A Pre-clinical Study of the Response Threshold of Intact and Transected Nerves to Stimulation by Transcutaneous Intense Focused Ultrasound.

We used diagnostic ultrasound imaging to guide individual bursts (0.1 s) of 2 MHz intense focused ultrasound (iFU) to determine the sensitivity of intact and transected nerves. We found that all nerves had greater sensitivity to iFU stimulation than surrounding muscle. Intact nerves from healthy volunteers had less sensitivity to iFU stimulation (272 ± 35 W/cm2 [median ± standard error]) than transected nerves (19 ± 37 W/cm2). Intact, contralateral nerves of amputees dichotomized naturally into two groups-one very sensitive to iFU stimulation (6 ± 2 W/cm2) and one relatively insensitive (539 ± 19 W/cm2), compared with the intact nerves of healthy volunteers. Our study demonstrates the ability of iFU under ultrasound image guidance to stimulate deep, intact and transected peripheral nerves. It also highlights differences in the receptivity to ultrasound stimulation of the peripheral nerves of amputees versus healthy volunteers.

Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, PFDR<0.05, kE=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, PFDR<0.05, kE=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.

Decreased synaptic and mitochondrial density in the postmortem anterior cingulate cortex in schizophrenia.

Schizophrenia (SZ) is a mental illness characterized by psychosis, negative symptoms, and cognitive deficits. The anterior cingulate cortex (ACC), a structurally and functionally diverse region, is one of several brain regions that is abnormal in SZ. The present study compared synaptic organization and mitochondrial number and morphology in postmortem ACC in SZ versus normal control (NC). Total synaptic density in the combined ACC was decreased in SZ, to 72% of normal controls (NCs), due to selective decreases in axospinous synapses, both asymmetric (excitatory) and symmetric (inhibitory). These changes were present in layers 3 and 5/6. The density of mitochondria in all axon terminals combined in SZ was decreased to 64% of NC. In layer 3, mitochondrial density was decreased only in terminals forming asymmetric synapses with spines, while in layers 5/6 mitochondrial density was decreased in terminals forming symmetric synapses with spines and dendrites. The proportion of terminals making symmetric synapses that contained mitochondria was significantly lower in SZ than in NCs, especially for symmetric axospinous synapses. The number of mitochondria per neuronal somata was decreased in the ACC in SZ compared to NCs; this finding was present in layers 5-6. The size of mitochondria in neuronal somata and throughout the neuropil was similar in SZ and NCs. Our results, though preliminary, are well supported by the literature, and support an anatomical substrate for some of the altered executive functions found in SZ.

A full-brain, bootstrapped analysis of diffusion tensor imaging robustly differentiates Parkinson disease from healthy controls.

There is a compelling need for early, accurate diagnosis of Parkinson's disease (PD). Various magnetic resonance imaging modalities are being explored as an adjunct to diagnosis. A significant challenge in using MR imaging for diagnosis is developing appropriate algorithms for extracting diagnostically relevant information from brain images. In previous work, we have demonstrated that individual subject variability can have a substantial effect on identifying and determining the borders of regions of analysis, and that this variability may impact on prediction accuracy. In this paper we evaluate a new statistical algorithm to determine if we can improve accuracy of prediction using a subjects left-out validation of a DTI analysis. Twenty subjects with PD and 22 healthy controls were imaged to evaluate if a full brain diffusion tensor imaging-fractional anisotropy (DTI-FA) map might be capable of segregating PD from controls. In this paper, we present a new statistical algorithm based on bootstrapping. We compare the capacity of this algorithm to classify the identity of subjects left out of the analysis with the accuracy of other statistical techniques, including standard cluster-thresholding. The bootstrapped analysis approach was able to correctly discriminate the 20 subjects with PD from the 22 healthy controls (area under the receiver operator curve or AUROC 0.90); however the sensitivity and specificity of standard cluster-thresholding techniques at various voxel-specific thresholds were less effective (AUROC 0.72-0.75). Based on these results sufficient information to generate diagnostically relevant statistical maps may already be collected by current MRI scanners. We present one statistical technique that might be used to extract diagnostically relevant information from a full brain analysis.

Synaptic proteins in the postmortem anterior cingulate cortex in schizophrenia: relationship to treatment and treatment response.

