Ketamine effects on default mode network activity and vigilance: A randomized, placebo-controlled crossover simultaneous fMRI/EEG study.

In resting-state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting-state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine-induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double-blind, placebo-controlled crossover study with subanesthetic S-Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting-state fMRI and EEG data. We conducted seed-based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine-induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009-012399-28).

Inflammatory demyelinating brain lesions heralding primary CNS lymphoma.

Brain biopsy plays a crucial role in the exploration of suspect white matter lesions in the differential diagnosis of primary central nervous system lymphoma (PCNSL) and inflammatory demyelination. We present the case of a previously healthy, immunocompetent woman, aged fifty-nine, who developed a histologically confirmed demyelinating white matter lesion months prior to the manifestation of a PCNSL. Similar cases of "sentinel lesions" preceding a PCNSL have been reported. In a literature review, we compared the diagnostic features that may be useful to differentiate a PCNSL from inflammatory demyelinating disease in older age. We conclude that the occurrence of large, contrast-enhancing cerebral lesions in older patients with a relapsing-remitting disease course and steroid-resistant vision disorders should lead to the consideration of a PCNSL.

Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.

BACKGROUND: Behavioral and electrophysiological human ketamine models of schizophrenia are used for testing compounds that target the glutamatergic system. However, corresponding functional neuroimaging models are difficult to reconcile with functional imaging and electrophysiological findings in schizophrenia. Resolving the discrepancies between different observational levels is critical to understand the complex pharmacological ketamine action and its usefulness for modeling schizophrenia pathophysiology. METHODS: We conducted a within-subject, randomized, placebo-controlled pharmacoimaging study in twenty-four male volunteers. Subjects were given low-dose S-ketamine (bolus prior to functional imaging: 0.1mg/kg during 5min, thereafter continuous infusion: 0.015625mg/kg/min reduced by 10% every ten minutes) or placebo while performing a visual oddball task during simultaneous functional magnetic resonance imaging (fMRI) with continuous recording of event-related potentials (P300) and electrodermal activity (EDA). Before and after intervention, psychopathological status was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale. RESULTS: P300 amplitude and corresponding BOLD responses were diminished in the ketamine condition in cortical regions being involved in sensory processing/selective attention. In both measurement modalities separation of drug conditions was achieved with area under the curve (AUC) values of up to 0.8-0.9. Ketamine effects were also observed in the clinical, behavioral and peripheral physiological domains (Positive and Negative Syndrome Scale, reaction hit and false alarm rate, electrodermal activity and heart rate) which were in part related to the P300/fMRI measures. CONCLUSION: The findings from our ketamine experiment are consistent across modalities and directly related to observations in schizophrenia supporting the validity of the model. Our investigation provides the first prototypic example of a pharmacoimaging study using simultaneously acquired fMRI/EEG.

MRI features of intraductal papilloma of the breast: sheep in wolf's clothing?

BACKGROUND: Intraductal papillomas often present as small, smooth masses, dilated ducts or microcalcifications at mammography and as smooth, hypoechoic masses at sonography. At magnetic resonance imaging (MRI), intraductal papillomas often present as small smooth masses, however, often with strong enhancement with type 2 or 3 time intensity curves. The result of the MR analysis is therefore not infrequently inconclusive in order to characterize the mass as benign or malignant. PURPOSE: To characterize the appearance of intraductal papillomas of the breast at MRI, and determine whether the application of diagnostic rules described in literature could contribute to correctly classifying the lesions as benign. MATERIAL AND METHODS: Twenty patients with histologically proven intraductal papillomas were included. Two radiologists independently reviewed the MR images of the breast. The BI-RADS(®) nomenclature was used to describe morphology and contrast-enhancement kinetics. Interobserver agreement in the interpretation of the MR images by the two investigators was performed. Kappa coefficient was calculated as index for the level of agreement. Subsequently, three sets of diagnostic rules, including the Göttinger score described by Fischer and the interpretation flowcharts according to Kinkel and to Tozaki were applied to characterize whether a biopsy should be recommended or not. RESULTS: All papillomas presented as masses on dynamic contrast-enhanced MRI. Only five papillomas showed a round, oval, or lobulated shape combined with smooth margins and continuous rise of the time intensity curve. Using the Göttingen score, biopsy would be recommended in 16 patients. Based on the interpretation flowcharts of Kinkel and of Tozaki, an additional 13 and 10 papillomas, respectively, were correctly classified as benign. Dilated ducts were visible in 10 patients. The interobserver agreement was good or excellent for all included variables. CONCLUSION: Including systematic analysis of breast MRI to the diagnostic protocol and interpreting the images according to predetermined diagnostic rules, most solitary intraductal papillomas of the breast may be correctly characterized as benign.

