Accelerated brain aging as a biomarker for staging in bipolar disorder: an exploratory study.

BACKGROUND: Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging. METHODS: In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored. RESULTS: A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages. CONCLUSIONS: These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.

Sex Differences Among Older Adults With Bipolar Disorder: Results From the Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) Project.

OBJECTIVE: Sex-specific research in adult bipolar disorder (BD) is sparse and even more so among those with older age bipolar disorder (OABD). Knowledge about sex differences across the bipolar lifespan is urgently needed to target and improve treatment. To address this gap, the current study examined sex differences in the domains of clinical presentation, general functioning, and mood symptoms among individuals with OABD. METHODS: This Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) study used data from 19 international studies including BD patients aged ≥50 years (N = 1,185: 645 women, 540 men).A comparison of mood symptoms between women and men was conducted initially using two-tailed t tests and then accounting for systematic differences between the contributing cohorts by performing generalized linear mixed models (GLMMs). Associations between sex and other clinical characteristics were examined using GLMM including: age, BD subtype, rapid cycling, psychiatric hospitalization, lifetime psychiatric comorbidity, and physical health comorbidity, with study cohort as a random intercept. RESULTS: Regarding depressive mood symptoms, women had higher scores on anxiety and hypochondriasis items. Female sex was associated with more psychiatric hospitalizations and male sex with lifetime substance abuse disorders. CONCLUSION: Our findings show important clinical sex differences and provide support that older age women experience a more severe course of BD, with higher rates of psychiatric hospitalization. The reasons for this may be biological, psychological, or social. These differences as well as underlying mechanisms should be a focus for healthcare professionals and need to be studied further.

Clinical profiles of subsequent stages in bipolar disorder: Results from the Dutch Bipolar Cohort.

INTRODUCTION: The manifestation of bipolar disorder (BD) is hypothesized to be determined by clinical characteristics such as familial loading, childhood abuse, age at onset, illness duration, comorbid psychiatric disorders, addiction, treatment resistance, and premorbid cognitive functioning. Which of these are associated with a more severe course and worse outcome is currently unknown. Our objective is to find a combination of clinical characteristics associated with advancement to subsequent stages in two clinical staging models for BD. METHODS: Using cross-sectional data from the Dutch Bipolar Cohort, staging was applied to determine the progression of bipolar-I-disorder (BD-I; N = 1396). Model A is primarily defined by recurrence of mood episodes, ranging from prodromal to chronicity. Model B is defined by level of inter-episodic functioning, ranging from prodromal to inability to function autonomously. For both models, ordinal logistic regression was conducted to test which clinical characteristics are associated with subsequent stages. RESULTS: For model A, familial loading, childhood abuse, earlier onset, longer illness duration, psychiatric comorbidity, and treatment resistance were all predictors for a higher stage in contrast to addiction and cognitive functioning. For model B, childhood abuse, psychiatric comorbidity, cognitive functioning, and treatment resistance were predictors for a more severe stage, whereas age at onset, illness duration, and addiction were not. DISCUSSION/CONCLUSIONS: Differences in clinical characteristics across stages support the construct validity of both staging models. Characteristics associated with a higher stage largely overlapped across both models. This study is a first step toward determining different clinical profiles, with a corresponding course and outcome.

Illness progression in older-age bipolar disorder: Exploring the applicability, dispersion, concordance, and associated clinical markers of two staging models for bipolar disorder in an older population.