The anterior cingulate cortex (ACC) is one of several brain regions that are abnormal in schizophrenia (SZ). Here we compared markers of synapse and mitochondrial function using western blots of postmortem ACC in: 1) normal controls (NCs, n=13) vs subjects with SZ (n=25); NC, treatment-resistant SZ, and treatment-responsive SZ; and 3) NC and SZ treated with typical or atypical antipsychotic drugs (APDs). Protein levels of synaptophysin, mitofusin-2, vGLUT1, and calcineurin did not differ between the NC and SZ group as a whole, or the NCs vs the SZ group divided by treatment response or type of APDs. In several cases, the levels of vGLUT1 were minuscule or absent. The proportion of NCs lacking vGLUT1 was significantly less than that of the SZ groups. There were several positive correlations across all subjects between: 1) synaptophysin and vGLUT1; 2) synaptophysin and calcineurin; 3) synaptophysin and mitofusin; and 4) calcineurin and mitofusin. Synaptophysin and calcineurin were positively correlated in responders, and this correlation was significantly stronger than that in treatment-resistant SZ subjects or in NCs. Synaptophysin and calcineurin were positively correlated in SZ patients on atypical APDs; this correlation was significantly stronger than that in SZ patients on typical APDs or in NCs. Mitofusin-2 and calcineurin were positively correlated in SZ patients on atypical APDs and in NCs; this correlation was stronger in SZ patients on atypical rather than typical APDs or in NCs. The correlation between these proteins, which have roles in synaptic vesicle cycling, glutamate transmission, mitochondrial fusion, and calcium buffering, is complex and was differentially regulated among the groups.

Heritability of functioning in families with schizophrenia in relation to neurocognition.

UNLABELLED: The role of daily functioning is an integral part of the schizophrenia (SZ) phenotype and deficits in this trait appear to be present in both affected persons and some unaffected relatives; hence we have examined its heritability in our cohort of African American schizophrenia families. There is now ample evidence that deficits in cognitive function can impact family members who are not themselves diagnosed with SZ; there is some, but less evidence that role function behaves likewise. We evaluate whether role function tends to "run in families" who were ascertained because they contain an African American proband diagnosed with SZ. METHODS: We analyzed heritability for selected traits related to daily function, employment, living situation, marital status, and Global Assessment Scale (GAS) score; modeling age, gender, along with neurocognition and diagnosis as covariates in a family based African-American sample (N=2488 individuals including 979 probands). RESULTS: Measures of role function were heritable in models including neurocognitive domains and factor analytically derived neurocognitive summary scores and demographics as covariates; the most heritable estimate was obtained from the current GAS scores (h2=0.72). Neurocognition was not a significant contributor to heritability of role function. CONCLUSIONS: Commonly assessed demographic and clinical indicators of functioning are heritable with a global rating of functioning being the most heritable. Measures of neurocognition had little impact on heritability of functioning overall. The family covariance for functioning, reflected in its heritability, supports the concept that interventions at the family level, such as evidenced-based family psychoeducation may be beneficial in schizophrenia.

TGFbeta inhibits IL-1 -induced iNOS expression and NO production in immortalized chondrocytes.

OBJECTIVE: The balance between anti-inflammatory (e.g. TGFbeta) and proinflammatory cytokines (e.g. IL-1 and TNFalpha), regulates destructive processes in OA cartilage. IL-1 and TNFalpha enhance nitric oxide (NO) production in OA cartilage through the inducible nitric oxide synthase (iNOS) pathway and NO mediates many of the destructive effects of these cytokines. The aim of the present study was to investigate the effects of TGFbeta on NO production in immortalized H4 chondrocytes exposed to IL-1. RESULTS: IL-1 induced NO production in chondrocytes through nuclear factor kappa B (NF-kappaB) sensitive and dexamethasone insensitive expression of iNOS. TGFbeta inhibited IL-1 -induced iNOS expression and NO production in chondrocytes, but it did not have any effect on iNOS mRNA levels. iNOS protein levels were similar in cells treated with IL-1 or IL-1+TGFbeta when measured after 8 h incubation, whereas when measured after 12 h and 24 h incubations, iNOS protein levels were 50% and 80% lower in cells treated with IL-1+TGFbeta than in cells treated with IL-1 alone. CONCLUSION: TGFbeta suppressed IL-1-induced iNOS expression and NO production in chondrocytes, probably by enhancing iNOS protein degradation. This finding suggests an additional mechanism for TGFbeta to counteract the destructive effects of IL-1 in OA.

Monitoring the European standard series in 10 centres 1996-2000.