The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation.

BACKGROUND: Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase (COMT) have been suggested to affect clinical and experimental pain-related phenotypes including regional mu-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography). The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been studied with activation measures such as functional magnetic resonance imaging (fMRI), PET or electroencephalography. In the present fMRI study we therefore sought to investigate the impact of the COMT val158met polymorphism on the blood oxygen level-dependent (BOLD) response to painful laser stimulation. RESULTS: 57 subjects were studied. We found that subjects homozygous for the met158 allele exhibit a higher BOLD response in the anterior cingulate cortex (ACC), foremost in the mid-cingulate cortex, than carriers of the val158 allele. CONCLUSION: This result is in line with previous studies that reported higher pain sensitivity in homozygous met carriers. It adds to the current literature in suggesting that this behavioral phenotype may be mediated by, or is at least associated with, increased ACC activity. More generally, apart from one report that focused on pain-induced opioid release, this is the first functional neuroimaging study showing an effect of the COMT val158met polymorphism on cerebral pain processing.

Dynamic EEG-informed fMRI modeling of the pain matrix using 20-ms root mean square segments.

Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid-cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain-induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole-brain coverage. In this study, we thought to investigate the spatio-temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference-free measure of event-related EEG activity) in a time window 0-400 ms poststimulus were used to model trial-to-trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG-derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG-time windows suggests largely parallel signal processing in the bilateral operculo-insular and mid-cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG.

Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia.

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.

Imaging inflammation in acute brain ischemia.

Brain inflammation holds promise as a therapeutic target in subacute stages of ischemic stroke. At the cellular level, postischemic inflammation is dominated by cells of the innate immune system with resident microglia/brain macrophages and blood-derived monocytes/macrophages being the most important cell types involved. Iron oxide nanoparticles such as ultrasmall superparamagnetic iron oxide (USPIO) are novel cell-specific contrast agents for MRI. After intravenous injection USPIO is taken up by circulating phagocytic cells. USPIO-laden macrophages cause typical signal changes in MRI of infarcted brain parenchyma, which has been demonstrated in studies of both experimental ischemia and human stroke. USPIO-enhanced MRI may therefore represent an important tool to address the role of macrophages for ischemic lesion development both in basic science and clinical studies.

Iron oxide particle-enhanced MRI suggests variability of brain inflammation at early stages after ischemic stroke.

BACKGROUND AND PURPOSE: Inflammation contributes to brain damage caused by ischemic stroke. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI allows noninvasive monitoring of macrophage recruitment into ischemic brain lesions. In this study, we determined the extent of USPIO enhancement during early stages of ischemic stroke. METHODS: Twelve consecutive patients with typical clinical signs of stroke underwent multimodal stroke imaging at 1.5-T within 24 hours of symptom onset. They received intravenous USPIO (ferumoxtran) infusion at 26 to 96 hours (mean, 44 hours) after stroke. A total of four follow-up MRI scans were performed 24 to 36 hours, 48 to 72 hours, 7 to 8 days, and 10 to 11 days after USPIO infusion. RESULTS: Nine patients were included in the final analysis. Parenchymal USPIO enhancement occurred in 3 of 9 analyzed patients and was mainly evident on T1-weighted spin-echo images. USPIO-dependent signal changes were spatially heterogeneous, reflecting the distinct patterns of hematogenous macrophage infiltration in different lesion types. CONCLUSIONS: Our findings suggest a variable extent and distribution of macrophage infiltration into early ischemic stroke lesions. USPIO-enhanced MRI may help to more specifically target antiinflammatory therapy in patients with stroke.

Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis.

