Biomedical subjects

Raquel E Gur

Publications and source records attributed to Raquel E Gur.

At least 55 records · Page 3Linked to original sources

PubMed2004

The effects of ketamine vary among inbred mouse strains and mimic schizophrenia for the P80, but not P20 or N40 auditory ERP components.

N-methyl-D-aspartate (NMDA) antagonists produce behavioral and electrophysiological effects similar to schizophrenia. The mouse P20, N40, and P80 event related potential (ERP) components were analyzed for genetic variance among inbred strains and ketamine-induced differences to model abnormalities in the P50, N100, and P200 in schizophrenia. Ketamine increased P20/N40 amplitude and decreased P80 amplitude. Therefore, the effects of ketamine in mice are inconsistent with alterations in the corresponding P50 and N100 in schizophrenia, suggesting that NMDA receptor dysfunction may not underlie abnormalities of these components in schizophrenia. However, the effects of ketamine on the mouse P80 were consistent with P200 ERP changes in schizophrenia and support the hypothesis that NMDA dysfunction may contribute to some neuronal abnormalities in schizophrenia. The current study lays the groundwork for defining the role of NMDA-mediated transmission for specific aspects of neuronal processing that vary with genetic background. Future studies could use transcription profiling to clarify such interactions between genetic background, specific neuronal circuits, and transmitter systems.

Animals↗

PubMed2004

Effects of chronic olanzapine and haloperidol differ on the mouse N1 auditory evoked potential.

Auditory evoked potentials have been used in a variety of animal models to assess information-processing impairments in schizophrenia. Previous mouse models have primarily employed a paired click paradigm to assess the transient measures of auditory gating. The current study uses stimulus trains at varied interstimulus intervals (ISI) between 0.25 and 8 s in mice to assess the effects of chronic olanzapine and haloperidol on auditory processing. Data indicate that olanzapine increases the amplitude of the N40, P80, and P20/N40 components of the auditory evoked potential, whereas haloperidol had no such effect. The ISI paradigm also allowed for an evaluation of several components of the mouse evoked potential to assess those that display response properties similar to the human P50 and N100. Data suggest that the mouse N40 displays an ISI response relationship that shares characteristics with the human N100, whereas the P20 appears more consistent with the human P50 across the ISI range evaluated in this task. This study suggests that olanzapine may help improve N100 impairments seen in schizophrenia, while haloperidol does not.

Acoustic Stimulation↗

PubMed2004

Patient attitudes towards surgically implantable, long-term delivery of psychiatric medicine.

The introduction of surgically implantable medication delivery systems provides psychiatric patients with reversible, uninterrupted access to medication for up to 14 months. This study designed and administered a survey to assess patients' attitudes and beliefs towards illness, medication, and this potential new treatment method. The survey included questions about demographics, insight and attitudes towards illness, current and past medication adherence, attitudes towards psychiatric and nonpsychiatric medications, and understanding and attitudes towards surgical implants. The sample of 206 psychiatric patients was almost equally split between favorably and unfavorably considering implants. Patients favorable towards implants ascribed forgetting and failure to refill medication on time as the reasons for missing doses, recognized the benefits of medication in general, and understood that the implant would be inserted under the skin. Favorable consideration of implants was positively correlated with the desire to avoid adverse consequences of missing medicine, stay well, avoid the need for daily oral medications, and decrease family burden. Unfavorable consideration of implants was related to a preference to take medication orally, concern about feeling controlled, unwillingness to try something new, and not understanding that the implant would be placed under the skin. Demographic variables, past/current medications, specific diagnosis, and illness severity did not influence the decision. This survey elucidates patients' attitudes and beliefs towards illness, medication, and surgical implants. The results indicate that a significant proportion of patients recognize the difficulties of medication adherence and the need for better methods to attain therapeutic response. Thus, the study provides impetus for future work in this area.

Adult↗

PubMed2004

Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia.

Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.

Adult↗

PubMed2004

Smaller nasal volumes as stigmata of aberrant neurodevelopment in schizophrenia.

