Eye pain caused by brainstem infarction.

Sudden pain of the eye, nose or face can be a symptom of stroke located to the pons. This case report is about a 73-year-old women with acute debut of right-sided hemiparesis, ataxia, gait disturbance, dysarthria, hemisensory defects and contralateral burning eye pain. MRI showed acute ischaemia of the left pons. The case adds to the growing literature of this rare presentation of posterior circulation stroke.

Parkinson's disease and changes in the appreciation of art: A comparison of aesthetic and formal evaluations of paintings between PD patients and healthy controls.

Parkinson's disease (PD) is a progressing neurodegenerative disease predominantly involving the loss of dopamine producing neurons with hallmark symptoms of motor disorders and cognitive, motivational, emotional, and perceptual impairments. Intriguingly, PD can also be connected-often anecdotally-with a sudden burst of artistic creativity, motivation, or changed quality/style of produced art. This has led to growing empirical interest, promising a window into brain function and the unique neurological signature of artists. This topic also fits a growing interest from researchers in other areas, including Alzheimer's or other dementia, which have suggested that specific changes in art production/appraisal may provide a unique basis for therapy, diagnosis, or understanding of these diseases. However, whether PD also shows similar impacts on how we perceive and evaluate art has never been systematically addressed. We compared a cohort of PD patients against age-matched healthy controls, asking participants to rate paintings using scales of liking and beauty and terms pertaining to artworks' formal and conceptual qualities previously designed to provide a rubric for symptom identification. We found no evidence for PD-related differences in liking or beauty. However, PD patients showed higher ratings on assessed "emotionality," potentially relating to the tie between PD, dopamine pathways, and emotion/reward.

Why would Parkinson's disease lead to sudden changes in creativity, motivation, or style with visual art?: A review of case evidence and new neurobiological, contextual, and genetic hypotheses.

Parkinson's disease (PD) is a devastating diagnosis with, however, potential for an extremely intriguing aesthetic component. Despite motor and cognitive deficits, an emerging collection of studies report a burst of visual artistic output and alterations in produced art in a subgroup of patients. This provides a unique window into the neurophysiological bases for why and how we might create and enjoy visual art, as well as into general brain function and the nature of PD or other neurodegenerative diseases. However, there has not been a comprehensive organization of literature on this topic. Nor has there been an attempt to connect case evidence and knowledge on PD with present understanding of visual art making in psychology and neuroaesthetics in order to propose hypotheses for documented artistic changes. Here, we collect the current research on this topic, tie this to PD symptoms and neurobiology, and provide new theories focusing on dopaminergic neuron damage, over-stimulation from dopamine agonist therapy, and context or genetic factors revealing the neurobiological basis of the visual artistic brain.

[Challenges in the differential diagnoses of parkinsonism].

Parkinsonism (PD) is the clinical syndrome of bradykinesia combined with rigidity and/or tremor at rest. These are the defining characteristics of PD, but they are present in many other diseases of the brain. The most frequent differential diagnosis of PD are the atypical parkinsonian syndromes and the conditions presenting with mainly lower body parkinsonism. Discrimination between these can be challenging, especially at early stages of the disease, but nevertheless of utmost importance, because treatment and prognosis vary. Diagnoses are clinical, as disease-specific biomarkers are still lacking.

Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels.

Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding.

Longitudinal assessment of cerebral 5-HT2A receptors in healthy elderly volunteers: an [18F]-altanserin PET study.