OBJECTIVES: The validity and applicability of two existing staging models reflecting illness progression have been studied in bipolar disorder (BD) in adults, but not in older adult populations. Staging model A is primarily defined by the number and recurrence of mood episodes, model B is defined by the level of inter-episodic functioning. This study aimed to explore the applicability, dispersion, and concordance of, and associations with clinical markers in these two staging models in older-age bipolar disorder (OABD). METHODS: Using cross-sectional data from the Dutch Older Bipolars study, OABD outpatients (N = 126, ≥50 years) were staged using models A and B. Dispersion over the stages and concordance between the models were assessed. Associations were explored between model stages and clinical markers (familial loading, childhood abuse, illness duration, episode density, treatment resistance, Mini-Mental State Examination, and composite cognitive score). RESULTS: Ninety subjects could be assigned to model A, 111 to model B, 80 cases to both. The majority (61%) had multiple relapses (model A, stage 3C) but were living independently (model B, stage I-III). Concordance between models was low. For model A, the markers childhood abuse, illness duration, and episode density significantly increased over subsequent stages. Model B was not associated with a significant change in any marker. CONCLUSIONS: Assigning stages to OABD subjects was possible for both models, with age-related adjustments for model B. Model B as currently operationalized may be less suitable for OABD or may measure different aspects of illness progression, reflected by its low correspondence with model A and lack of associated clinical markers.

Exploring the clinical utility of two staging models for bipolar disorder.

OBJECTIVE: To assess the clinical utility of two staging models for bipolar disorder by examining distribution, correlation, and the relationship to external criteria. These are primarily defined by the recurrence of mood episodes (model A), or by intra-episodic functioning (model B). METHODS: In the Dutch Bipolar Cohort, stages according to models A and B were assigned to all patients with bipolar-I-disorder (BD-I; N = 1396). The dispersion of subjects over the stages was assessed and the association between the two models calculated. For both models, change in several clinical markers were concordant with the stage was investigated. RESULTS: Staging was possible in 87% of subjects for model A and 75% for model B. For model A, 1079 participants (93%) were assigned to stage 3c (recurrent episodes). Subdividing stage 3c with cut-offs at 5 and 10 episodes resulted in subgroups containing 242, 510, and 327 subjects. For model B, most participants were assigned to stage II (intra-episodic symptoms, N = 431 (41%)) or stage III (inability to work, N = 451 (43%)). A low association between models was found. For both models, the clinical markers "age at onset," "treatment resistance," and "episode acceleration" changed concordant with the stages. CONCLUSION: The majority of patients with BD-I clustered in recurrent stage 3 of Model A. Model B showed a larger dispersion. The stepwise change in several clinical markers supports the construct validity of both models. Combining the two staging models and sub-differentiating the recurrent stage into categories with cut-offs at 5 and 10 lifetime episodes improves the clinical utility of staging for individual patients.

Testing a clinical staging model for bipolar disorder using longitudinal life chart data.

OBJECTIVE: Bipolar disorder has a wide range of clinical manifestations which may progress over time. The aim of this study was to test the applicability of a clinical staging model for bipolar disorder and to gain insight into the nature of the variables influencing progression through consecutive stages. METHODS: Using retrospectively reported longitudinal life chart data of 99 subjects from the Stanley Foundation Bipolar Network Naturalistic Follow-up Study, the occurrence, duration and timely sequence of stages 2-4 were determined per month. A multi-state model was used to calculate progression rates and identify determinants of illness progression. Stages 0, 1 and several other variables were added to the multi-state model to determine their influence on the progression rates. RESULTS: Five years after onset of BD (stage 2), 72% reached stage 3 (recurrent episodes) and 21% had reached stage 4 (continuous episodes), of whom 8% recovered back to stage 3. The progression from stage 2 to 3 was increased by a biphasic onset for both the depression-mania and the mania-depression course and by male sex. CONCLUSIONS: Staging is a useful model to determine illness progression in longitudinal life chart data. Variables influencing transition rates were successfully identified.

The clinical course of late-life bipolar disorder, looking back and forward.

