Rivastigmine effects on EEG spectra and three-dimensional LORETA functional imaging in Alzheimer's disease

OBJECTIVE The objective of the study is to investigate the electrocortical and the global cognitive effects of 3 months rivastigmine medication in a group of mild to moderate Alzheimer's disease patients. MATERIALS AND METHODS Multichannel EEG and cognitive performances measured with the Mini Mental State Examination in a group of 16 patients with mild to moderate Alzheimer's Disease were collected before and 3 months after the onset of rivastigmine medication. RESULTS Spectral analysis of the EEG data showed a significant power decrease in the delta and theta frequency bands during rivastigmine medication, i.e., a shift of the power spectrum towards 'normalization'. Three-dimensional low resolution electromagnetic tomography (LORETA) functional imaging localized rivastigmine effects in a network that includes left fronto-parietal regions, posterior cingulate cortex, bilateral parahippocampal regions, and the hippocampus. Moreover, a correlation analysis between differences in the cognitive performances during the two recordings and LORETA-computed intracortical activity showed, in the alpha1 frequency band, better cognitive performance with increased cortical activity in the left insula. CONCLUSION The results point to a 'normalization' of the EEG power spectrum due to medication, and the intracortical localization of these effects showed an increase of cortical activity in frontal, parietal, and temporal regions that are well-known to be affected in Alzheimer's disease. The topographic convergence of the present results with the memory network proposed by Vincent et al. (J. Neurophysiol. 96:3517-3531, 2006) leads to the speculation that in our group of patients, rivastigmine specifically activates brain regions that are involved in memory functions, notably a key symptom in this degenerative disease.

Functional differentiation of spider hemocytes by light and transmission electron microscopy, and MALDI-MS-imaging

The most abundant cell types in the hemolymph of Cupiennius salei are plasmatocytes (70–80%) and granulocytes (20–30%). Both cells differ in shape, cytochemical and transmission electron microscopy staining of their cytoplasma and granules. According to MALDI-IMS (matrix-assisted laser desorption ionization mass spectrometry imaging), granulocytes exhibit ctenidin 1 (9510 Da) and ctenidin 3 (9568 Da), SIBD-1 (8675 Da), and unknown peptides with masses of 2207 and 6239 Da. Plasmatocytes exhibit mainly a mass of 6908 Da. Unknown peptides with masses of 1546 and 1960 Da were detected in plasmatocytes and granulocytes. Transmission electron microscopy confirms the presence of two compounds in one granule and cytochemical staining (light microscopy) tends to support this view. Two further hemocyte types (cyanocytes containing hemocyanin and prehemocytes as stem cells) are only rarely detected in the hemolymph. These four hemocyte types constitute the cellular part of the spider immune system and this is discussed in view of arachnid hemocyte evolution.

Lung Volume Reduction in Pulmonary Emphysema from the Radiologist's Perspective

Pulmonary emphysema causes decrease in lung function due to irreversible dilatation of intrapulmonary air spaces, which is linked to high morbidity and mortality. Lung volume reduction (LVR) is an invasive therapeutical option for pulmonary emphysema in order to improve ventilation mechanics. LVR can be carried out by lung resection surgery or different minimally invasive endoscopical procedures. All LVR-options require mandatory preinterventional evaluation to detect hyperinflated dysfunctional lung areas as target structures for treatment. Quantitative computed tomography can determine the volume percentage of emphysematous lung and its topographical distribution based on the lung's radiodensity. Modern techniques allow for lobebased quantification that facilitates treatment planning. Clinical tests still play the most important role in post-interventional therapy monitoring, but CT is crucial in the detection of postoperative complications and foreshadows the method's high potential in sophisticated experimental studies. Within the last ten years, LVR with endobronchial valves has become an extensively researched minimally-invasive treatment option. However, this therapy is considerably complicated by the frequent occurrence of functional interlobar shunts. The presence of "collateral ventilation" has to be ruled out prior to valve implantations, as the presence of these extraanatomical connections between different lobes may jeopardize the success of therapy. Recent experimental studies evaluated the automatic detection of incomplete lobar fissures from CT scans, because they are considered to be a predictor for the existence of shunts. To date, these methods are yet to show acceptable results. KEY POINTS Today, surgical and various minimal invasive methods of lung volume reduction are in use. Radiological and nuclear medical examinations are helpful in the evaluation of an appropriate lung area. Imaging can detect periinterventional complications. Reduction of lung volume has not yet been conclusively proven to be effective and is a therapeutical option with little scientific evidence.