PURPOSE: The serotonin 2A (5-HT(2A)) receptor is of interest in several psychiatric and neurological diseases. In the present study we investigated the longitudinal stability of 5-HT(2A) receptors and the stability of the quantification procedure in the elderly in order to be able to study elderly patients with neuropsychiatric diseases on a longitudinal basis. METHODS: [(18)F]-Altanserin PET was used to quantify 5-HT(2A) receptors in 12 healthy elderly individuals at baseline and at 2 years in six volumes of interest. A bolus/infusion protocol was used to achieve the binding potential, BP(P). The reproducibility as assessed in terms of variability and the reliability as assessed in terms of intraclass correlation coefficient (ICC) were used to compare inter- and intraobserver stability and to evaluate the effects of increasing complexity of partial volume (PV) corrections. We also compared the stability of our measurements over 2 years with the stability of data from an earlier study with 2-week test-retest measurements. RESULTS: BP(P) was unaltered at follow-up without the use of PV correction and when applying two-tissue PV correction, test-retest reproducibility was 12-15% and reliability 0.45-0.67 in the large bilateral regions such as the parietal, temporal, occipital and frontal cortices, while orbitofrontal and anterior cingulate cortical regions were less stable. The use of PV correction decreased the variability but also decreased the between-subject variation, thereby worsening the reliability. CONCLUSION: In healthy elderly individuals, brain 5-HT(2A) receptor binding remains stable over 2 years, and acceptable reproducibility and reliability in larger regions and high intra- and interobserver stability allow the use of [(18)F]-altanserin in longitudinal studies of patients with neuropsychiatric disorders.

The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined.

With the appropriate radiolabeled tracers, positron emission tomography (PET) enables in vivo human brain imaging of markers for neurotransmission, including neurotransmitter synthesis, receptors, and transporters. Whereas structural imaging studies have provided compelling evidence that the human brain anatomy is largely genetically determined, it is currently unknown to what degree neuromodulatory markers are subjected to genetic and environmental influence. Changes in serotonin 2A (5-HT(2A)) receptors have been reported to occur in various neuropsychiatric disorders and an association between 5-HT(2A) receptor gene variants and neuropsychiatric illness susceptibility also exists. In a classical twin design involving 24 healthy male subjects (6 monozygotic twin pairs and 6 dizygotic twin pairs), we examined the relative contribution of genetic and environmental factors to interindividual variability in cortical 5-HT(2A) receptor binding as measured with [(18)F]altanserin PET imaging. The intraclass correlation coefficients were 0.67 for dizygotic and 0.87 for monozygotic twin pairs. For comparison, the intraclass correlation coefficient was 0.93 in a group of six male healthy subjects examined twice within two weeks with an identical experimental setup. Multivariate analysis was used to separate the phenotypic variance of individuals into additive genetic (heritability) effect (A), shared (family) environment (C), and non-shared (individual-specific) environment (E). Irrespective of whether a full ACE model or a reduced AE model was used to fit the data, the variance due to non-shared environment was below 10% indicating that the contribution of individual specific environmental factors to 5-HT(2A) receptor binding is limited.

Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients.

The serotonin 5-HT(2A) receptor is suspected to be involved in a number of psychiatric disorders, including schizophrenia. In particular, atypical antipsychotics have antagonistic effects on the 5-HT(2A) receptors, supporting a specific role of the 5-HT(2A) receptor in the pathophysiology of this disease. The aim of this study is to investigate cortical and subcortical 5-HT(2A) binding in neuroleptic-naive schizophrenic patients. Fifteen neuroleptic-naive patients diagnosed with schizophrenia (age 27.5+/-4.5 years), 11 men and 4 women, and 15 healthy control subjects matched for age (28.5+/-5.7 years) and gender underwent a 40 min positron emission tomography (PET) study using the 5-HT(2A) antagonist, [(18)F]altanserin, as a radioligand. PET images were co-registered to 3 T magnetic resonance images (MRIs) for each individual subject, and ROIs were applied automatically onto the individual MRIs and PET images. The cerebellum was used as a reference region. The binding potential of specific tracer binding (BP(p)) was used as the outcome measure. No significant difference was seen in cortical receptor distribution between patients and controls. An increase in 5-HT(2A) receptor binding in the caudate nucleus was detected in the group of schizophrenic patients (0.7+/-0.1) when compared to the healthy controls (0.5+/-0.3) (p=0.02). Our results confirm other in vivo findings of no difference in cortical 5-HT(2A) receptor binding between first-episode antipsychotic-naive schizophrenic patients and age- and gender-matched healthy control subjects. However, a preliminary finding of increased 5-HT(2A) binding in the caudate nucleus requires further investigation to explore the relation of subcortical and cortical 5-HT(2A) receptor binding.

Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder.