A 5-year retrospective study of the frequency of sensitization to the 25 allergens of the European standard series (ESS) was conducted in 10 centres in 8 European countries. Included were the results of 26 210 patients. The range in sensitivities differed moderately between the centres. Combining results of different centres and drawing conclusions on incidences can be done only with great care. The information on the ranking of the allergens and their sensitization incidence in the clinics are useful for decisions on the future composition of the standard series. The ESS is still a valid screening tool, and no substances should be deleted.

Patch test reactions to cosmetic allergens in 1995-1997 and 2000-2002 in Finland--a multicentre study.

Contact sensitivity to cosmetics is common, but the sensitizing chemicals vary between countries and study periods. The present survey aimed at revealing the recent trends in patch test sensitivity with cosmetic chemicals in Finland. We report a retrospective multicentre survey of patch test reactions focusing on cosmetic-related substances and comparing the test results in 1995-97 with those in 2000-02. The most striking increases in the frequency of the patch test sensitivity were found with balsam of Peru and propolis from 4.0% to 6.2% (P < 0.001) and from 0.5% to 1.4% (P < 0.001), respectively, whereas the most prominent decreases were found with methylchloro/methylisothiazolinone and chlorhexidine diglugonate from 2.4% to 1.3% (P < 0.001) and from 1.2% to 0.5% (P < 0.001), respectively. The level of patch test sensitivity to methyldibromo glutaronitrile increased, although not significantly, from 1.0% to 1.5%. An increasing tendency was also found with hair dye chemicals 4-aminophenol and toluene-2,5-diamine or toluene-2,5-diamine sulfate from 1.3% to 3.8% and from 1.4% to 5.2%, respectively, while such a tendency was not found among permanent wave chemicals. The sensitivity level of fragrance mix remained the same (6% - 7%). We conclude that surveys revealing the state of sensitivity to cosmetic chemicals should be performed periodically in different countries.

Patch testing with methyldibromo glutaronitrile, a multicentre study within the EECDRG.

Contact allergy to and allergic contact dermatitis from methyldibromo glutaronitrile (MDBGN) have frequently been reported. As there has been no agreement on which MDBGN test preparation to use, a study was initiated to help determine the optimal patch test preparation for MDBGN. 2661 consecutively patch tested patients at 11 test clinics representing 9 European countries participated. Petrolatum preparations with MDBGN at 1.0%, 0.5%, 0.3% and 0.1% were inserted in the standard series. Contact allergy rates were noted in the range 4.4-1.1% following decreasing test concentrations. Reactions not fulfilling all criteria to be classified as allergic reactions could represent either weak allergic or irritant reactions, and such reactions were noted in the range 8.2-0.5% with decreasing concentrations. A significant number of these reactions represented weak allergic reactions, as allergic reactions were obtained to higher patch test concentrations in the same individual. Morphologically irritant reactions were noted only for the highest test concentrations. In summary, the contact allergy rates and frequencies of doubtful and irritant reactions vary with the patch test concentration. The final decision on patch test concentration for MDBGN should not only rely on these factors but also include information on patch test concentrations required to diagnose individual cases with allergic contact dermatitis from MDBGN as well as results of repeated open application tests.

Repeated open application test with methyldibromo glutaronitrile, a multicentre study within the EECDRG.

Contact allergy to and allergic contact dermatitis from methyldibromo glutaronitrile (MDBGN) have frequently been reported. This study was initiated to help determine the optimal patch test preparation for MDBGN. In 51 patients with a doubtful or a positive patch test reaction to at least 1 of 4 test preparations with MDBGN in petrolatum at 1.0% w/w, 0.5%, 0.3% and 0.1%, a repeated open application test (ROAT) with moisturizers with and without MDBGN at 0.03% w/w was performed on the upper arms for 2 weeks. 18 of the 51 (35.3%) patients developed a positive ROAT. In all patients, there was a positive ROAT only to the moisturizer with MDBGN (P < 0.001). A statistically significant association was also found between the patch test reactivity (PTRL) and the outcome of the ROAT (P < 0.001). If only considering those with a PTRL above 0.3%, thus with negative or doubtful test reactions to 0.1% and 0.3%, there were still statistically significantly more patients with a positive ROAT to the moisturizer with MDBGN than to the moisturizer without MDBGN. The study demonstrates that patch testing with MDBGN at 0.3% and 0.1% will miss clinically relevant patch test reactions to MDBGN.

