A Volumetric Metric for Monitoring Intracranial Aneurysms: Repeatability and Growth Criteria in a Longitudinal MR Imaging Study.

BACKGROUND AND PURPOSE: The reliability of contrast-enhanced MRA in monitoring serial volumetric changes of unruptured intracranial aneurysms has not been established. We aimed to determine the coefficient of variance of contrast-enhanced MRA in measuring aneurysm volumes, thus establishing criteria for aneurysm growth and permitting identification of variables predictive of growth. MATERIALS AND METHODS: Aneurysm volumes were measured from serial contrast-enhanced MRA studies of patients with untreated intracranial aneurysms who underwent >2 sequential MR imaging evaluations. After coregistering all sequential studies in 3D space for each aneurysm and signal intensity normalization, aneurysm volume was determined across all time points. A linear mixed effects model was built to estimate the coefficient of variance of the measurement as well as to determine predictive variables. Growth was defined as relative growth exceeding 2 times the measurement coefficient of variance (sudden growth, as 4 times the coefficient of variance). RESULTS: A total of 95 patients with 112 aneurysms were included (5.9 scans during 4.0 years on average, 616 scan measurements in total). The coefficient of variance was 5.5% of the aneurysm volume, and the relative growth rate was dependent on the location: anterior cerebral artery, 4.52% per year; vertebral artery, 2.46% per year; middle cerebral artery, 2.74% per year; basilar artery, 2.36% per year; internal carotid artery, 1.14% per year. Thirty-six of 112 (32%) aneurysms were characterized as growing, and 11/36 of them had an episode of sudden growth. CONCLUSIONS: Volume measurement of unruptured intracranial aneurysms by contrast-enhanced MRA seems a reliable metric for tracking the growth trajectory of aneurysms. Furthermore, the aneurysm growth rate differs among different locations.

Trail Making Test, Stroop, and Verbal Fluency: Regression-Based Norms for the Icelandic Population.

OBJECTIVE: The aim of this study was to construct regression-based norms for 3 executive-function tests: the Trail Making Test, Stroop, and Verbal Fluency. METHOD: A sample of 1,034 healthy Icelandic adults (18-64 years) was used to calculate predicted scores for test measures from all 3 tests, controlled for the effects of age, gender, and education, as well as the interaction between these variables. RESULTS: The 3 demographic variables showed significant effects on most test measures and were included in the final equation for estimating predicted scores. An older age and less education predicted worse cognitive performances in most cases, and women tended to outperform men. CONCLUSION: These results highlight the importance of adjusting for age, gender, and educational level when constructing normative data. Controlling for age alone may be insufficient or misleading in clinical-practice settings. A simple, user-friendly program for predicting executive-function test scores is provided.

Cognitive Measures and Performance on the Antisaccade Eye Movement Task.

The antisaccade (AS) task is considered a prominent measure of inhibitory control, but it is still unclear which cognitive processes are used for successful performance of the task. Previous results have provided evidence for the involvement of several processes, including working memory (WM), inhibition and attention. Thus, the aim of this study was to explore, using a range of neuropsychological tests, which cognitive factors predict individual differences in AS performance. To do so, 143 healthy participants underwent a battery including tests measuring inhibition, working memory, cognitive flexibility, sustained attention, IQ and fluency. Hierarchical stepwise regression analyses were conducted to assess the association with AS performance. Performance on the Trail-Making-Test, version B (TMT-B), a test measuring flexibility, divided attention and WM, was found to significantly predict AS latency. Rapid Visual Information Processing (RVIP), used to assess sustained attention and WM, significantly predicted AS error rate. Other cognitive measures, however, did not significantly predict AS performance. Bayesian Model Averaging supported these conclusions and showed that non-significant predictors are unlikely to be associated with AS outcomes. Several explanations are provided for the associations of TMT-B and RVIP with AS performance; as the tests measure a range of different cognitive processes, interpretation of these results remains less clear. For a better understanding of the cognitive mechanisms underlying AS performance, future research should make use of a wider range of attention and WM tests.

Reduced Jet Velocity in Venous Flow after CSF Drainage: Assessing Hemodynamic Causes of Pulsatile Tinnitus.

BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension is commonly associated with transverse sinus stenosis, a venous cause of pulsatile tinnitus. In patients with idiopathic intracranial hypertension, CSF drainage via lumbar puncture decreases intracranial pressure, which relieves the stenosis, and may provide at least temporary cessation of pulsatile tinnitus. The objective of this study was to evaluate changes in venous blood flow caused by lowered intracranial pressure in patients with pulsatile tinnitus to help identify the cause of pulsatile tinnitus. MATERIALS AND METHODS: Ten patients with suspected transverse sinus stenosis as a venous etiology for pulsatile tinnitus symptoms underwent MR imaging before and after lumbar puncture in the same session. The protocol included flow assessment and rating of pulsatile tinnitus intensity before and after lumbar puncture and MR venography before lumbar puncture. Post-lumbar puncture MR venography was performed in 1 subject. RESULTS: There was a lumbar puncture-induced reduction in venous peak velocity that correlated with the opening pressure (r = -0.72, P = .019) without a concomitant reduction in flow rate. Patients with flow jets had their peak velocity reduced by 0.30 ± 0.18 m/s (P = .002), correlating with a reduction in CSF pressure (r = 0.82, P = .024) and the reduction in subjectively scored pulsatile tinnitus intensity (r = 0.78, P = .023). The post-lumbar puncture MR venography demonstrated alleviation of the stenosis. CONCLUSIONS: Our results show a lumbar puncture-induced reduction in venous peak velocity without a concomitant reduction in flow rate. We hypothesize that the reduction is caused by the expansion of the stenosis after lumbar puncture. Our results further show a correlation between the peak velocity and pulsatile tinnitus intensity, suggesting the flow jet to be instrumental in the development of sound.

MR Venous Flow in Sigmoid Sinus Diverticulum.

BACKGROUND AND PURPOSE: Case reports demonstrate that coiling of a sigmoid sinus diverticulum can treat pulsatile tinnitus. We hypothesized that MR imaging 4D flow and computational fluid dynamics would reveal distinct blood flow patterns in the venous outflow tract in these patients. MATERIALS AND METHODS: Patients with pulsatile tinnitus of suspected venous etiology underwent MR imaging at 3T, using venous phase contrast-enhanced MR angiography, 4D flow, and 2D phase contrast. The contrast-enhanced MRA contours were evaluated to determine the presence and extent of a sigmoid sinus diverticulum. Computational fluid dynamics analysis was performed using the 4D flow inlet flow and the luminal contours from contrast-enhanced MRA as boundary conditions. In addition, computational fluid dynamics was performed for the expected post treatment conditions by smoothing the venous geometry to exclude the sigmoid sinus diverticulum from the anatomic boundary conditions. Streamlines were generated from the 4D flow and computational fluid dynamics velocity maps, and flow patterns were examined for the presence of rotational components. RESULTS: Twenty-five patients with pulsatile tinnitus of suspected venous etiology and 10 control subjects were enrolled. Five (20%) of the symptomatic subjects had sigmoid sinus diverticula, all associated with an upstream stenosis. In each of these patients, but none of the controls, a stenosis-related flow jet was directed toward the opening of the sigmoid sinus diverticulum with rotational flow patterns in the sigmoid sinus diverticulum and parent sigmoid sinus on both 4D flow and computational fluid dynamics. CONCLUSIONS: Consistent patterns of blood flow can be visualized in a sigmoid sinus diverticulum and the parent sinus using 4D flow and computational fluid dynamics. Strong components of rotational blood flow were seen in subjects with sigmoid sinus diverticula that were absent in controls.

Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users.

BACKGROUND AND AIMS: Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. METHODS: A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. RESULTS: Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p<0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time-consuming than for the other MPH samples. No differences were observed between users and non-users. CONCLUSIONS: To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations.

Intravenous Use of Prescription Psychostimulants; A Comparison of the Pattern and Subjective Experience between Different Methylphenidate Preparations, Amphetamine and Cocaine.

