were matched to four comparison groups on age: low risk (n=21), first-degree family members of schizophrenia patients (genetic risk, n=20), individuals exhibiting putatively prodromal symptoms (clinical risk, n=19), and patients with schizophrenia (n=21). All participants received semi-structured interviews [Diagnostic Interview for Genetic Studies (DIGS) and the Structured Interview for Prodromal Syndromes (SIPS)], and a computerized neurocognitive battery (CNB) measuring the following domains: Abstraction and Mental Flexibility, Attention, Working Memory, Verbal Memory, Face Memory, Spatial Memory, Language, Spatial Processing, Sensorimotor Dexterity, and Emotion Processing.
60% of 22q11DS participants met SIPS criteria for prodromal symptoms and one participant met criteria for paranoid schizophrenia. 38% met criteria for Depressive Disorders. All 22q11DS participants successfully completed the CNB. 22q11DS participants were significantly less accurate in nearly all domains, but had similar speed of response compared to the other groups. Their profile resembled that of the psychosis groups in accuracy and speed, except for more pronounced deficits in accuracy for face memory and emotion processing.
Subthreshold psychotic symptoms are present in a high proportion of 22q11DS participants. Deficits shown in the CNB are more pronounced for accuracy than speed relative to the psychosis groups with similar profiles. Similar deficits have been described in the 22q11DS population using non-computerized measures, which require increased testing time.
PMCID: PMC3272485  PMID: 22170773
22q11.2 Deletion Syndrome; VCFS; schizophrenia risk; neuropsychology
20.  SOCS1 Mutation Subtypes Predict Divergent Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients 
Oncotarget  2012;4(1):35-47.
Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in DLBCL.
PMCID: PMC3702206  PMID: 23296022
Lymphoma; DLBCL; SOCS1 mutation
21.  Extracytoplasmic function (ECF) sigma factor σF is involved in Caulobacter crescentus response to heavy metal stress 
BMC Microbiology  2012;12:210.
The α-proteobacterium Caulobacter crescentus inhabits low-nutrient environments and can tolerate certain levels of heavy metals in these sites. It has been reported that C. crescentus responds to exposure to various heavy metals by altering the expression of a large number of genes.
In this work, we show that the ECF sigma factor σF is one of the regulatory proteins involved in the control of the transcriptional response to chromium and cadmium. Microarray experiments indicate that σF controls eight genes during chromium stress, most of which were previously described as induced by heavy metals. Surprisingly, σF itself is not strongly auto-regulated under metal stress conditions. Interestingly, σF-dependent genes are not induced in the presence of agents that generate reactive oxygen species. Promoter analyses revealed that a conserved σF-dependent sequence is located upstream of all genes of the σF regulon. In addition, we show that the second gene in the sigF operon acts as a negative regulator of σF function, and the encoded protein has been named NrsF (Negative regulator of sigma F). Substitution of two conserved cysteine residues (C131 and C181) in NrsF affects its ability to maintain the expression of σF-dependent genes at basal levels. Furthermore, we show that σF is released into the cytoplasm during chromium stress and in cells carrying point mutations in both conserved cysteines of the protein NrsF.
A possible mechanism for induction of the σF-dependent genes by chromium and cadmium is the inactivation of the putative anti-sigma factor NrsF, leading to the release of σF to bind RNA polymerase core and drive transcription of its regulon.
PMCID: PMC3511200  PMID: 22985357
Stress response; ECF sigma factor σF; Chromium; Cadmium; Caulobacter crescentus
22.  Automated Facial Action Coding System for Dynamic Analysis of Facial Expressions in Neuropsychiatric Disorders 
Journal of Neuroscience Methods  2011;200(2):237-256.
Facial expression is widely used to evaluate emotional impairment in neuropsychiatric disorders. Ekman and Friesen’s Facial Action Coding System (FACS) encodes movements of individual facial muscles from distinct momentary changes in facial appearance. Unlike facial expression ratings based on categorization of expressions into prototypical emotions (happiness, sadness, anger, fear, disgust, etc.), FACS can encode ambiguous and subtle expressions, and therefore is potentially more suitable for analyzing the small differences in facial affect. However, FACS rating requires extensive training, and is time consuming and subjective thus prone to bias. To overcome these limitations, we developed an automated FACS based on advanced computer science technology. The system automatically tracks faces in a video, extracts geometric and texture features, and produces temporal profiles of each facial muscle movement. These profiles are quantified to compute frequencies of single and combined Action Units (AUs) in videos, which can facilitate statistical study of large populations in disorders affecting facial expression. We derived quantitative measures of flat and inappropriate facial affect automatically from temporal AU profiles. Applicability of the automated FACS was illustrated in a pilot study, by applying it to data of videos from eight schizophrenia patients and controls. We created temporal AU profiles that provided rich information on the dynamics of facial muscle movements for each subject. The quantitative measures of flatness and inappropriateness showed clear differences between patients and the controls, highlighting their potential in automatic and objective quantification of symptom severity.