BACKGROUND: Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain regions of relevance for affective disorders. METHODS: Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [(18)F]altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding. The correlation between the neuroticism score and frontolimbic serotonin 2A receptor binding was evaluated by multiple linear regression analysis with adjustment for age and gender. RESULTS: Neuroticism correlated positively with frontolimbic serotonin 2A receptor binding [r(79) = .24, p = .028]. Post hoc analysis of the contributions from the six constituent traits of neuroticism showed that the correlation was primarily driven by two of them: vulnerability and anxiety. Indeed, vulnerability, defined as a person's difficulties in coping with stress, displayed the strongest positive correlation, which remained significant after correction for multiple comparisons (r = .35, p = .009). CONCLUSIONS: In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point to a neurobiological link between personality risk factors for affective disorder and the serotonergic transmitter system and identify the serotonin 2A receptor as a biomarker for vulnerability to affective disorder.

Decreased gene expression of neuropeptide Y and its receptors in hippocampal regions during ethanol withdrawal in rats.

Ethanol withdrawal is associated with neuronal hyperexcitability and increased hippocampal glutamate release. Neuropeptide Y (NPY) appears to play an important role in regulation of hippocampal neuronal excitability by inhibiting glutamate release. Expression of NPY and its receptors Y1, Y2, and Y5 was studied in hippocampal areas of rats during ethanol withdrawal after repeated intragastric ethanol administration for 2 or 4 days using in situ hybridization. Withdrawal was associated with decreased hippocampal expression of NPY and each of its receptors, particularly Y2, after 2 and/or 4 days of ethanol compared to control rats. These data suggest that the hippocampal NPY system is downregulated during ethanol withdrawal and these neuroadaptational changes could play a role in mediating withdrawal hyperexcitability.

Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome.

Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's syndrome, PET imaging was performed. Twenty adults with Tourette's syndrome and 20 healthy control subjects were investigated with PET-[18F]altanserin using a bolus-infusion protocol. Regions of interest were delineated automatically on co-registered MRI images, and partial volume-corrected binding parameters were extracted from the PET images. Comparison between control subjects and Tourette's syndrome patients showed increased specific [18F]altanserin binding, not only in the a-priori selected brain regions hypothesized to be involved in Tourette's syndrome, but also post-hoc analysis showed a global up-regulation when testing for a overall difference with a randomization test (p<0.03). Increased 5-HT2A receptor binding was found not only in regions closely related to subcortical regions in patients with Tourette's syndrome, but also in most other brain regions. Our data suggest that the serotonergic transmitter system is pathophysiologically involved in Tourette's syndrome and that a clinical trial with 5-HT2A receptor antagonists may be justified.

Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach.

PURPOSE: To determine the reproducibility of measurements of brain 5-HT2A receptors with an [18F]altanserin PET bolus/infusion approach. Further, to estimate the sample size needed to detect regional differences between two groups and, finally, to evaluate how partial volume correction affects reproducibility and the required sample size. METHODS: For assessment of the variability, six subjects were investigated with [18F]altanserin PET twice, at an interval of less than 2 weeks. The sample size required to detect a 20% difference was estimated from [18F]altanserin PET studies in 84 healthy subjects. Regions of interest were automatically delineated on co-registered MR and PET images. RESULTS: In cortical brain regions with a high density of 5-HT2A receptors, the outcome parameter (binding potential, BP1) showed high reproducibility, with a median difference between the two group measurements of 6% (range 5-12%), whereas in regions with a low receptor density, BP1 reproducibility was lower, with a median difference of 17% (range 11-39%). Partial volume correction reduced the variability in the sample considerably. The sample size required to detect a 20% difference in brain regions with high receptor density is approximately 27, whereas for low receptor binding regions the required sample size is substantially higher. CONCLUSION: This study demonstrates that [18F]altanserin PET with a bolus/infusion design has very low variability, particularly in larger brain regions with high 5-HT2A receptor density. Moreover, partial volume correction considerably reduces the sample size required to detect regional changes between groups.

Quantification of 123I-PE2I binding to dopamine transporter with SPECT after bolus and bolus/infusion.

