Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Tunable narrow-linewidth laser at 2†µm wavelength for gravitational wave detector research.

We present and characterize a narrow-linewidth external-cavity diode laser at 2 µm, and show that it represents a low-cost, high-performance alternative to fiber lasers for research into 2 µm photonic technologies for next-generation gravitational-wave detectors. A linewidth of 20 kHz for a 10 ms integration time was measured without any active stabilization, with frequency noise of ∼ 15 Hz/Hz between 3 kHz and 100 kHz. This performance is suitable for the generation of quantum squeezed light, and we measure intensity noise comparable to that of master oscillators used in current gravitational wave interferometers. The laser wavelength is tunable over a 120 nm range, and both the frequency and intensity can be modulated at up to 10 MHz by modulating the diode current. These features also make it suitable for other emerging applications in the 2 µm wavelength region including gas sensing, optical communications and LIDAR.

Angioedema associated with thrombolysis for ischemic stroke: analysis of a case-control study.

BACKGROUND: Bradykinin-mediated angioedema (AE) is a complication associated with thrombolysis for acute ischemic stroke. Risk factors are unknown and management is discussed. OBJECTIVES: To clarify risk factors associated with bradykinin-mediated AE after thrombolysis for acute ischemic stroke. METHODS: In a case-control study conducted at a French reference centre for bradykinin angiœdema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angiœdema, were compared to controls treated with thrombolysis treatment without angiœdema. RESULTS: Fifty-three thrombolysis-related AE were matched to 106 control subjects. The sites of attacks following thrombolysis for ischemic stroke mainly included tongue (34/53, 64%) and lips (26/53, 49%). The upper airways were involved in 37 (70%) cases. Three patients required mechanical ventilation. Patients with bradykinin-mediated angiœdema were more frequently women [33 (62%) vs. 44 (42%); P = 0.01], had higher frequency of prior ischemic stroke [12 (23%) vs. 9 (8%); P = 0.01], hypertension [46 (87%) vs. 70 (66%); P = 0.005], were more frequently treated with angiotensin-converting enzyme inhibitor [37 (70%) vs. 28 (26%); P < 0.001] and were more frequently hospitalized in intensive care medicine [ICU; 11 (21%) vs. 5 (5%); P = 0.004]. In multivariate analysis, factors associated with thrombolysis-related AE were female sex [odds ratio (OR), 3.04; 95% confident interval (CI), 1.32-7.01; P = 0.009] and treatment with angiotensin-converting enzyme inhibitors [(OR), 6.08; 95% (CI), 2.17-17.07; P < 0.001]. CONCLUSIONS: This case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykinin AE associated with thrombolysis for ischemic stroke.

Metrics of progress in the understanding and management of threats to Australian birds.

Although evidence-based approaches have become commonplace for determining the success of conservation measures for the management of threatened taxa, there are no standard metrics for assessing progress in research or management. We developed 5 metrics to meet this need for threatened taxa and to quantify the need for further action and effective alleviation of threats. These metrics (research need, research achievement, management need, management achievement, and percent threat reduction) can be aggregated to examine trends for an individual taxon or for threats across multiple taxa. We tested the utility of these metrics by applying them to Australian threatened birds, which appears to be the first time that progress in research and management of threats has been assessed for all threatened taxa in a faunal group at a continental scale. Some research has been conducted on nearly three-quarters of known threats to taxa, and there is a clear understanding of how to alleviate nearly half of the threats with the highest impact. Some management has been attempted on nearly half the threats. Management outcomes ranged from successful trials to complete mitigation of the threat, including for one-third of high-impact threats. Progress in both research and management tended to be greater for taxa that were monitored or occurred on oceanic islands. Predation by cats had the highest potential threat score. However, there has been some success reducing the impact of cat predation, so climate change (particularly drought), now poses the greatest threat to Australian threatened birds. Our results demonstrate the potential for the proposed metrics to encapsulate the major trends in research and management of both threats and threatened taxa and provide a basis for international comparisons of evidence-based conservation science.