PMCID: PMC3402717  PMID: 21741407
Facial Expressions; Facial Action Coding System; action units; Computerized Method
23.  Actively Paranoid Patients with Schizophrenia Over Attribute Anger to Neutral Faces 
Schizophrenia research  2010;125(2-3):174-178.
Previous investigations of the influence of paranoia on facial affect recognition in schizophrenia have been inconclusive as some studies demonstrate better performance for paranoid relative to non-paranoid patients and others show that paranoid patients display greater impairments. These studies have been limited by small sample sizes and inconsistencies in the criteria used to define groups. Here, we utilized an established emotion recognition task and a large sample to examine differential performance in emotion recognition ability between patients who were actively paranoid (AP) and those who were not actively paranoid (NAP). Accuracy and error patterns on the Penn Emotion Recognition test (ER40) were examined in 132 patients (64 NAP and 68 AP). Groups were defined based on the presence of paranoid ideation at the time of testing rather than diagnostic subtype. AP and NAP patients did not differ in overall task accuracy; however, an emotion by group interaction indicated that AP patients were significantly worse than NAP patients at correctly labeling neutral faces. A comparison of error patterns on neutral stimuli revealed that the groups differed only in misattributions of anger expressions, with AP patients being significantly more likely to misidentify a neutral expression as angry. The present findings suggest that paranoia is associated with a tendency to over attribute threat to ambiguous stimuli and also lend support to emerging hypotheses of amygdala hyperactivation as a potential neural mechanism for paranoid ideation.
PMCID: PMC3031724  PMID: 21112186
Paranoia; facial emotion recognition; amygdala; social cognition
24.  Ventrolateral prefrontal cortex and the effects of task demand context on facial affect appraisal in schizophrenia 
Schizophrenia patients display impaired performance and brain activity during facial affect recognition. These impairments may reflect stimulus-driven perceptual decrements and evaluative processing abnormalities. We differentiated these two processes by contrasting responses to identical stimuli presented under different contexts. Seventeen healthy controls and 16 schizophrenia patients performed an fMRI facial affect detection task. Subjects identified an affective target presented amongst foils of differing emotions. We hypothesized that targeting affiliative emotions (happiness, sadness) would create a task demand context distinct from that generated when targeting threat emotions (anger, fear). We compared affiliative foil stimuli within a congruent affiliative context with identical stimuli presented in an incongruent threat context. Threat foils were analysed in the same manner. Controls activated right orbitofrontal cortex (OFC)/ventrolateral prefrontal cortex (VLPFC) more to affiliative foils in threat contexts than to identical stimuli within affiliative contexts. Patients displayed reduced OFC/VLPFC activation to all foils, and no activation modulation by context. This lack of context modulation coincided with a 2-fold decrement in foil detection efficiency. Task demands produce contextual effects during facial affective processing in regions activated during affect evaluation. In schizophrenia, reduced modulation of OFC/VLPFC by context coupled with reduced behavioural efficiency suggests impaired ventral prefrontal control mechanisms that optimize affective appraisal.
PMCID: PMC3023083  PMID: 20212004
schizophrenia; social cognition; face; emotion; amygdala; ventrolateral prefrontal cortex (VLPFC); orbitofrontal cortex (OFC); fMRI
25.  Facial Emotion Perception in Schizophrenia: A Meta-analytic Review 
Schizophrenia Bulletin  2009;36(5):1009-1019.
Objectives: A considerable body of literature has reported on emotion perception deficits and the relevance to clinical symptoms and social functioning in schizophrenia. Studies published between 1970–2007 were examined regarding emotion perception abilities between patient and control groups and potential methodological, demographic, and clinical moderators. Data Sources and Review: Eighty-six studies were identified through a computerized literature search of the MEDLINE, PsychINFO, and PubMed databases. A quality of reporting of meta-analysis standard was followed in the extraction of relevant studies and data. Data on emotion perception, methodology, demographic and clinical characteristics, and antipsychotic medication status were compiled and analyzed using Comprehensive Meta-analysis Version 2.0 (Borenstein M, Hedges L, Higgins J and Rothstein H. Comprehensive Meta-analysis. 2. Englewood, NJ: Biostat; 2005). Results: The meta-analysis revealed a large deficit in emotion perception in schizophrenia, irrespective of task type, and several factors that moderated the observed impairment. Illness-related factors included current hospitalization and—in part—clinical symptoms and antipsychotic treatment. Demographic factors included patient age and gender in controls but not race. Conclusion: Emotion perception impairment in schizophrenia represents a robust finding in schizophrenia that appears to be moderated by certain clinical and demographic factors. Future directions for research on emotion perception are discussed.
PMCID: PMC2930336  PMID: 19329561
schizophrenia; meta-analysis; emotion perception

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