OBJECTIVE: Anatomical and functional deficits of the olfactory neural system have been identified in patients with schizophrenia. Since olfactory structures develop in conjunction with both the palate and ventral forebrain, the authors hypothesized that schizophrenia patients might have structural abnormalities of the nasal cavity, which could represent specific markers of embryological dysmorphogenesis underlying schizophrenia. METHOD: A measurement of nasal volume was acquired by acoustic rhinometry for 40 male schizophrenia patients and 24 healthy male comparison subjects. RESULTS: The patients had smaller posterior nasal volumes than the comparison subjects but did not differ in anterior nasal volumes. This difference persisted after covarying for height and smoking history. CONCLUSIONS: The lower observed posterior nasal volume likely reflects a specific developmental craniofacial abnormality. This finding confirms an early disruption in embryological development in males with schizophrenia and may represent a genetic or environmental "first hit" that leaves the individual vulnerable to subsequent pathology.

Adult↗

PubMed2004

Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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 prefrontal 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. CONCLUSIONS: 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.

Adult↗

PubMed2004

Normative data for the symbol cancellation test in young healthy adults.

Mesulam's (1985) symbol cancellation test (SCT) provides a measure of neglect, organizational process, and attention. Although the SCT lends itself to qualitative interpretation, normative data would be helpful for interpreting errors and time to complete this test. SCT normative data are provided for healthy young adults and the contribution of age, education, ethnicity, and gender to SCT performance is examined. Results were as follows: Age was significant (p < .05) and education approached significance (p = .06) as predictors of SCT performance, but percentile ranks revealed an unstable performance pattern across age and education. Thus, normative data for the SCT are provided for the entire sample (n = 136). Conclusions are as follows: Healthy young adults make few errors and complete the SCT in under 2 min, consistent with general findings (Mesulam, 1985). In addition, a relation likely exists between SCT performance and age and education, but a larger sample seems warranted to reliably model the pattern.

Adult↗

PubMed2003

Levels-of-processing effect on word recognition in schizophrenia.

BACKGROUND: Individuals with schizophrenia have difficulty organizing words semantically to facilitate encoding. This is commonly attributed to organizational rather than semantic processing limitations. By requiring participants to classify and encode words on either a shallow (e.g., uppercase/lowercase) or deep level (e.g., concrete/abstract), the levels-of-processing paradigm eliminates the need to generate organizational strategies. METHODS: This paradigm was administered to 30 patients with schizophrenia and 30 healthy comparison subjects to test whether providing a strategy would improve patient performance. RESULTS: Word classification during shallow and deep encoding was slower and less accurate in patients. Patients also responded slowly during recognition testing and maintained a more conservative response bias following deep encoding; however, both groups showed a robust levels-of-processing effect on recognition accuracy, with unimpaired patient performance following both shallow and deep encoding. CONCLUSIONS: This normal levels-of-processing effect in the patient sample suggests that semantic processing is sufficiently intact for patients to benefit from organizational cues. Memory remediation efforts may therefore be most successful if they focus on teaching patients to form organizational strategies during initial encoding.

Adult↗

PubMed2003

Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse substrains.

Previous data have shown differences among inbred mouse strains in sensory gating of auditory evoked potentials, prepulse inhibition (PPI) of startle, and startle amplitude. These measures of sensory and sensorimotor gating have both been proposed as models for genetic determinants of sensory processing abnormalities in patients with schizophrenia and their first-degree relatives. Data from our laboratory suggest that auditory evoked potentials of DBA/2J mice differ from those previously described for DBA/2Hsd. Therefore, we compared evoked potentials and PPI in these two closely related substrains based on the hypothesis that any observed endophenotypic differences are more likely to distinguish relevant from incidental genetic heterogeneity than similar approaches using inbred strains that vary across the entire genome. We found that DBA/2Hsd substrain exhibited reduced inhibition of evoked potentials and reduced startle relative to the DBA/2J substrain without alterations in auditory sensitivity, amplitude of evoked potentials or PPI of startle. These results suggest that gating of auditory evoked potentials and PPI of startle measure different aspects of neuronal function. The differences between the substrains might reflect genetic drift. Alternatively, differences could arise from different rearing environments or other non-genetic factors. Future studies will attempt to determine the cause of these differences in sensory and sensorimotor processing between these two closely related inbred mouse strains.

Acoustic Stimulation↗

PubMed2003

Physiologic impairment of olfactory stimulus processing in schizophrenia.