The Nordic Reference Interval Project 2000: recommended reference intervals for 25 common biochemical properties.

Each of 102 Nordic routine clinical biochemistry laboratories collected blood samples from at least 25 healthy reference individuals evenly distributed for gender and age, and analysed 25 of the most commonly requested serum/plasma components from each reference individual. A reference material (control) consisting of a fresh frozen liquid pool of serum with values traceable to reference methods (used as the project "calibrator" for non-enzymes to correct reference values) was analysed together with other serum pool controls in the same series as the project samples. Analytical data, method data and data describing the reference individuals were submitted to a central database for evaluation and calculation of reference intervals intended for common use in the Nordic countries. In parallel to the main project, measurements of commonly requested haematology properties on EDTA samples were also carried out, mainly by laboratories in Finland and Sweden. Aliquots from reference samples were submitted to storage in a central bio-bank for future establishment of reference intervals for other properties. The 25 components were, in alphabetical order: alanine transaminase, albumin, alkaline phosphatase, amylase, amylase pancreatic, aspartate transaminase, bilirubins, calcium, carbamide, cholesterol, creatine kinase, creatininium, gamma-glutamyltransferase, glucose, HDL-cholesterol, iron, iron binding capacity, lactate dehydrogenase, magnesium, phosphate, potassium, protein, sodium, triglyceride and urate.

Descriptive analytical data and consequences for calculation of common reference intervals in the Nordic Reference Interval Project 2000.

In the Nordic Reference Interval Project (NORIP), data from 102 Nordic clinical chemical laboratories were obtained. Each laboratory reported analytical data on up to 25 of the most commonly used clinical biochemical properties, including results from each of a minimum of 25 reference individuals. A reference material consisting of a liquid frozen pool of serum with values traceable to reference methods (used as the project "calibrator" for non-enzymes to correct reference values) was measured together with other serum pool controls in each laboratory in the same analytical series as the project samples. The data on the controls were used to evaluate the analytical quality of the routine methods. For reference interval calculations, only such reference values on enzymes were accepted that were obtained by applying the International Federation of Clinical Chemistry (IFCC) compatible methods (37 degrees C), while "calibrator"-corrected reference values were used in the cases of non-enzymes. For each property, gender- and age-specific reference intervals were estimated, based on simple non-parametric calculations and using objective criteria to perform partitioning into subgroups. It is concluded that the same reference intervals are applicable in all five Nordic countries. The following descriptive data for the considered properties are presented in the tables: number of measurement values from each country and measurement system, certified/indicative target values for controls, differences between methods and measurement systems together with coefficients of variation, effects of control correction on the measurement values, differences between subgroups as determined by age, gender, country and material, and comparison of the new reference intervals with those presented in standard textbooks. The 25 components involved in this project were (listed in alphabetical order): Alanine transaminase, albumin, alkaline phosphatase, amylase, amylase pancreatic type, aspartate transaminase, bilirubin, calcium, carbamide, cholesterol, creatine kinase, creatininium, gamma-glutamyltransferase, glucose, HDL-cholesterol, iron, iron-binding capacity, lactate dehydrogenase, magnesium, phosphate, potassium, protein, sodium, triglyceride and urate.

Are the common reference intervals truly common? Case studies on stratifying biochemical reference data by countries using two partitioning methods.

The Harris-Boyd method, recommended for partitioning biochemical reference data into subgroups by the NCCLS, and a recently proposed new method for partitioning were compared in three case studies concerning stratification by countries (Denmark, Finland, Norway, and Sweden) of reference data collected in the Nordic Reference Interval Project (NORIP) for the enzymes alkaline phosphatase (ALP), creatine kinase (CK), and gamma-glutamyl transpeptidase (GGT). The new method is based on direct estimation of the proportions of two subgroups outside the reference limits of the combined distribution, while the Harris-Boyd method uses easy-to-calculate test parameters as correlates for these proportions. The decisions on partitioning suggested by the Harris-Boyd method deviated from those obtained by using the new method for each of the three enzymes when considering pair-wise partitioning tests. The reasons for the poor performance, as it seems to be, of the Harris-Boyd method were discussed. Stratification of reference data into more than two subgroups was considered as both a theoretical problem and a practical one, using the four country-specific distributions for each enzyme as illustration. Neither the Harris-Boyd method nor the new method seems ideal to solve the partitioning problem in the case of several subgroups. The results obtained by using prevalence-adjusted values for the proportions seemed, however, to warrant the conclusion to be made that there are no major differences in terms of the partitioning criteria between the levels of each of the three enzymes in the four countries. Because these three enzymes include those two tests (CK, GGT), which in the preliminary analyses of the project data had shown largest variation between countries, the tentative conclusion was drawn that application of common reference intervals in the Nordic countries is feasible, not only for the three enzymes examined in the present study but for all of the tests involved in the NORIP project.