BACKGROUND: The anti-CD20 monoclonal antibody rituximab effectively depletes B lymphocytes and has been successfully used in the therapy of immune-mediated disorders of the peripheral nervous system. A limited effect of rituximab on B lymphocytes in the cerebrospinal fluid compartment of patients with primary progressive multiple sclerosis (MS) was recently reported. OBJECTIVE: To determine the effect of rituximab on clinical, magnetic resonance imaging, and immunological variables in a patient with relapsing-remitting MS. DESIGN: A patient with relapsing-remitting MS was treated with rituximab. The patient was repeatedly examined clinically and by magnetic resonance imaging. The frequency of peripheral blood and cerebrospinal fluid B lymphocytes was assessed by flow cytometry before, during, and after rituximab therapy. RESULTS: Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on magnetic resonance imaging were also reduced. B lymphocytes were depleted in the cerebrospinal fluid and peripheral blood. CONCLUSIONS: Our data demonstrate beneficial clinical effects of rituximab in relapsing-remitting MS, mediated through modulation of humoral systemic and central nervous system intrinsic immune responses. Clinical trials should determine optimal therapeutic strategies for patients with relapsing-remitting MS.

Coverage of anterior fossa in whole-brain irradiation.

PURPOSE: Whole-brain irradiation is indispensable in the treatment of several brain tumors and requires coverage of the entire subarachnoid space. Retrospective studies have revealed frequent recurrences in the frontobasal fossa above the cribriform plate (CP). We sought to determine how accurately the latter could actually be identified on lateral radiographs such as those used for radiotherapy planning. METHODS AND MATERIALS: The CP was localized by five radiation oncologists and five radiologists on lateral radiographs of 30 human skulls from an anatomic collection. Reference radiographs were acquired under identical conditions except for lead markers pointing to the CP and the ethmoid cells. The targeting accuracy was analyzed. RESULTS: In 39% (n = 116), the location of the CP was correctly estimated within 2 mm. Mislocations of 2-5, 5-10, and >10 mm were noted in 34% (n = 102), 20% (n = 61), and 7% (n = 21), respectively. Neither specialty nor experience (years of training) exerted a significant influence on targeting accuracy. If the roofs of the ethmoid cells formed prominent bony edges, they were mistaken for the CP in 37%. CONCLUSION: Lateral radiographs provide insufficient information to locate the CP accurately in whole brain irradiation. Additionally, localization was significantly impaired by prominent ethmoid cells.

Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging.

The long blood circulating time and the progressive macrophage uptake in inflammatory tissues of ultrasmall superparamagnetic iron oxide (USPIO) particles are 2 properties of major importance for magnetic resonance imaging (MRI) pathologic tissue characterization. This article reviews the proof of principle of applications such as imaging of carotid atherosclerotic plaque, stroke, brain tumor characterization, or multiple sclerosis. In the human carotid artery, USPIO accumulation in activated macrophages induced a focal drop in signal intensity compared with preinfusion MRI. The USPIO signal alterations observed in ischemic areas of stroke patients is probably related to the visualization of inflammatory macrophage recruitment into human brain infarction since animal experiments in such models demonstrated the internalization of USPIO into the macrophages localized in these areas. In brain tumors, USPIO particles which do not pass the ruptured blood-brain barrier at early times postinjection can be used to assess tumoral microvascular heterogeneity. Twenty-four hours after injection, when the cellular phase of USPIO takes place, the USPIO tumoral contrast enhancement was higher in high-grade than in low-grade tumors. Several experimental studies and a pilot multiple sclerosis clinical trial in 10 patients have shown that USPIO contrast agents can reveal the presence of inflammatory multiple sclerosis lesions. The enhancement with USPIO does not completely overlap with the gadolinium chelate enhancement. While the proof of concept that USPIO can visualize macrophage infiltrations has been confirmed in animals and patients in several applications (carotid atherosclerotic lesions, stroke, brain tumors and multiple sclerosis), larger prospective clinical studies are needed to demonstrate the clinical benefit of using USPIO as an MRI in vivo surrogate marker for brain inflammatory diseases.

Neuroendocrine neoplasms of the gastrointestinal tract.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are complex tumors whose incidence is rising and whose treatment requires precise classification and risk stratification. METHOD: Selective review of the relevant literature, including recently published guidelines. RESULTS: GEP-NENs are initially classified by their degree of histological differentiation and their graded cell proliferation (Ki-67 index). In addition, there are GEP-NEN specific TNM staging protocols. The laboratory assessment includes the measurement of general tumor markers (synaptophysin, chromogranin A) as well as specific ones (hormones). The most important imaging technique for diagnosis is octreotide scintigraphy. The surgical treatment of GEP-NEN is based on oncological resection criteria whose aim is to achieve locally radical resection while preserving as much organ function as possible. Metastases, too, may be amenable to resection. The treatment options for unresectable metastases include radiofrequency ablation and chemoembolization, both of which are palliative methods of reducing tumor volume and hormone production. Other chemotherapeutic and nuclear-medical treatments can be applied depending on the extent of metastatic spread, the proliferation index, and the degree of hormone production by the tumor. CONCLUSION: The accurate diagnosis and appropriate treatment of GEP-NET currently gives most patients with this tumor a good prognosis, as long as it is discovered early. Early GEP-NETs have a favorable prognosis. Further advances in the diagnosis and treatment of this disease may result from structural changes in patient care, including the establishment of NET centers.