Medidas de Progreso en el Entendimiento y el Manejo de las Amenazas que Enfrentan las Aves Australianas Resumen Aunque los métodos basados en evidencias se han vuelto muy comunes para la determinación del éxito de las medidas de conservación del manejo de los taxones amenazados, hoy en día no existen medidas estandarizadas para la evaluación del progreso de la investigación o el manejo. Desarrollamos cinco medidas para cumplir con esta necesidad que tienen los taxones amenazados y para cuantificar la necesidad de una mayor acción y un alivio efectivo de las amenazas. Estas medidas (falta de investigación, éxito de la investigación, falta de manejo, éxito del manejo y porcentaje de reducción de amenazas) pueden agregarse para examinar las tendencias de un taxón individual o las tendencias de las amenazas para múltiples taxones. Probamos la utilidad de estas medidas por medio de su aplicación en aves australianas amenazadas, que parece ser la primera vez que se evalúa el progreso en la investigación y en el manejo de amenazas para el caso de varios taxones amenazados dentro de un grupo faunístico a escala continental. Se ha realizado algún tipo de investigación sobre casi tres cuartas partes de las amenazas conocidas para los taxones, y hay un claro entendimiento de cómo aliviar casi la mitad de las amenazas con el impacto más alto. Se ha intentado algún tipo de manejo con casi la mitad de las amenazas. Los resultados del manejo variaron desde ensayos exitosos hasta la mitigación completa de la amenaza, incluso para un tercio de las amenazas de alto impacto. Tanto el progreso en la investigación como en el manejo tendió a ser mayor para los taxones que estaban siendo monitoreados, o que ocurrían en islas oceánicas. La depredación por gatos tuvo el puntaje más como amenaza potencial. Sin embargo, ha habido poco de éxito en la reducción del impacto de la depredación por gatos, así que ahora el cambio climático (particularmente la sequía) es la mayor amenaza para las aves amenazadas en Australia. Nuestros resultados demuestran el potencial que tienen las medidas propuestas de encapsular las tendencias más importantes en la investigación y en el manejo tanto de las amenazas como de los taxones amenazados y de proporcionar una base para comparaciones internacionales de la ciencia de la conservación basada en evidencias.

How to improve threatened species management: An Australian perspective.

Targeted threatened species management is a central component of efforts to prevent species extinction. Despite the development of a range of management frameworks to improve conservation outcomes over the past decade, threatened species management is still commonly characterised as ad hoc. Although there are notable successes, many management programs are ineffective, with relatively few species experiencing improvements in their conservation status. We identify underlying factors that commonly lead to ineffective and inefficient management. Drawing attention to some of the key challenges, and suggesting ways forward, may lead to improved management effectiveness and better conservation outcomes. We highlight six key areas where improvements are needed: 1) stakeholder engagement and communication; 2) fostering strong leadership and the development of achievable long-term goals; 3) knowledge of target species' biology and threats, particularly focusing on filling knowledge gaps that impede management, while noting that in many cases there will be a need for conservation management to proceed initially despite knowledge gaps; 4) setting objectives with measurable outcomes; 5) strategic monitoring to evaluate management effectiveness; and 6) greater accountability for species declines and failure to recover species to ensure timely action and guard against complacency. We demonstrate the importance of these six key areas by providing examples of innovative approaches leading to successful species management. We also discuss overarching factors outside the realm of management influence that can help or impede conservation success. Clear recognition of factors that make species' management more straightforward - or more challenging - is important for setting realistic management objectives, outlining strategic action, and prioritising resources. We also highlight the need to more clearly demonstrate the benefit of current investment, and communicate that the risk of under-investment is species extinctions. Together, improvements in conservation practice, along with increased resource allocation and re-evaluation of the prioritisation of competing interests that threaten species, will help enhance conservation outcomes for threatened species.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.

Body-condition indices are repeatable across short, but not long, time periods in crimson finches Neochmia phaeton.

Abstract It is common in evolutionary ecology to interpret body-condition indices as indicators of individual quality, but this hypothesized relationship has been questioned and remains poorly validated. Here, we test one of the fundamental predictions of this condition-quality hypothesis, that relative-condition indices are repeatable within individuals, that is, that the index score of an individual relative to others is consistent over time. We sampled crimson finches (Neochmia phaeton) for seven commonly used condition indices and tested whether individual condition relative to conspecifics in the same context (e.g., breeding stage) was repeatable. We calculated the relative indices' repeatability across several temporal scales, from short (within breeding season) to long (more than 2 yr) time periods, as well as without consideration of timescale. Most relative-condition indices were repeatable when sampled without consideration of timescale, all were repeatable within a short time period, and none were repeatable over the longest time period. This provides only partial support for the condition-quality hypothesis, because although relative-condition indices were generally repeatable, this was primarily attributed to short-term, instead of long-term, repeatability. Condition indices may be meaningful indicators of short-term survival or fitness potential, but our findings are inconsistent with the idea that condition indices are indicators of inherent individual quality.