Effect of alpha-trinositol on secretion induced by Escherichia coli ST-toxin in rat jejunum.

AIM: d-myo-inositol-1,2,6-trisphosphate (alpha-trinositol, PP56), is a synthetic isomer of the intracellular second messenger, d-myo-inositol-1,4,5-trisphospahate. The pharmacological actions of alpha-trinositol include potent anti-inflammatory properties and inhibition of the secretion induced by cholera toxin and obstructive ileus. In the present study, we investigated whether alpha-trinositol was able to influence the secretion induced by heat-stable ST-toxin from Escherichia coli in the rat jejunum. METHODS: A midline abdominal incision was performed in anaesthetized male Sprague-Dawley rats and a 6-7 cm long jejunal segment was isolated with intact vascular supply and placed in a chamber suspended from a force displacement transducer connected to a Grass(R) polygraph. Intestinal net fluid transport was continuously monitored gravimetrically. Crystalline ST-toxin (120 mouse units) was introduced into the intestinal lumen and left there for the rest of the experiment. When a stable secretion was observed, alpha-trinositol (60 mg kg-1 h-1) or saline were infused during 2 h, followed by a 2-h control period. RESULTS: alpha-Trinositol induced a significant (P < 0.001) inhibition of ST-toxin secretion within 30 min, lasting until 2 h after infusion had stopped. The agent also moderately increased (P < 0.05) net fluid absorption in normal jejunum. Mean arterial pressure (P < 0.001) and heart rate (P < 0.001) were reduced by alpha-trinositol. CONCLUSION: The inhibition by alpha-trinositol of ST-toxin induced intestinal secretion is primarily secondary to inhibition of secretory mechanisms and only to lesser extent due to increased absorption. The detailed mechanisms of action have not been clarified but may involve suppression of inflammation possibly by means of cellular signal transduction.

Routine patch testing with frullanolide mix: an European Environmental and Contact Dermatitis Research Group multicentre study.

Contact sensitivity to plants containing 1 or more sesquiterpene lactones (SLs) is difficult to diagnose. The mixture of SLs (SL mix) has been shown to detect only about 60% of sensitized individuals. In order to improve the diagnosis of sensitization to plants containing SLs, we have tested a mixture of frullanolides contained in Frullania dilatata and Frullania tamarisci at 3 different concentrations (0.01%, 0.033% and 0.1% in petrolatum). 8605 consecutive eczema patients in 1 North American and 15 European dermatology departments were tested with this mix, and 0.35% of positive cases to the different concentrations were found. Routine use of this mix permitted detection of only a small percentage of extra cases and did not improve the SL mix score. The frullanolide mix should therefore be restricted to investigations in particular geographical zones and/or in particular occupations.

Monitoring levels of preservative sensitivity in Europe. A 10-year overview (1991-2000).

A 10-year multicentre analysis of the frequency of sensitivity to common preservatives collected in 16 centres in 11 countries has shown stable but persisting high levels of sensitivity to formaldehyde and 5-chloro-2-methyl-4-isothiazolin-3-one + 2-methyl-4-isothiazolin-3-one (MCI/MI). It has also revealed a significant increase in the level of reactivity to methyldibromoglutaronitrile (MDBGN) from 0.7% in 1991 to 3.5% in 2000. The current high level of sensitivity to MDBGN requires an urgent safety re-evaluation and risk assessment update along with consideration of immediate lowering of use concentrations, especially in leave-on products.

Effect of inositol-trisphosphate on fluid transport and protein extravasation in the obstructed small bowel.