BACKGROUND: Behavioral studies of olfaction have demonstrated impairments in the ability to detect and identify odors in patients with schizophrenia. These deficits appear to be independent of either symptom severity or other cognitive impairment. Only limited efforts have been made to investigate the neurophysiologic substrate of these olfactory abnormalities. This article reports the first examination of olfactory electrophysiologic responses in patients with schizophrenia. METHODS: Olfactory event-related potential responses to three different concentrations of hydrogen sulfide were recorded in a sample of 21 patients and 20 healthy control subjects. Odors were presented via an olfactometer to ensure there was no associated trigeminal nerve stimulation. RESULTS: Patients exhibited abnormalities in the amplitudes of the N1 and P2 components of the olfactory evoked potential, and delayed latency of the P2. The N1 abnormality, which denotes primary olfactory cortex activity, was related to impaired odor detection threshold sensitivity; the P2 abnormality was related to impaired odor identification. CONCLUSIONS: These data indicate the presence of a primary physiologic impairment in the olfactory cortex underlying behavioral olfactory deficits seen in patients with schizophrenia. This is consistent with postmortem and in vitro studies suggesting abnormalities in olfactory receptor neurons. Understanding the nature of these physiologic olfactory impairments could offer clues to the basic neuropathology of this disorder.

Adolescent↗

PubMed2003

Decrements in volume of anterior ventromedial temporal lobe and olfactory dysfunction in schizophrenia.

CONTEXT: Patients with schizophrenia exhibit olfactory deficits, but it is unclear whether these represent a specific abnormality. The link between olfactory impairments and regional brain abnormalities has yet to be established. OBJECTIVES: To determine whether patients with schizophrenia exhibit volumetric deficits in the anterior ventromedial temporal lobe, the target for neuronal inputs from the olfactory bulb, and whether these are related to olfactory performance deficits. DESIGN: A cohort study of patients and healthy control subjects who underwent both 1-mm spoiled-gradient echo magnetic resonance imaging and behavioral tests of olfaction and memory. SETTING: Schizophrenia Research Center at the University of Pennsylvania, Philadelphia. PARTICIPANTS: Fifty-two patients with a DSM-IV diagnosis of schizophrenia and 38 healthy control subjects. Individuals were excluded for history of head trauma, significant substance abuse, and medical conditions affecting brain function or olfactory capacity. MAIN OUTCOME MEASURES: Gray matter volumes of the left and right temporal poles and the perirhinal and entorhinal cortexes; olfactory threshold detection sensitivity and identification test scores; composite indexes of verbal and spatial memory ability. RESULTS: Patients had reduced volumes, relative to cranial size, in left (P =.003) and right (P =.01) perirhinal and left (P =.002) and right (P =.002) entorhinal cortexes, but not in the temporal pole. Perirhinal, but not entorhinal, cortical volume decrement was associated with decreased olfactory threshold sensitivity. Neither region was associated with impaired memory performance. CONCLUSIONS: Patients with schizophrenia have reduced cortical volumes in brain regions that receive afferents directly from the olfactory bulb. Behavioral olfactory deficits are related to structural brain abnormalities in these regions.

Adolescent↗

PubMed2003

Neurocognitive performance and clinical changes in olanzapine-treated patients with schizophrenia.

Diffuse cognitive impairment characterizes patients with schizophrenia throughout the course of illness. The deficits persist despite clinical improvement associated with neuroleptic intervention and are related to outcome. It is unclear whether treatment with atypical agents is associated with improved cognition that relates to symptoms and outcome. Using a set of computerized neurocognitive measures, we evaluated whether the effects of olanzapine are greater than practice effects for specific neurocognitive domains that could provide targets for large-scale randomized studies. We enrolled 19 patients with schizophrenia before initiation of treatment with olanzapine and 16 of them were examined at 6 weeks and 6 months of follow-up. They were compared to 34 healthy participants who enrolled, 24 of whom were evaluated longitudinally. Improvement exceeding practice effects was observed in patients for abstraction and spatial memory and the latter correlated with clinical improvement in negative symptoms. These results suggest that some effects of olanzapine may impact both symptoms and cognitive performance.

Adolescent↗

PubMed2003

Facial emotion recognition in schizophrenia: intensity effects and error pattern.