OBJECTIVES: Little is known about the course of late-life bipolar disorder (LLBD). First, we studied patients with LLBD retrospectively with regard to age at first mood episode, onset polarity, predominant polarity and episode density and its associations with other clinical variables. Next, we examined prospectively the clinical course and its associated factors. METHODS: Data were used from a dynamic cohort (Dutch Older Bipolars [DOBi]) including 101 patients with LLBD (mean age of 68.9 years) at baseline in 2012, with 3-year follow-up measurements available for 64 of these patients. Retrospective course was assessed by diagnostic interviews, and at follow-up polarity and duration for each consecutive episode were noted. Linear and logistic analyses were performed to assess associations between relevant factors and outcome. RESULTS: The mean age at the first episode was 33.0 years. Onset polarity was depression in 44.6% of patients, with a predominant polarity of depression in 47.5%. At 3-year follow-up, 37.5% of patients reported at least one mood episode, mainly depression. Life events, somatic illness, use of lithium and other factors were not associated with recurrence during the 3-year follow-up. DISCUSSION: A relapse rate of 37.5% in 3 years is high, considering that LLBD patients generally have a longer history of disease and were receiving care and medication. The course of LLBD can provide important information on which clinical factors are associated with recurrence. Further phenotyping may reveal unique predictors for outcome, and both course specifiers and clinical variables should be included.

Could pramipexole induce acute mania? A case report.

OBJECTIVE: In patients with bipolar disorder, olanzapine is commonly used to prevent episodes of acute mania. The drug pramipexole can, in theory, undermine the protective effect of olanzapine. Olanzapine is a dopamine D2 receptor antagonist and pramipexole is a mixed dopamine D2 /D3 receptor agonist. These drugs may therefore theoretically counteract their pharmacological effects. To date, there are no known cases in the literature where this interaction has been described. METHODS: We report on a case where a patient with bipolar disorder developed mania after taking pramipexole in combination with olanzapine, and describe the pharmacological background of this interaction. RESULTS: A patient with bipolar I disorder was hospitalized with a manic episode characterized by agitation and insomnia after taking pramipexole for restless leg syndrome (RLS) in combination with olanzapine. Co-medication, i.e., lithium and mirtazapine, and other circumstances are not likely to have contributed to this effect. CONCLUSION: There is a probable interaction between pramipexole and olanzapine, where pramipexole undermines the protective effect of olanzapine, provoking an episode of acute mania and hospitalization. This interaction is of clinical importance since pramipexole is the treatment of choice for RLS, a condition often seen in end-stage renal disease, and has also been investigated as an antidepressant therapy in patients with bipolar disorder.

[Perfectionism in healthcare: handy or handicap?] / Perfectionisme in de gezondheidszorg: handig of handicap?

Perfectionism is common amongst medical doctors and, further, it is becoming more frequently seen in young people. Factors associated with this include the rise of social media and the increasing focus on social performance. Whilst perfectionism can be associated with positive characteristics such as accuracy and perseverance, it may also have a dark side: it is associated with significant mental and physical health problems. In this context, developing greater insight into one's perfectionism and means to address it would be of benefit to doctors. Perfectionism can be divided into three forms - perfectionistic concerns (PC), perfectionistic strivings (PS), perfectionism oriented at others (PO) - each of which has a different relationship to health problems and can reinforce each other. High PC are associated with many health complaints. The relationship between PS and health complaints is possibly U-shaped: both too little and too much PS are associated with many health complaints. Doctors could benefit from more balance in their perfectionism and this could be achieved by understanding their own perfectionism as well as daring to show vulnerability and leniency towards themselves and those around them.

Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results.

PURPOSE: Major depressive disorder (MDD) has been related to both a dysfunctional gamma-amino butyric acid (GABA) system and to hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA). Although GABA has been suggested to inhibit HPA axis activity, their relationship has never been studied at the level of the central GABA(A)-benzodiazepine receptor in depressed patients or in relation to antidepressant treatment. METHODS: Eleven depressed outpatients were compared, before and after treatment with citalopram, with nine age-matched healthy controls. The subjects were scanned using the positron emission tomography (PET) tracer [(11)C]flumazenil ([(11)C]FMZ). Parametric voxel-by-voxel Logan plots were compared with methods based on regions of interest (ROI), to provide volume of distribution (V(T)) and binding potential (BP(ND)) values. Plasma GABA levels were determined and a dexamethasone-corticotropin releasing hormone (DEX-CRH) test was performed. RESULTS: In MDD, parametric voxel-by-voxel Logan plots showed bilateral reduced [(11)C]FMZ binding in the parahippocampal gyrus and right lateral superior temporal gyrus (p uncorrected < or =0.001). In the temporal area, [(11)C]FMZ binding showed a strong inverse correlation with HPA axis activity. Plasma GABA did not discriminate MDD from controls, but correlated inversely with [(11)C]FMZ binding in the right insula. Following treatment with citalopram, voxel-based analysis revealed reduced binding in the right lateral temporal gyrus and dorsolateral prefrontal cortex. CONCLUSION: The bilateral reduction in limbic parahippocampal and right temporal [(11)C]FMZ binding found in MDD indicates decreased GABA(A)-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABA(A) binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition.