BACKGROUND/AIMS: Methylphenidate (MPH) has been the most commonly used intravenous (i.v.) substance in Iceland in recent years. In Iceland, MPH is available in 3 forms: immediate-release (IR) tablets (MPH IR, short-acting), sustainable-release (SR) capsules (MPH SR, long-acting) and osmotic-release (OROS) tablets (MPH OROS, long-acting). The aims of the study were to compare the pattern and subjective effects of i.v. MPH use to other i.v. psychostimulants and examine whether the pattern of use differs among MPH preparations. METHODS: This is a nationwide descriptive study. Information was collected from 95 i.v. substance users undergoing inpatient detoxification and reporting i.v. MPH use in the last 30 days using a semi-structured interview. RESULTS: MPH SR was both the most commonly used (96%) and preferred i.v. psychostimulant (57%). The intensity and duration of 'euphoria' did not differ between cocaine and MPH SR. No participant reported MPH OROS as their preferred substance even though a third had used it in the past month. CONCLUSIONS: The pattern of i.v. MPH use is similar to other psychostimulants among treatment seeking patients. MPH OROS was the least preferred i.v. psychostimulant, despite having the largest market share in Iceland. The results indicate that MPH OROS has less abuse potential than other MPH preparations.

Modulation of antisaccade costs through manipulation of target-location probability: only under decisional uncertainty.

Latencies of antisaccades made in the direction opposite to a peripheral target are typically slower longer than of prosaccades towards such a target by 50-100 ms. Antisaccades have proved to be an important tool for diagnostic purposes in neurology, psychology and psychiatry, providing invaluable insights into attentional function, decision making and the functionality of eye movement control. Recent findings have suggested, however, that latency differences between pro- and antisaccades can be eliminated by manipulating target-location probabilities. Pro- and antisaccades were equally fast to locations where a target rarely appeared, a finding that may be of promise for more elaborate diagnoses of neurological and psychiatric illness and further understanding of the eye movement system. Here, we tested probability manipulations for a number of different pro- and antisaccade tasks of varied difficulty. Probability only modulated antisaccade costs in a difficult antisaccade task involving decisional uncertainty with low target saliency. For other tasks including standard ones from the literature, target-location probability asymmetries had minimal effects. Probability modulation of antisaccade costs may therefore reflect effects upon decision making rather than saccade generation. This may limit the usefulness of probability manipulations of antisaccades for diagnostic purposes in neurology, psychology and related disciplines.

Developments in schizophrenia genetics: from linkage to microchips, deletions and duplications.

BACKGROUND: There is strong evidence for significant contributions of genetic factors to the risk of schizophrenia. In the past 10 years, studies employing linkage and association approaches have identified multiple putative schizophrenia risk genes. For most of these, the evidence for association with schizophrenia remains weak and attempts of replication not always successful nor easy to interpret. AIM: To give an overview of new developments in genetic research of schizophrenia. METHODS: The present literature on schizophrenia genetics was reviewed with special emphasis on new developments such as genome-wide association studies (GWAS), associations of copy number variations (CNVs) with schizophrenia and the role of endophenotypes in genetic research. RESULTS: The first GWAS of schizophrenia have identified new putative candidate risk genes and opened avenues for investigating how multiple genes may act in functional biological pathways forming the genetic basis of schizophrenia and other complex diseases. There is growing evidence that rare de novo CNVs as well as some inherited CNVs contribute to the susceptibility to several neuropsychiatric disorders including schizophrenia. Schizophrenia endophenotypes, which possibly better represent biological phenomena than the complex clinical phenotype, are turning out to be helpful for investigating neurobiological pathways of putative risk genes. CONCLUSIONS: Recent studies suggest that individual common gene variants make relatively small contributions to risk of schizophrenia but some rare CNVs may be associated with much higher risk when present. Future studies employing new technologies for identifying common and rare risk markers are likely to deepen our understanding of the genetic architecture of schizophrenia.

Neuregulin-1 genotypes and eye movements in schizophrenia.

Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms (SNPs); SNP8NRG222662, a surrogate marker for the originally described Icelandic NRG-1 risk haplotype, and SNP8NRG243177, which has recently been associated with individual differences in brain function. Subjects underwent infrared oculographic assessment of AS and SPEM. The study replicates previous findings of impaired AS and SPEM performance in schizophrenia patients (all P < 0.005; all d = 0.5-1.5). SNP8NRG243177 risk allele carriers had marginally increased variability of AS spatial error (P = 0.050, d = 0.3), but there were no significant genotype effects on other eye movement variables and no significant diagnosis-by-genotype interactions. Generally, risk allele carriers (G allele for SNP8NRG222662 and T allele for SNP8NRG243177) had numerically worse performance than non-carriers on most AS and SPEM variables. The results do not suggest that NRG-1 genotype significantly affects AS and SPEM task performance. However, the power of the sample to identify small effects is limited and the possibility of a type II error must be kept in mind. Larger samples may be needed to reliably investigate such gene effects on oculomotor endophenotypes.

COMT val(158)met genotype and smooth pursuit eye movements in schizophrenia.

The association between the catechol-O-methyltransferase (COMT) val(158)met polymorphism (rs4680) and smooth pursuit eye movements (SPEM) was investigated in 110 schizophrenia patients and 96 controls. Patients had lower steady-state pursuit gain and made more frequent saccades than controls. Genotype was not associated with schizophrenia or SPEM, in either group or the combined sample. SPEM deficits in schizophrenia appear to be determined by genotypes other than rs4680, although the study may have lacked power to detect small effects.

Eye movement deficits in schizophrenia: investigation of a genetically homogenous Icelandic sample.

BACKGROUND: Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes in genetic studies of schizophrenia. The Icelandic population lends itself ideally to genetic studies due to its ethnic homogeneity and well-documented genealogy. The primary aim of this study was to assess AS and SPEM performance in a large Icelandic sample. Additional aims were to investigate the relationship between AS and SPEM task performance and to assess internal consistency, within-session performance changes and effects of SPEM target velocity on performance. METHOD: Patients with schizophrenia (N = 118) and healthy controls (N = 109) matched for age and gender underwent infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees /s). RESULTS: On the AS task patients displayed significantly more reflexive errors, longer latency, increased intra-individual latency variability, and reduced amplitude gain compared to controls. On the SPEM task, patients had significantly lower velocity gain and more frequent saccades during pursuit at all velocities, but group differences in velocity gain increased with increasing target velocity. Internal consistency of performance was high for all variables in both groups (Cronbach's alpha >0.77 for AS and >0.85 for SPEM) except for AS spatial error in patients (alpha = 0.38). A moderate association was found between AS and SPEM performance. By and large, patients and controls showed similar patterns of systematic within-session performance changes. CONCLUSIONS: Our findings confirm the existence of robust eye movement deficits in schizophrenia in a large sample. These measures may be studied as endophenotypes in future studies of potential schizophrenia risk genotypes in the genetically homogenous Icelandic population.

Stress decreases, while central nucleus amygdala lesions increase, IL-8 and MIP-1alpha gene expression during tissue healing in non-human primates.

Stress impairs healing and in part this effect is thought to be mediated by glucocorticoids. However, the brain systems that underlie the effects of stress on healing remain to be determined. Since the central nucleus of the amygdala (CeA) plays a role in mediating an individual's behavioral and physiological reactivity to stress, we investigated, in rhesus monkeys, whether selective lesions of the CeA altered the gene expression of chemokines (IL-8 and MIP-1alpha) that are associated with early dermal healing. We used rhesus monkeys because they provide an excellent animal model to investigate brain mechanisms relevant to human stress, anxiety, and psychopathology. Hypothalamic-pituitary-adrenal (HPA) activity was assessed in the monkeys prior to the wound healing experiment demonstrating that the CeA lesions reduce HPA activity. In the healing experiment, stress decreased IL-8 and MIP-1alpha gene expression in both CeA lesioned and non-lesioned animals. Conversely, the CeA lesions increased the tissue expression of IL-8 and MIP-1alpha mRNA prior to and after stress exposure. These results demonstrate that in primates the CeA is a key brain region involved in the regulation of processes associated with wound healing. Because of brain and behavioral similarities between rhesus monkeys and humans, these results are particularly relevant to understanding brain mechanisms that influence healing in humans.

Transcranial Magnetic Stimulation in the investigation and treatment of schizophrenia: a review.