BACKGROUND: Small-bowel obstruction is characterized by accumulation of fluid in the obstructed intestine. A pronounced inflammation in the obstructed gut wall has been shown to play an important role in the pathogenesis of the profuse fluid losses. alpha-Trinositol (D-myo-inositol-1,2,6-trisphosphate; PP56) has potent anti-inflammatory as well as antisecretory properties. The effects of alpha-Trinositol on inflammation and fluid losses in the obstructed small intestine are examined. METHODS: A total obstruction of the proximal part of the rat jejunum was induced during 18 h by thread ligation. A small segment of the obstructed intestine, with intact vascular and nervous supply, was placed in a chamber suspended from a force displacement transducer allowing for continuous registration of net fluid transport on a Grass polygraph. Three groups were included. One group (n = 12) received low-dose alpha-Trinositol (bolus: 2 mg kg(-1); IV infusion: 10 mg kg(-1) min(-1)), a second group (n = 10) received high-dose alpha-Trinositol (bolus: 12 mg kg(-1); IV infusion: 60 mg kg(-1) min(-1)), while a control group (n = 9) received corresponding volumes of isotonic saline (bolus: 0.5 ml; IV infusions 15 microl min(-1)). Quantitative measurement of extra-vasated Evans blue albumin in the obstructed jejunum was used as a marker of inflammation. RESULTS: High-dose alpha-Trinositol induced a significant (P < 0.001) inhibition of net fluid secretion, while low-dose alpha-Trinositol had no significant effect versus saline. In contrast, both doses of alpha-Trinositol induced significant inhibition of EB-albumin leakage (P < 0.05). CONCLUSION: High-dose alpha-Trinositol is a potent inhibitor of fluid secretion in obstructive ileus, most probably involving an anti-inflammatory mechanism.

Probing the human hippocampus using rCBF: contrasts in schizophrenia.

Regional cerebral blood flow (rCBF) data from two PET-15O water schizophrenia studies were analyzed using individually placed, magnetic resonance (MR)-guided hippocampal volumes of interest (VOI). In one study, normal (N = 10) and schizophrenic (N = 18) volunteers performed an overlearned auditory discrimination task in rest, control, and decision conditions. In the other study, schizophrenic and normal volunteers received the noncompetitive NMDA receptor antagonist ketamine and placebo and had sequential rCBF evaluations. Moreover, the schizophrenic volunteers were off drug in one study and on antipsychotic drug in the second study, allowing an additional comparison of medication status. VOIs were placed on anterior, middle, and posterior hippocampal areas in each PET image from both studies, redirected from an MR scan, and individually adjusted. While no hippocampal activation was apparent in either the normal or schizophrenic group in the task vs. condition comparison, rCBF was higher in the schizophrenic than in the normal hippocampus in both task and control conditions, independently. In addition, at rest rCBF was significantly higher in the unmedicated group of schizophrenics than in the group of medicated patient volunteers and higher than in the normal comparison group. This suggests that schizophrenia is associated with elevated rCBF in the hippocampus, which "normalizes" with antipsychotic drug treatment. Ketamine, the noncompetitive NMDA receptor antagonist, was more potent in reducing rCBF in the schizophrenic group compared to the normal volunteer group. These data are consistent with a previous report from our laboratory of reduced NMDA receptor NR1 subunit expression and possible abnormal NMDA receptor composition in schizophrenia. These data show an abnormality of hippocampal function in schizophrenia and suggest that this abnormality may be associated with the pathophysiology of the illness.

Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task.

OBJECTIVE: Using functional brain imaging, the authors sought to replicate their earlier finding of low metabolism in the middle frontal and inferior parietal cortices of schizophrenic patients with primary negative symptoms. METHOD: According to the presence or absence of enduring negative symptoms, patients with schizophrenia were classified as having deficit or nondeficit schizophrenia, respectively. Twelve normal volunteers and 18 drug-free schizophrenic volunteers (deficit, N=8; nondeficit, N=10) were trained in a tone discrimination task. They were trained to perform with 70%-80% accuracy and were then scanned with positron emission tomography with [(15)O]H(2)O during three conditions: rest, sensory-motor control task, and decision task. RESULTS: Levels of performance of the auditory recognition task were similar in the three groups. An initial hypothesis-driven analysis revealed that across tasks the deficit group failed to show significant activation in the middle frontal cortex. This was in contrast to both the normal volunteers and nondeficit patients. When the patient groups were contrasted, the deficit patients showed significantly less activation in the middle frontal cortex bilaterally during the control task and in the right middle frontal cortex and inferior parietal cortex during the decision task. An exploratory analysis contrasting deficit and nondeficit patients across conditions did not reveal further differences between groups. CONCLUSIONS: This study replicated the finding of low activation in the middle frontal cortex and inferior parietal cortex in deficit schizophrenia. This deficit was observed without performance confound and may provide a marker of primary negative symptoms and a target for new therapies.