Comparison of plasma input and reference tissue models for analysing [(11)C]flumazenil studies.

A single-tissue compartment model with plasma input is the established method for analysing [(11)C]flumazenil ([(11)C]FMZ) studies. However, arterial cannulation and measurement of metabolites are time-consuming. Therefore, a reference tissue approach is appealing, but this approach has not been fully validated for [(11)C]FMZ. Dynamic [(11)C]FMZ positron emission tomography scans with arterial blood sampling were performed in nine drug-free depressive patients and eight healthy subjects. Regions of interest were defined on co-registered magnetic resonance imaging scans and projected onto dynamic [(11)C]FMZ images. Using a Hill-type metabolite function, single (1T) and reversible two-tissue (2T) compartmental models were compared. Simplified reference tissue model (SRTM) and full reference tissue model (FRTM) were investigated using both pons and (centrum semiovale) white matter as reference tissue. The 2T model provided the best fit in 59% of cases. Two-tissue V(T) values were on average 1.6% higher than 1T V(T) values. Owing to the higher rejection rate of 2T fits (7.3%), the 1T model was selected as plasma input method of choice. SRTM was superior to FRTM, irrespective whether pons or white matter was used as reference tissue. BP(ND) values obtained with SRTM correlated strongly with 1T V(T) (r=0.998 and 0.995 for pons and white matter, respectively). Use of white matter as reference tissue resulted in 5.5% rejected fits, primarily in areas with intermediate receptor density. No fits were rejected using pons as reference tissue. Pons produced 23% higher BP(ND) values than white matter. In conclusion, for most clinical studies, SRTM with pons as reference tissue can be used for quantifying [(11)C]FMZ binding.

Symposia in undergraduate medical education: tailoring training in competencies to students' needs.

INTRODUCTION: In mastering competencies, it is a challenge to create training sessions which acknowledge individual students' needs and are logistically feasible in the medical master's program. METHODS: Symposia were implemented in the medical master's program to provide knowledge and training of skills in a number of topics, providing a positive contribution to students' competencies and personal development. Each symposium contained a morning and afternoon program, structured around medical and societal themes addressing various competencies and covering current national and international events. Alternating interactive teaching methods were used. Students were asked to rate each daypart program on a 5-point Likert scale in terms of both teaching methods and content, and to comment on the best aspects of the symposium as well as areas for improvement. Scores higher than 3.5 were interpreted as a predominantly favourable outcome. RESULTS: In 2016, 10 symposia were organized with an average of 108 attendees and a response rate of 63% (1,366 completed questionnaires). Mean overall scores on 'teaching methods' and 'usefulness for professional development' were 3.8 and 3.7, respectively. The overall results corresponded with a high level of student appreciation. CONCLUSION: Symposia offer a podium for training students in subject matter and competencies that is greatly appreciated. Using alternating interactive teaching methods, symposia are structured around medical and societal themes and adjusted to the latest developments and current events in healthcare. By allowing students to select the symposia they would like to participate in, a tailor-made medical master's program in competencies is created.

Neurophysiological effects of sleep deprivation in healthy adults, a pilot study.