UNLABELLED: The aim of the present study was to describe a method combining easy implementation in a clinical setting with accuracy and precision in quantification of 123I-labeled N-(3-iodoprop-(2E)-enyl)-2beta-carboxymethoxy-3beta-(4'-methylphenyl)nortropane (PE2I) binding to brain dopamine transporter. METHODS: Five healthy subjects (mean age, 50 y; range, 40-68 y) were studied twice. In the first experiment, dynamic SPECT data and arterial plasma input curves obtained after 123I-PE2I bolus injection were assessed using Logan, kinetic, transient equilibrium, and peak equilibrium analyses. Accurate and precise determination of BP1 (binding potential times the free fraction in the metabolite-corrected plasma compartment) and BP2 (binding potential times the free fraction in the intracerebral nonspecifically bound compartment) was achieved using Logan analysis and kinetic analysis, with a total study time of 90 min. In the second experiment, (123)I-PE2I was administrated as a combined bolus and constant infusion. The bolus was equivalent to 2.7 h of constant infusion. RESULTS: The bolus-to-infusion ratio of 2.7 h was based on the average terminal clearance rate from plasma in the bolus experiments. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 2 h. Even when an average bolus-to-infusion ratio was used, the striatal BP1 and BP2 values calculated with kinetic analysis (BP1 = 21.1 +/- 1.1; BP2 = 4.1 +/- 0.4) did not significantly differ from those calculated with bolus/infusion analysis (BP1 = 21.0 +/- 1.2; BP2 = 4.3 +/- 0.3). Computer simulations confirmed that a 2-fold difference in terminal clearance rate from plasma translates into only a 10% difference in BP1 and BP2 calculated from 120 to 180 min after tracer administration. CONCLUSION: The bolus/infusion approach allows accurate and precise quantification of 123I-PE2I binding to dopamine transporter and is easily implemented in a clinical setting.

MR-based automatic delineation of volumes of interest in human brain PET images using probability maps.

The purpose of this study was to develop and validate an observer-independent approach for automatic generation of volume-of-interest (VOI) brain templates to be used in emission tomography studies of the brain. The method utilizes a VOI probability map created on the basis of a database of several subjects' MR-images, where VOI sets have been defined manually. High-resolution structural MR-images and 5-HT(2A) receptor binding PET-images (in terms of (18)F-altanserin binding) from 10 healthy volunteers and 10 patients with mild cognitive impairment were included for the analysis. A template including 35 VOIs was manually delineated on the subjects' MR images. Through a warping algorithm template VOI sets defined from each individual were transferred to the other subjects MR-images and the voxel overlap was compared to the VOI set specifically drawn for that particular individual. Comparisons were also made for the VOI templates 5-HT(2A) receptor binding values. It was shown that when the generated VOI set is based on more than one template VOI set, delineation of VOIs is better reproduced and shows less variation as compared both to transfer of a single set of template VOIs as well as manual delineation of the VOI set. The approach was also shown to work equally well in individuals with pronounced cerebral atrophy. Probability-map-based automatic delineation of VOIs is a fast, objective, reproducible, and safe way to assess regional brain values from PET or SPECT scans. In addition, the method applies well in elderly subjects, even in the presence of pronounced cerebral atrophy.

Upregulation of glutamate receptor subtypes during alcohol withdrawal in rats.

AIMS: To investigate glutamate receptor subtypes during alcohol withdrawal. METHODS: Rats were exposed to severe alcohol intoxication for 84 h and then decapitated at 0, 12 and 36 h after the last alcohol dose (n = 7 per group). Alcohol was administered five times a day by intragastric intubation. The densities of N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were studied in membranes from the forebrain by using the specific ligands [3H]MK-801 and [3H]AMPA, respectively. RESULTS: Although no change in the maximal density (B(max)) of [3H]MK-801 binding sites was observed at the time of withdrawal, [3H]MK-801 binding was increased by 49% 12 h into the withdrawal reaction compared with the control group. At 36 h post alcohol the B(max) of the [3H]MK-801 binding was still increased by 24% compared with the control group; however, this difference was not statistically significant. When investigated at the time of withdrawal from chronic alcohol intoxication, no significant alterations in the B(max) of the [3H]AMPA binding was detected, but 12 h into the withdrawal reaction the [3H]AMPA binding was markedly increased by 94%. At 36 h post alcohol the [3H]AMPA binding had returned to control levels. No significant alterations in the dissociation constant (K(D)) of either [3H]MK-801 or [3H]AMPA binding was observed at any time point. CONCLUSIONS: NMDA and AMPA receptors are involved in the cerebral hyperactivity of alcohol withdrawal.