Evidence that duplications of 22q11.2 protect against schizophrenia.

A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.

Transcranial direct current stimulation of the affected hemisphere does not accelerate recovery of acute stroke patients.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (TDCS) is a potential tool to improve motor deficits in chronic stroke patients. Safety and efficacy of this procedure in acute stroke patients have not yet been addressed. METHODS: We performed in our stroke unit a single-centre randomized, double-blind, sham-controlled study to investigate safety and efficacy of anodal TDCS of the affected hemisphere in acute stroke patients. The second day from stroke onset, 50 acute stroke patients received either five-daily sessions of anodal (n=25) at 2mA for 20min or sham TDCS (n=25) to the ipsilesional primary motor cortex (M1). Motor deficit was assessed by the short form of the Fugl-Meyer motor scale (FM) and overall neurological deficit by the National Institute of Health Stroke Scale (NIHSS) at onset, at 5days after stroke and after 3months. RESULTS: No side effects were detected during either TDCS or sham. In both groups, there was a significant improvement in NIHSS and FM scores, which did not significantly differ when comparing TDCS and sham. CONCLUSIONS: Five-daily sessions of anodal TDCS to the ipsilesional M1 appear to be safe in acute stroke patients but do not improve clinical outcome.

Acute stroke with hyperdense middle cerebral artery sign benefits from IV rtPA.

OBJECTIVES: The current management of acute ischemic stroke is intravenous (IV) recombinant tissue plasminogen activator (rtPA). The presence of a hyperdense middle cerebral artery sign (HMCAS) on pre-treatment head computed tomogram (CT) is considered a poor prognostic sign. We compared the clinical outcome in IV rtPA-treated patients with and without a HMCAS. DESIGN: Retrospective analysis of prospectively collected cases treated with IV rtPA within three hours. Inclusion criteria were the presence of: i) an anterior circulation stroke; ii) a pre-treatment CT available; iii) a pre-treatment National Institutes of Health (NIH) stroke scale (NIHSS) score; and iv) a modified Rankin Score (mRS) at three months. RESULTS: One hundred and thirty patients were eligible for the analysis, 64 (49%) had a HMCAS. The HMCAS group had a trend toward a higher mean (+/-SD) pre-treatment NIHSS score compared to the non-HMCAS group (13.9+/-6 vs. 12.2+/-6; p=0.12). Accordingly, there were more patients with severe strokes (NIHSS>10) in the HMCAS group compared to the non-HMCAS one (48/64=75% vs. 35/66=53%; p=0.009). The mean (+/-SD) NIHSS score 24 hours after treatment was 10.6 (+/-8) in the HMCAS group and 8.3 (+/-7) in the non-HMCAS group (p=0.08). In a multiple logistic regression analysis, the only independent predictor of poor outcome (mRS 3-6) was pre-treatment NIHSS score (p<0.001). CONCLUSION: Patients with a HMCAS receiving IV rtPA did not fare worse at three months despite a greater proportion of patients with more severe strokes. Based on the current knowledge, IV rtPA remains a good treatment for patients with a HMCAS within three hours of symptom onset.

Joint effect of stroke and APOE 4 on dementia risk: the Canadian Study of Health and Aging.

BACKGROUND: Although stroke and APOE 4 are independent risk factors for dementia, their combined effect remains uncertain. We assessed their joint effect on dementia risk. METHODS: Subjects participated in Phases 1 and 2 of the Canadian Study of Health and Aging (CSHA). Dementia was diagnosed by consensus, and stroke was diagnosed by history or clinical examination. Analyses were first conducted among clinical participants only, and then rerun with the screening sample included as well. RESULTS: Analyses included 949 participants from CSHA-1 and 1,413 from CSHA-2. During a median 4.6-year follow-up, 740 were included in the CSHA-1 to -2 incidence study. Among clinical participants, the highest prevalence (40.6% for CSHA-1 and 57.6% for CSHA-2) and incidence (8.4 per 100 person-years) of dementia occurred in elderly having both stroke and APOE 4; the lowest prevalence (19.8% for CSHA-1 and 23.3% for CSHA-2) and incidence (4.3 per 100 person-years) were among persons having neither. These findings held true when the screening sample was included. The adjusted hazard ratios of incident dementia, relative to elderly with neither stroke nor APOE 4, were 1.33 (95% CI 0.73 to 2.43) for stroke alone, 2.06 (95% CI 1.42 to 2.99) for APOE 4 alone, and 2.57 (95% CI 1.11 to 5.94) for both. No interaction on additive or multiplicative scales was suggested. CONCLUSIONS: The joint presence of stroke and APOE 4 was associated with a greater risk of dementia compared with absence of these two factors. The effect of stroke on dementia does not seem to be modified by APOE 4.