Total sleep deprivation (TSD) may induce fatigue, neurocognitive slowing and mood changes, which are partly compensated by stress regulating brain systems, resulting in altered dopamine and cortisol levels in order to stay awake if needed. These systems, however, have never been studied in concert. At baseline, after a regular night of sleep, and the next morning after TSD, 12 healthy subjects performed a semantic affective classification functional magnetic resonance imaging (fMRI) task, followed by a [11C]raclopride positron emission tomography (PET) scan. Saliva cortisol levels were acquired at 7 time points during both days. Affective symptoms were measured using Beck Depression Inventory (BDI), Spielberger State Trait Anxiety Index (STAI) and visual analogue scales. After TSD, perceived energy levels, concentration, and speed of thought decreased significantly, whereas mood did not. During fMRI, response speed decreased for neutral words and positive targets, and accuracy decreased trendwise for neutral words and for positive targets with a negative distracter. Following TSD, processing of positive words was associated with increased left dorsolateral prefrontal activation. Processing of emotional words in general was associated with increased insular activity, whereas contrasting positive vs. negative words showed subthreshold increased activation in the (para)hippocampal area. Cortisol secretion was significantly lower after TSD. Decreased voxel-by-voxel [11C]raclopride binding potential (BPND) was observed in left caudate. TSD induces widespread cognitive, neurophysiologic and endocrine changes in healthy adults, characterized by reduced cognitive functioning, despite increased regional brain activity. The blunted HPA-axis response together with altered [11C]raclopride binding in the basal ganglia indicate that sustained wakefulness requires involvement of additional adaptive biological systems.

Neurological signs in parents of schizophrenic patients.

The importance of neurological abnormalities in relatives of schizophrenic patients is not completely clear and has been questioned. The hypothesis that neurological abnormalities are trait markers for a vulnerability to develop schizophrenia was tested in 32 parents of patients with schizophrenia and 34 healthy controls. A comprehensive and standardized neurological assessment battery was used. The examiners were blind as to whether they tested a parent of a patient or a healthy control. Four function domains were investigated; higher cerebral functions, cranial nerve functions, general motor functions and gait. There were no significant differences between parents of patients and healthy controls on any of the neurological function domains, or on the total number of neurological abnormalities. No difference was found between parents with a positive family history of schizophrenia spectrum disorders, parents with a negative family history and controls. Results suggest that the neurological functions investigated are not related to a genetic liability to develop schizophrenia.

Prevalence and predictors of unexplained neurological symptoms in an academic neurology outpatient clinic--an observational study.

OBJECTIVES: (a) To determine the prevalence of unexplained symptoms among newly referred patients in a Dutch academic outpatient clinic for general neurology; (b) To identify factors that can serve as characteristics and possibly as screening instruments for unexplained symptoms in this population. METHODS: Observational study, consisting of self-assessment questionnaires. Patients and resident neurologists completed self-designed questionnaires, which included questions about possible features of unexplained symptoms. Patients also completed the Hospital Anxiety and Depression Scale (HADS), evaluating the existence of anxiety and depressive symptoms. Diagnosis of unexplained symptoms was based on the final classification of the patient's symptoms as non-organic, after assessment by a senior neurologist. In the analysis, separate predicting factors and groups of factors were adjusted for age, sex and HADS-score, and analysed as possible characteristics of unexplained symptoms. RESULTS: 35% of the patients (208 total, 174 completed questionnaires) were considered to suffer from unexplained symptoms. Young age (p < 0.001) and female sex (p = 0.007) were significantly associated with unexplained symptoms, high HADS-scores were not (p = 0.10). Characteristics associated with unexplained symptoms were the resident's preliminary impression of symptoms being non-organic, after reading of the referral letter [OR 96.8, 95% confidence interval (95 %-CI) 29.7-315, PPV 82%, NPV 96%] and after the first encounter (OR 305, 95 %-CI 37.3-2494.6, PPV 83%, NPV 98%), but before the actual history taking and neurological examination. The only other non-demographic characteristic of unexplained symptoms was a visit in order to obtain a second opinion (OR 2.43, 95 %-CI 1.15-5.10). Clustering of these factors, however, did not have sufficient predictive power to result in an accurate screening instrument. CONCLUSIONS: Unexplained symptoms are common in the neurology outpatient clinic and are to some extent predicted by the physician's preliminary judgement of symptoms. However, history taking and neurological examination remain indispensable for the detection of less obvious organic disorders.