OBJECTIVE: The authors used color photographs of emotional and neutral expressions to investigate recognition patterns of five universal emotions in schizophrenia. METHOD: Twenty-eight stable outpatients with schizophrenia (19 men and nine women) and 61 healthy subjects (29 men and 32 women) completed an emotion discrimination test that presented mild and extreme intensities of happy, sad, angry, fearful, disgusted, and neutral faces, balanced for gender and ethnicity. Analyses evaluated accuracy of identifying emotions as a function of intensity, diagnosis, and gender of poser and rater. RESULTS: Patients performed worse than comparison subjects on recognition of all emotions and neutral faces combined, including mild and extreme expressions. For specific emotions, patients performed worse on recognition of fearful, disgusted, and neutral expressions. For all emotions except disgust, recognition of extreme intensity was better than recognition of mild intensity. However, patients showed less benefit from increased intensity for all emotions combined, and the difference was most pronounced for fear. Thus, patients were more impaired than healthy comparison subjects in identifying high-intensity expressions, even though this was an easier task than identifying low-intensity expressions. In the comparison of patterns of errors, patients and healthy subjects differed only in misattributions of neutral expressions; patients overattributed disgusted expressions and underattributed happy expressions. CONCLUSIONS: Patients with schizophrenia were impaired in overall emotion recognition, particularly fear and disgust, and did not benefit from increased emotional intensity. Error patterns indicate that patients misidentified neutral cues as negatively valenced.

Adult↗

PubMed2003

Impairment of odor hedonics in men with schizophrenia.

OBJECTIVE: Olfactory deficits in patients with schizophrenia, including those of odor identification, detection threshold sensitivity, discrimination, and memory, have been well described. Deficits in emotional perception, processing, and experience have also been reported, with anhedonia being one of the core features. While anatomical connections testify to the relationship between olfaction and emotion, there has been little investigation of the hedonic properties of odors in schizophrenia. This study examined intensity and hedonic judgments in patients with schizophrenia to determine whether these functions were differentially impaired. METHOD: Suprathreshold scaling of odor intensity and pleasantness was acquired by using the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test given to 30 patients (15 men and 15 women) with a DSM-IV diagnosis of schizophrenia and 30 age- and sex-matched healthy comparison subjects. RESULTS: Despite virtually identical ratings of odor intensity, male patients were impaired in the assignment of odor pleasantness to amyl acetate. This gender-specific diagnostic group difference was not explained by variability in symptom severity or negative/positive symptoms. The impact of smoking status and general cognitive impairment on this deficit was also insignificant. CONCLUSIONS: Findings reveal a gender-specific disruption in the ability to attribute appropriate hedonic valence to odors in male patients with schizophrenia. This difficulty in identifying the hedonic valence of odors, despite intact intensity ratings, is consistent with clinical observations of anhedonia and points to a neural substrate that might contribute to the emotional disturbances seen in patients with schizophrenia.

Adult↗

PubMed2003

Low olfactory bulb volume in first-degree relatives of patients with schizophrenia.

OBJECTIVE: There is a substantial genetic contribution to schizophrenia but no way to readily identify individuals at risk. Biological abnormalities reflecting greater genetic vulnerability may be discovered by examining healthy family members of patients with schizophrenia. There is evidence that olfactory impairments are common in patients. The authors previously reported that patients have abnormal olfactory bulbs, assessed by magnetic resonance imaging (MRI). This study examined olfactory bulbs in patients' relatives to determine whether low bulb volume represents an endophenotypic marker of genetic vulnerability. METHOD: Olfactory psychophysical measures and MRI scans of olfactory bulbs were acquired from 19 healthy first-degree relatives, 20 healthy comparison subjects with similar age and gender distributions, and the 11 patient probands of these relatives. Olfactory bulb volumes were measured by using a reliable region-of-interest procedure. RESULTS: The patients had impaired ability to detect odors and had lower olfactory bulb volumes than the comparison subjects. Although the family members had normal olfactory ability, they exhibited low right bulb volume. The patients had smaller left, but not right, olfactory bulbs than their own healthy relatives. CONCLUSIONS: The findings in family members suggest that structural abnormalities of the olfactory system in schizophrenia may partly reflect preexisting genetic vulnerability to illness. Preliminary analyses suggest that right olfactory bulb volume may serve as an endophenotypic marker of genetic vulnerability, while left bulb volume may reflect overt disease among individuals who share genetic vulnerability. Bulb abnormalities in patients are consistent with reports of cellular abnormalities affecting peripheral olfactory receptor neurons.