Monthly brain magnetic resonance imaging scans in patients with clinically isolated syndrome.

We investigated if monthly gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) can assist the clinician in anticipating the diagnosis of multiple sclerosis (MS) in the very first few months following a clinically isolated syndrome (CIS). A consecutive series of CIS patients with > or = 3 T2-weighted (T2W) hyperintense brain MRI lesions suggestive of MS were followed up for the first six consecutive months after enrollment with monthly triple-dose Gd-enhanced brain MRI scan. MRI conversion to MS was defined by the presence of either > or = 1 new Gd-enhancing lesion or > or = 1 new T2W lesions in the subsequent MRI scan. Sixty patients were included. Of them, 30 (50%) had at least one Gd-enhancing lesion on the baseline MRI scan. After three months, MRI conversion to MS was observed in 80% and 62% of patients based on the appearance of > or = 1 new T2 lesion and > or = 1 new Gd-enhancing lesions, respectively. The presence of > or = 1 new T2W lesion was observed in 90% and 82% of patients who had, at baseline, a Gd-positive MRI scan and dissemination in space based on the new McDonald's criteria, respectively The rate of MRI conversion remained almost stable in the last two MRI scans. Our study suggests that the majority of CIS patients with an abnormal baseline scan showed an MRI conversion to MS after three months. The model of six months as the optimal interval for repeating MRI exam is not supported by the present data.

Effect of external stresses on protein conformation: a computer modelling study.

The increasing use of digital technologies such as mobile phones has led to major health concerns about the effects of non-ionizing pulsed radiation exposure. We believe that the health implications of exposure to radiation cannot be fully understood without establishing the molecular mechanisms of biological effects of pulsed microwaves. We aim to establish methods for studying the molecular mechanisms of protein structural and energetic changes occurring due to external stresses related to non-ionizing radiation by using a combination of experimental and theoretical approaches. In this paper, we present the results from our fully atomistic simulation study of chemical and thermal stress response of a prototype protein, insulin. We performed a series of molecular dynamics simulations of insulin in solution under equilibrium conditions, under chemical stress (imitated by reducing the disulfide bonds in the protein molecule), and under short-lived thermal stress (imitated by increasing simulation temperature for up to 2 ns). The resultant protein conformational behaviour was analysed for various properties with the aim of establishing analysis routines for classification of protein unfolding pathways and associated molecular mechanisms.

Longitudinal evaluation of depression and anxiety in patients with clinically isolated syndrome at high risk of developing early multiple sclerosis.

We investigated the relationship between emotional changes, brain lesion burden and development of multiple sclerosis (MS). Thirty-seven consecutive patients with clinically isolated syndrome (CIS) were prospectively assessed with the Expanded Disability Status Scale (EDSS), the 21-item Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI) and gadolinium enhanced (Gd+) MRI scans. BDI and STAI were also administered to 36 age-matched controls. Conversion to MS was defined as the occurrence of a clinical relapse. CIS patients were more likely to endorse symptoms of anxiety and depression than controls. Baseline scores for depression and anxiety did not correlate with the total lesion load (i.e., volume of Gd+, T2 and T1 lesions) and the number of Gd+ lesions during the first six months of follow-up. A positive correlation was found between severity of depressive scores and the lesion load in the right temporal region (P = 0.005). After 33+/-6 months of the study entry, patients who had a clinical relapse were more frequently depressed (P = 0.001) than those relapse free. Emotional disturbances are frequently observed in CIS patients and show a tendency towards a normalization in relapse-free patients. The increased rate of depressive symptoms observed in patients who developed MS seems to result from a combination of psychological and organic features. The lesion load in the right temporal region is confirmed as a key area for developing depressive symptoms, even in the early phase of the disease.

Carotid endarterectomy and gliofibrillar S100b protein release.