Responsivity to stress in chronic posttraumatic stress disorder due to childhood sexual abuse.

The purpose of this study was to investigate psychological, cardiovascular, and neuroendocrine reactivity to standardized stress tests (orthostatic challenge, Stroop Color Word Test) in drug-free adult women with chronic PTSD due to repetitive childhood sexual abuse. At baseline, the 11 patients showed significantly higher mean scores on the Symptom Check List-90 and the Profile of Mood States than 13 healthy female controls, whereas baseline cardiovascular or hormonal parameters showed no differences between the groups. Also, no significant differences were found between the two groups in cardiovascular and hormonal responsivity to the stress tests. Thus, in the presence of robust psychological differences, the patients with chronic PTSD due to childhood sexual abuse did not show alterations in baseline values of neurobiological parameters, nor did they react differently to a physical and mental stress test when compared to healthy controls.

Parametric [11C]flumazenil images.

OBJECTIVE: This [11C]flumazenil (FMZ) study evaluates the performance of various parametric analysis methods and their ability to detect statistically significant group differences. METHODS: Dynamic 60-min FMZ scans were performed in eight healthy and nine individuals with major depressive disorder. Parametric volume of distribution (VT) images were generated using a basis function method (BFM) implementation of the single tissue compartment model (1T) and Logan plot analysis, both with a metabolite-corrected arterial plasma input function. Parametric binding potential (BP ND) images were generated using multilinear reference tissue methods (MRTM0-4), reference Logan and receptor parametric mapping (RPM1-2), with pons as a reference region. Standardized uptake value (SUV) and SUV ratio-to-pons (SUVr) images were calculated over the time interval 30-40 and 20-60 min postinjection. The resulting VT, BP ND, SUV and SUVr values were compared with nonlinear regression values, using both the 1T model and the simplified reference tissue model. Statistical parametric mapping (SPM5) was used to detect group differences, with an emphasis on the bilateral parahippocampal gyri. RESULTS: BFM was more accurate than Logan, but showed more variability. Both RPM methods and MRTM2 showed the best average correlation with the simplified reference tissue model. In using SPM, SUV and SUVr images provided the best contrast between groups in the parahippocampal gyri, but provided large underestimation and overestimation in quantitative comparisons. BFM and RPM methods allowed for the determination of perfusion effects. CONCLUSION: Parametric Logan VT, MRTM2 and RPM1-2 BP ND methods allow the best quantitative comparison of FMZ binding between groups and show good discriminating performance in SPM analysis.

Partial volume corrected image derived input functions for dynamic PET brain studies: methodology and validation for [11C]flumazenil.

Extraction of arterial input functions from dynamic brain scans may obviate the need for arterial sampling and would increase the clinical applicability of quantitative PET studies. The aim of the present study was to evaluate applicability and accuracy of image derived input functions (IDIFs) following reconstruction based partial volume correction (PVC). Settings for the PVC ordered subset expectation maximization (PVC-OSEM) reconstruction algorithm were varied. In addition, different methods for defining arterial regions of interest (ROI) in order to extract IDIFs were evaluated. [(11)C]flumazenil data of 10 subjects were used in the present study. Results obtained with IDIFs were compared with those using standard on-line measured arterial input functions. These included areas under the curve (AUC) for peak (1-2 min) and tail (2-60 min), volume of distribution (V(T)) obtained using Logan analysis, and V(T) and K(1) obtained with a basis function implementation of a single tissue compartment model. Best results were obtained with PVC-OSEM using 4 iterations and 16 subsets. Based on (11)C point source measurements, a 4.5 mm FWHM (full width at half maximum) resolution kernel was used to correct for partial volume effects. A ROI consisting of the four hottest pixels per plane (over the carotid arteries) was the best method to extract IDIFs. Excellent peak AUC ratios (0.99+/-0.09) between IDIF and blood sampler input function (BSIF) were found. Furthermore, extracted IDIFs provided V(T) and K(1) values that were very similar to those obtained using BSIFs. The proposed method appears to be suitable for analysing [(11)C]flumazenil data without the need for online arterial sampling.