A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables.

This study presents the results of an analysis of 5-hydroxytryptamine (5-HT)(2A) receptors in 52 healthy subjects. Thirty men and twenty-two women aged between 21 and 79 years were investigated with magnetic resonance imaging (MRI) and [(18)F]-altanserin positron emission tomography (PET). The distribution volumes of specific tracer binding (DV(3)') was calculated for 15 brain regions using either cerebellum or pons as reference regions and correlations between DV(3)' and physiological and demographic variables were made. The regional distribution of [(18)F]-altanserin binding in the healthy human brain was in agreement with existing in vitro post-mortem human 5-HT(2A) data. Apart from nonspecific cerebellar binding (DV(2)), there was no gender difference in 5-HT(2A) binding. A positive correlation between cerebellar binding and age was observed and negative correlations between age and DV(3)' were found in all cortical regions, except occipital cortex, corresponding to a decrease in DV(3)' of 6% or 4% per decade with cerebellum or pons as reference regions, respectively. In several temporal and frontal cortical regions, positive correlations were found between body mass index (BMI) and DV(3)'. Our findings provide a resource to aid design of clinical studies of the 5-HT(2A) receptors. [(18)F]-altanserin binding appears to be unaffected by gender, but the effects of ageing must be considered for clinical studies. The correlations between different cortical regions' 5-HT(2A) binding and BMI should be explored in future studies.

Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach.

The aim of the present study is to describe and validate a method for accurate quantification of 5-hydroxytryptamine (5-HT)(2A) receptors using [18F]altanserin-positron emission tomography (PET) and the bolus/infusion approach. A bolus/infusion ratio of 1.75 h aimed at attaining rapid steady state in blood and brain was predicted from previous bolus studies performed in our laboratory. The infusion schedule was tested in normal subjects (n = 10) using dynamic PET and frequent plasma sampling for 6 h. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 3 h. To represent free and nonspecifically bound [18F]altanserin and its radiolabeled metabolites only, cerebellum must show no displacement in 5-HT(2A) displacement studies. To validate this, saturating doses of cold ketanserin were administered and it was found that specific binding of [18F]altanserin decreased uniformly to the level of the cerebellum and no change in the cerebellar time-activity curve was found after ketanserin administration. A shorter experimental setup was tested in a second group (n = 20) including patients with neuropsychiatric disorders. Dynamic PET (five frames of 8 minutes each) and venous blood sampling at midscan time started 2 h after [18F]altanserin administration. The mean percentage rate of change per hour in the outcome parameter, DV(3)', was low (mean -0.3% h-1; range -7.3-7.2% h-1) and no correlation of DV(3)' versus time was demonstrated. It is concluded that 5-HT(2A) receptor studies can be conducted within 2 h of [18F]altanserin infusion, yielding reliable results.

Ethanol withdrawal in rats is attenuated by intracerebroventricular administration of neuropeptide Y.

AIMS: The effects of intracerebroventricular administration of neuropeptide Y (NPY) on ethanol withdrawal were studied in rats. METHODS: Ethanol was administered intragastrically five times daily for 4 days. At 16-17 h after the last infusion of ethanol, rats were rated for withdrawal using a score based on three signs: irritability, tremor and rigidity. Subsequently, the rats received an injection of NPY (12 or 24 nmol) or vehicle and were rated for signs of withdrawal. RESULTS: At both doses, NPY significantly reduced ethanol withdrawal, the effect of the larger dose being more pronounced. CONCLUSIONS: Our results are consistent with the concept that NPY receptors are centrally involved in the regulation of neuronal excitability and might form a novel therapeutic target for treatment of ethanol withdrawal and other states of neuronal hyperexcitability.