Increased levels of the gliofibrillar S100b protein can be detected during carotid endarterectomy (CEA). Whether the S100b protein increase is marker of brain ischemic sufferance and predictor of cognitive decline is controversial. Twenty-eight patients underwent clinical assessment and cranial computed tomography (CT) 24-48 hours before and 3 months after CEA. S100b serum levels were evaluated before surgery, at cross-clamping, 10 minutes later, at declamping, and 24-48 hours and 10-12 weeks after CEA. Increased S100b levels were detected in 11 patients (39%); eight (73%) of these patients had symptomatic carotid artery disease. Increased S100b level correlated with history of TIA or stroke ( p=0.005), low mini-mental state examination score ( p=0.02), and ischemic infarctions at preoperative CT ( p=0.03). Slight and transient increased S100b levels were detected in 39% of patients during CEA. The protein levels increased despite the absence of clinical events during surgery. Our findings suggest a failure of compensatory hemodynamic or metabolic mechanisms in peri-ischemic tissue, whose longterm effects on cognition remain to be investigated.

Blood cholesterol and MRI activity in first clinical episode suggestive of multiple sclerosis.

OBJECTIVES: The present study was planned to investigate the relationship between the plasma lipid profile and disease activity in patients with a first clinical episode suggestive of multiple sclerosis (MS). MATERIAL AND METHODS: Eighteen consecutive out-patients underwent a monthly brain magnetic resonance imaging (MRI), blood sample and neurological assessment over 6 months. Blood samples were used to evaluate total cholesterol and triglyceride levels as well as their lipoprotein fractions. Plasma total apolipoprotein E concentration was also determined. RESULTS: We found a significant correlation between the mean number of enhancing lesions and the mean plasma level of both total and low density lipoprotein cholesterol. The total plasma cholesterol level increased on average by 4.4 mg/dl for each enhancing lesion. CONCLUSION: Our preliminary data suggest a potential role of plasma cholesterol level as a biological marker of disease activity after a first demyelinating event. Further studies need, however, to be designed to determine whether the plasma cholesterol level is of practical use in monitoring the disease course.

Metallic orthopaedic implants and airport metal detectors.

Airport security can detect in vivo metallic implants. We hypothesized that a soft tissue shield and fast transit through archway detectors would decrease implant detectability, whereas greater implant mass would increase detectability. Twelve patients with 8 orthopaedic implants in vivo and 60 trauma and arthroplasty implants in vitro were subjected to standard airport security measures at Stanstead Airport (British Airports Authority), including arch and standard and nonstandard hand-held detectors. Archway detectors failed to detect some implants; hand-held detectors detected almost all implants except an ankle arthroplasty. Positive archway detection was related to implant transit speed through the detection field. The implant mass consistently affected detection in stainless steel and titanium implants, and a 1-inch wax shield had no effect. Patients with metallic implants should prepare routinely with documentation of their implant before traveling through security ports.

Diazepam effects on the cerebral responses to tonic pain: a SPET study.

RATIONALE: Pain is a complex phenomenon with a strong affective-emotional component in addition to a sensory-discriminative one. This causes the activation of multiple brain areas, which process different aspects of pain simultaneously. OBJECTIVES: We investigated the effects of diazepam (DZ) on a well-known pattern of brain regions activated by cold, tonic pain stimuli. METHODS: Quantitative cerebral blood flow (CBF) was assessed by single photon emission tomography (SPET) and the Xe-133 inhalatory method, at rest and during tonic pain activation in eight normal, right-handed, male volunteers. The cold pressor test (CPT) was performed by immersion of the left hand in cold water twice, first during CPT alone, and again 30 min after intravenous administration of diazepam (CPT+DZ). RESULTS: During CPT we observed a significant CBF increase in the right thalamus, primary sensory-motor cortex (S1/M1), frontal and temporal regions, and in the left temporal region and anterior cingulate cortex (ACC). During CPT+DZ, the average CBF was significantly lower than during the CPT state (-11%, P<0.05). After normalisation, during CPT+DZ we again observed a significant CBF increase in the right thalamus, S1/M1 and frontal regions, and in the left ACC, though not in the temporal regions. DZ administration first causes a global reduction in CBF, then modifies the pattern of brain activation. CONCLUSIONS: During CPT, activation of the temporal regions has been interpreted as part of the affective-emotional component of pain response. DZ seems to affect the "pain-related" pattern of activation by abolishing the CBF increase in the temporal regions, without, however, modifying the pain perception or determining a sedating effect.