Ventilation/perfusion SPECT or SPECT/CT for lung function imaging in patients with pulmonary emphysema?

PURPOSE To evaluate the utility of attenuation correction (AC) of V/P SPECT images for patients with pulmonary emphysema. MATERIALS AND METHODS Twenty-one patients (mean age 67.6 years) with pulmonary emphysema who underwent V/P SPECT/CT were included. AC/non-AC V/P SPECT images were compared visually and semiquantitatively. Visual comparison of AC/non-AC images was based on a 5-point likert scale. Semiquantitative comparison assessed absolute counts per lung (aCpLu) and lung lobe (aCpLo) for AC/non-AC images using software-based analysis; percentage counts (PC = (aCpLo/aCpLu) × 100) were calculated. Correlation between AC/non-AC V/P SPECT images was analyzed using Spearman's rho correlation coefficient; differences were tested for significance with the Wilcoxon rank sum test. RESULTS Visual analysis revealed high conformity for AC and non-AC V/P SPECT images. Semiquantitative analysis of PC in AC/non-AC images had an excellent correlation and showed no significant differences in perfusion (ρ = 0.986) or ventilation (ρ = 0.979, p = 0.809) SPECT/CT images. CONCLUSION AC of V/P SPECT images for lung lobe-based function imaging in patients with pulmonary emphysema do not improve visual or semiquantitative image analysis.

Detection of significant coronary artery disease by noninvasive anatomical and functional imaging.

BACKGROUND The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD. METHODS AND RESULTS A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ≤0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001). CONCLUSIONS In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT00979199.

Assessment of cone beam computed tomography techniques for imaging lung damage in mice in vivo

Lung damage is a common side effect of chemotherapeutic drugs such as bleomycin. This study used a bleomycin mouse model which simulates the lung damage observed in humans. Noninvasive, in vivo cone-beam computed tomography (CBCT) was used to visualize and quantify fibrotic and inflammatory damage over the entire lung volume of mice. Bleomycin was used to induce pulmonary damage in vivo and the results from two CBCT systems, a micro-CT and flat panel CT (fpCT), were compared to histologic measurements, the standard method of murine lung damage quantification. Twenty C57BL/6 mice were given either 3 U/kg of bleomycin or saline intratracheally. The mice were scanned at baseline, before the administration of bleomycin, and then 10, 14, and 21 days afterward. At each time point, a subset of mice was sacrificed for histologic analysis. The resulting CT images were used to assess lung volume. Percent lung damage (PLD) was calculated for each mouse on both the fpCT (PLDfpcT) and the micro-CT (PLDμCT). Histologic PLD (PLDH) was calculated for each histologic section at each time point (day 10, n = 4; day 14, n = 4; day 21, n = 5; control group, n = 5). A linear regression was applied to the PLDfpCT vs. PLDH, PLDμCT vs. PLDH and PLDfpCT vs. PLDμCT distributions. This study did not demonstrate strong correlations between PLDCT and PLDH. The coefficient of determination, R, was 0.68 for PLDμCT vs. PLDH and 0.75 for the PLD fpCT vs. PLDH. The experimental issues identified from this study were: (1) inconsistent inflation of the lungs from scan to scan, (2) variable distribution of damage (one histologic section not representative of overall lung damage), (3) control mice not scanned with each group of bleomycin mice, (4) two CT systems caused long anesthesia time for the mice, and (5) respiratory gating did not hold the volume of lung constant throughout the scan. Addressing these issues might allow for further improvement of the correlation between PLDCT and PLDH. ^

Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung

The binding of immune inhibitory receptor Programmed Death 1 (PD-1) on T cells to its ligand PD-L1 has been implicated as a major contributor to tumor induced immune suppression. Clinical trials of PD-L1 blockade have proven effective in unleashing therapeutic anti-tumor immune responses in a subset of patients with advanced melanoma, yet current response rates are low for reasons that remain unclear. Hypothesizing that the PD-1/PD-L1 pathway regulates T cell surveillance within the tumor microenvironment, we employed intravital microscopy to investigate the in vivo impact of PD-L1 blocking antibody upon tumor-associated immune cell migration. However, current analytical methods of intravital dynamic microscopy data lack the ability to identify cellular targets of T cell interactions in vivo, a crucial means for discovering which interactions are modulated by therapeutic intervention. By developing novel imaging techniques that allowed us to better analyze tumor progression and T cell dynamics in the microenvironment; we were able to explore the impact of PD-L1 blockade upon the migratory properties of tumor-associated immune cells, including T cells and antigen presenting cells, in lung tumor progression. Our results demonstrate that early changes in tumor morphology may be indicative of responsiveness to anti-PD-L1 therapy. We show that immune cells in the tumor microenvironment as well as tumors themselves express PD-L1, but immune phenotype alone is not a predictive marker of effective anti-tumor responses. Through a novel method in which we quantify T cell interactions, we show that T cells are largely engaged in interactions with dendritic cells in the tumor microenvironment. Additionally, we show that during PD-L1 blockade, non-activated T cells are recruited in greater numbers into the tumor microenvironment and engage more preferentially with dendritic cells. We further show that during PD-L1 blockade, activated T cells engage in more confined, immune synapse-like interactions with dendritic cells, as opposed to more dynamic, kinapse-like interactions with dendritic cells when PD-L1 is free to bind its receptor. By advancing the contextual analysis of anti-tumor immune surveillance in vivo, this study implicates the interaction between T cells and tumor-associated dendritic cells as a possible modulator in targeting PD-L1 for anti-tumor immunotherapy.

Objective Assessment of Olfactory Function Using Functional Magnetic Resonance Imaging=Estudio objetivo del olfato mediante resonancia magnética funcional

Objective: To show the results of a device that generates automated olfactory stimuli suitable for functional magnetic resonance imaging (fMRI) experiments. Material and methods: Te n normal volunteers, 5 women and 5 men, were studied. The system allows the programming of several sequences, providing the capability to synchronise the onset of odour presentation with acquisition by a trigger signal of the MRI scanner. The olfactometer is a device that allows selection of the odour, the event paradigm, the time of stimuli and the odour concentration. The paradigm used during fMRI scanning consisted of 15-s blocks. The odorant event took 2 s with butanol, mint and coffee. Results: We observed olfactory activity in the olfactory bulb, entorhinal cortex (4%), amygdala (2.5%) and temporo-parietal cortex, especially in the areas related to emotional integration. Conclusions: The device has demonstrated its effectiveness in stimulating olfactory areas and its capacity to adapt to fMRI equipment.RESUMEN Objetivo: Mostrar los resultados del olfatómetro capaz de generar tareas olfativas en un equipo de resonancia magnética funcional (fMRI). Material y métodos: Estudiamos 10 sujetos normales: 5 varones y 5 mujeres. El olfatómetro está dise ̃ nado para que el estímulo que produce se sincronice con el equipo de fMRI mediante la se ̃ nal desencadenante que suministra el propio equipo. El olfatómetro es capaz de: selec- cionar el olor, secuenciar los distintos olores, programar la frecuencia y duración de los olores y controlar la intensidad del olor. El paradigma utilizado responde a un dise ̃ no de activación asociada a eventos, en el que la duración del bloque de activación y de reposo es de 15 s. La duración del estímulo olfativo (butanol, menta o café) es de 2 segundos, durante toda la serie que consta de 9 ciclos. Resultados: Se ha observado reactividad (contraste BOLD) en las diferentes áreas cerebrales involucradas en las tareas olfativas: bulbo olfatorio, córtex entorrinal (4%), amigdala (2,5%) y córtex temporoparietal. Las áreas relacionadas con integración de las emociones tienen una reactividad mayor. Conclusiones: El dispositivo propuesto nos permite controlar de forma automática y sincronizada los olores necesarios para estudiar la actividad de las áreas olfatorias cerebrales mediante fMRI.