Adrenal venous sampling: evaluation of the German Conn's registry.

In patients with primary aldosteronism, adrenal venous sampling is helpful to distinguish between unilateral and bilateral adrenal diseases. However, the procedure is technically challenging, and selective bilateral catheterization often fails. The aim of this analysis was to evaluate success rate in a retrospective analysis and compare data with procedures done prospectively after introduction of measures designed to improve rates of successful cannulation. Patients were derived from a cross-sectional study involving 5 German centers (German Conn's registry). In the retrospective phase, 569 patients with primary aldosteronism were registered between 1990 and 2007, of whom 230 received adrenal venous sampling. In 200 patients there were sufficient data to evaluate the procedure. In 2008 and 2009, primary aldosteronism was diagnosed in 156 patients, and adrenal venous sampling was done in 106 and evaluated prospectively. Retrospective evaluation revealed that 31% were bilaterally selective when a selectivity index (cortisol adrenal vein/cortisol inferior vena cava) of ≥2.0 was applied. Centers completing <20 procedures had success rates between 8% and 10%. Overall success rate increased in the prospective phase from 31% to 61%. Retrospective data demonstrated the pitfalls of performing adrenal venous sampling. Even in specialized centers, success rates were poor. Marked improvements could be observed in the prospective phase. Selected centers that implemented specific measures to increase accuracy, such as rapid-cortisol-assay and introduction of standard operating procedures, reached success rates of >70%. These data demonstrate the importance of throughput, expertise, and various potentially beneficial measures to improve adrenal vein sampling.

Typical atypical findings on dynamic MRI of the breast.

Dynamic contrast enhanced magnetic resonance imaging (DCE MRI) of the breast has become an important tool to detect and characterize breast disease. The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS(®)) provides a standardized vocabulary for describing the morphologic features and contrast kinetics of breast lesions. However, some lesions may show morphologic and dynamic MR features not consistent with their histologic nature resulting in incorrect categorization as malignant or benign. Another cause of diagnostic problems is artifacts. Thus correct interpretation of dynamic MRI of the breast demands knowledge of the most common pitfalls encountered in clinical practice. A pictorial overview of these is presented, with particular reference to the differentiation of malignant tumors from benign lesions.

Natalizumab treatment in a patient with chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To study clinical and paraclinical effects of natalizumab in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP). DESIGN: Case report. SETTING: Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany. Patient A patient with highly active CIDP who did not respond to standard therapies. Intervention Standard therapy then treatment with natalizumab (300 mg). MAIN OUTCOME MEASURES: Clinical disability, magnetic resonance imaging, and saturation of the alpha(4) integrin on T lymphocytes. RESULTS: T cells expressing the alpha(4) integrin were found in the inflamed peripheral nerve. Natalizumab bound with high affinity to the alpha(4) integrin on T lymphocytes in our patient. However, the patient's clinical condition deteriorated and as seen on magnetic resonance imaging without any measurable effect after treatment with this antibody. CONCLUSIONS: Although experimental evidence suggests that natalizumab could theoretically be effective in immune-mediated disorders of the peripheral nervous system, our patient with CIDP did not benefit from this therapeutic approach. Natalizumab cannot be recommended in CIDP at present and should only be explored in controlled clinical trials.

Severe aseptic leucoencephalopathy as immune reconstitution inflammatory syndrome in Caucasian and African patients.

Immune reconstitution inflammatory syndrome (IRIS) after HAART may become manifest in form of aseptic severe leucoencephalopathy. All HIV-1-positive patients in this case series had widespread laboratory tests and follow-up MRI in order to investigate the course and the underlying pathophysiology of IRIS-associated leucoencephalopathy. All patients were treated with corticosteroids, in spite of additional immunosuppression. Three patients were successfully treated with corticosteroids and survived up to now, one died. A neuropathological examination was performed showing massive aseptic intraparenchymal and perivascular invasion of cytotoxic CD8 cells. It is assumed that IRIS-associated leucoencephalopathy is based on other preconditions in Africans and Caucasians.