Transcranial Magnetic Stimulation (TMS) is a non-invasive method of stimulating the brain that is increasingly being used in neuropsychiatric research and clinical psychiatry. This review examines the role of TMS in schizophrenia research as a diagnostic and a therapeutic resource. After a brief overview of TMS, we describe the application of TMS to schizophrenia in studies of cortical excitability and inhibition, and we discuss the potential confounding role of neuroleptic medications. Based on these studies, it appears that some impairment of cortical inhibition may be present in schizophrenic subjects. We then review attempts to employ TMS for treating different symptoms of schizophrenia. Some encouraging results have been obtained, such as the reduction of auditory hallucinations after slow TMS over auditory cortex and an improvement of psychotic symptoms after high frequency TMS over left prefrontal cortex. However, these results need to be confirmed using better placebo conditions. Future studies are likely to employ TMS in combination with functional brain imaging to examine the effects produced by the stimulated area on activity in other brain regions. Such studies may reveal impaired effective connectivity between specific brain areas, which could identify these regions as targets for selective stimulation with therapeutic doses of TMS.

A [17F]-fluoromethane PET/TMS study of effective connectivity.

We used transcranial magnetic stimulation (TMS) in combination with positron emission tomography (PET) to investigate the effective connectivity of four cortical regions within the same study. By employing [17F]-[CH3F] ([17F]-fluoromethane) as a radiotracer of blood-flow, we were able to obtain increased sensitivity compared to [15O]-H2O for both cortical and subcortical structures. The brain areas investigated were left primary motor cortex, right primary visual cortex, and left and right prefrontal areas. We found that each site of stimulation yielded a different pattern of activation/deactivation consistent with its anatomical connectivity. Moreover, we found that TMS of prefrontal and motor cortical areas gave rise to trans-synaptic activation of subcortical circuits.

Performance of prothrombin-proconvertin time as a monitoring test of oral anticoagulation therapy.

Outcome and anticoagulation intensity was evaluated during 121 patient years of oral anticoagulant therapy monitored with the prothrombin-proconvertin clotting time (PP, also known as P&P). The PP-based international normalized ratio (INR; PP-INR) correlated well with the INR calculated from the prothrombin clotting time (PT; r = 0.92), and results were almost identical over a wide range after linear conversion (1/INR). When the PP-INR was 4.5 or less, the risk of major bleeding was 1 for every 118 treatment years, but it was 1 for every 73 days when the INR was 6 or more. The 1/PP-INR correlated better with factor II coagulant activity (r = 0.85) than did the 1/PT-INR (r = 0.78). The 1/PP-INR also correlated better with the native prothrombin antigen (r = 0.76) than did the 1/PT-INR (r = 0.68). The PP and PT results correlated better with factor II coagulant activity than with native prothrombin antigen. Thus, the PP clotting time results can be accurately converted to INR. The results also suggest that the PP may have advantages over the PT as an indicator of anticoagulation intensity during oral anticoagulation.

Plasminogen depletion during streptokinase treatment or two-chain urokinase incubation correlates with decreased clot lysability ex vivo and in vitro.

The relationship between lytic state variables and ex vivo clot lysability was investigated in blood drawn from patients during streptokinase administration for acute myocardial infarction. A lytic state was already evident after 5 min of treatment and after 20 min the plasminogen concentration had decreased to 24%, antiplasmin to 7% and fibrinogen 0.2 g/l. Lysis of radiolabeled retracted clots in the patient plasmas decreased from 37 +/- 8% after 5 min to 21 +/- 8% at 10 min and was significantly lower (8 +/- 9%, p < 0.005) in samples drawn at 20, 40 and 80 min. Clot lysability correlated positively with the plasminogen concentration (r = 0.78, p = 0.003), but not with plasmin activity. Suspension of radiolabeled clots in normal plasma pre-exposed to 250 U/ml two-chain urokinase for varying time to induce an in vitro lytic state was also associated with decreasing clot lysability in direct proportion with the duration of prior plasma exposure to urokinase. The decreased lysability correlated with the time-dependent reduction in plasminogen concentration (r = 0.88, p < 0.0005). Thus, clot lysability decreases in conjunction with the development of the lytic state and the associated plasminogen depletion. The lytic state may therefore limit reperfusion during thrombolytic treatment.