Adolescent↗

PubMed2003

Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol.

OBJECTIVE: Few long-term studies have compared the efficacy and safety of typical and atypical antipsychotic medications directly in patients with a first episode of psychosis who met the criteria for schizophrenia or a related psychotic disorder. This study compared the acute and long-term effectiveness of haloperidol with that of olanzapine in patients with first-episode psychosis in a large, controlled clinical trial. METHOD: Patients with first-episode psychosis (N=263) were randomly assigned under double-blind conditions to receive haloperidol or olanzapine and were followed for up to 104 weeks. Domains measured included psychopathology, psychosocial variables, neurocognitive functioning, and brain morphology and metabolism. This report presents data from clinical measures of treatment response and safety data from the 12-week acute treatment phase. RESULTS: Haloperidol and olanzapine were associated with substantial and comparable baseline-to-endpoint reductions in symptom severity, which did not differ significantly in last-observation-carried-forward analyses. However, in a mixed-model analysis, olanzapine-treated subjects had significantly greater decreases in symptom severity as measured by the Positive and Negative Syndrome Scale total score and negative and general scales and by the Montgomery-Asberg Depression Rating Scale but not as measured by the Positive and Negative Syndrome Scale positive scale and by the Clinical Global Impression severity rating. Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients. Overall, significantly more olanzapine-treated subjects than haloperidol-treated subjects completed the 12-week acute phase of the study (67% versus 54%). CONCLUSIONS: As expected on the basis of previous studies, both olanzapine and haloperidol were effective in the acute reduction of psychopathological symptoms in this group of patients with first-episode psychosis. However, olanzapine had several relative advantages in therapeutic response. Although the nature of adverse events differed between the two agents, retention in the study was greater with olanzapine. Retention in treatment is important in this patient population, given their risk of relapse. Longer-term results are needed to determine whether treatment with atypical antipsychotics results in superior outcomes for a first episode of schizophrenia.

Adolescent↗

PubMed2002

Development of an abbreviated schizophrenia quality of life scale using a new method.

The goal of the study was to develop and apply a predictive model approach to reduce the number of items collected for scales that yield a total summary score. A parsimonious subset of items from the 21-item Quality of Life Scale (QLS) that can accurately predict the total scale score was sought and evaluated in 198 patients with schizophrenia, using a statistical modeling approach. Two additional data sets were used for model validation: the subset of 101 patients used in the model construction who had the QLS administered approximately 1 year later and a new sample of 37 patients. Using only seven QLS items as predictors, the correlation was 0.9831 between the predicted and true QLS totals. Applying the model based for these seven QLS items, the correlations from the first and second validation data sets were 0.9791 and 0.9637, respectively. The study demonstrates that a small subset of items of the QLS predicts the entire 21-item scale with high accuracy. Two validation samples have confirmed the finding. This reduces the effort associated with scale administration and is likely to increase the assessment of an important functional domain. Such models can guide efforts for item reduction in other rating instruments.

Adolescent↗

PubMed2002

Effects of strain, novelty, and NMDA blockade on auditory-evoked potentials in mice.

People with schizophrenia exhibit impaired ability to modify electroencephalographic event-related potential (ERP) responses to novel stimuli. These deficits serve as a window into the abnormalities of neuronal organization and function and are thought to reflect a component of genetic vulnerability for schizophrenia. We describe differences among inbred mouse strains for ERPs following a novelty detection paradigm, as a model for genetic contributions to disease vulnerability. Auditory-evoked potentials were recorded during an auditory oddball task in nonanesthetized C57BL/6J, C3H/HeJ, and DBA/2J mice prior to and following ketamine (10 mg/kg). Stimuli consisted of 80 sets of 24 standard tones followed by one novel tone. Principal component analysis yielded four temporal components that contribute to the auditory ERP responses to standard and novel stimuli. Two principal components that varied between standard and novel stimuli also differed among inbred mouse strains. Post hoc analyses indicate that strain effects on novelty detection are due to a significant difference between the response to novel and standard tones in C3H/HeJ mice that is absent in the other two strains. Inbred strains of mice vary in their ability to perform neuronal detection of change in the auditory environment. The ability to model novelty detection deficits in mice will aid in identifying genetic contributions to abnormal neuronal organization in people with schizophrenia.

Acoustic Stimulation↗