Optical imaging of functional domains in the cortex of the awake and behaving monkey

As demonstrated by anatomical and physiological studies, the cerebral cortex consists of groups of cortical modules, each comprising populations of neurons with similar functional properties. This functional modularity exists in both sensory and association neocortices. However, the role of such cortical modules in perceptual and cognitive behavior is unknown. To aid in the examination of this issue we have applied the high spatial resolution optical imaging methodology to the study of awake, behaving animals. In this paper, we report the optical imaging of orientation domains and blob structures, approximately 100–200 μm in size, in visual cortex of the awake and behaving monkey. By overcoming the spatial limitations of other existing imaging methods, optical imaging will permit the study of a wide variety of cortical functions at the columnar level, including motor and cognitive functions traditionally studied with positron-emission tomography or functional MRI techniques.

Signal changes in the spinal cord of the rat after injection of formalin into the hindpaw: Characterization using functional magnetic resonance imaging

Changes in metabolism and local circulation occur in the spinal cord during peripheral noxious stimulation. Evidence is presented that this stimulation also causes signal intensity alterations in functional magnetic resonance images of the spinal cord during formalin-induced pain. These results indicate the potential of functional magnetic resonance imaging in assessing noninvasively the extent and intensity of spinal cord excitation in this well characterized pain model. Therefore, the aim of this study was to establish functional magnetic resonance imaging as a noninvasive method to characterize temporal changes in the spinal cord after a single injection of 50 μl of formalin subcutaneously into the hindpaw of the anesthetized rat. This challenge produced a biphasic licking activity in the freely moving conscious animal. Images of the spinal cord were acquired within 2 min, enabling monitoring of the site and the temporal evolution of the signal changes during the development of formalin-induced hyperalgesia without the need of any surgical procedure. The time course of changes in the spinal cord functional image in the isoflurane-anesthetized animal was similar to that obtained from behavioral experiments. Also, comparable physiological data, control experiments, and the inhibition of a response through application of the local anesthetic agent lidocaine indicate that the signal changes observed after formalin injection were specifically related to excitability changes in the relevant segments of the lumbar spinal cord. This approach could be useful to characterize different models of pain and hyperalgesia and, more importantly, to evaluate effects of analgesic drugs.

Detection of cortical activation during averaged single trials of a cognitive task using functional magnetic resonance imaging

Functional neuroimaging studies in human subjects using positron emission tomography or functional magnetic resonance imaging (fMRI) are typically conducted by collecting data over extended time periods that contain many similar trials of a task. Here methods for acquiring fMRI data from single trials of a cognitive task are reported. In experiment one, whole brain fMRI was used to reliably detect single-trial responses in a prefrontal region within single subjects. In experiment two, higher temporal sampling of a more limited spatial field was used to measure temporal offsets between regions. Activation maps produced solely from the single-trial data were comparable to those produced from blocked runs. These findings suggest that single-trial paradigms will be able to exploit the high temporal resolution of fMRI. Such paradigms will provide experimental flexibility and time-resolved data for individual brain regions on a trial-by-trial basis.

Retinotopic mapping of lateral geniculate nucleus in humans using functional magnetic resonance imaging

Subcortical nuclei in the thalamus, which play an important role in many functions of the human brain, provide challenging targets for functional mapping with neuroimaging techniques because of their small sizes and deep locations. In this study, we explore the capability of high-resolution functional magnetic resonance imaging at 4 Tesla for mapping the retinotopic organization in the lateral geniculate nucleus (LGN). Our results show that the hemifield visual stimulation only activates LGN in the contralateral hemisphere, and the lower-field and upper-field visual stimulations activate the superior and inferior portion of LGN, respectively. These results reveal a similar retinotopic organization between the human and nonhuman primate LGN and between LGN and the primary visual cortex. We conclude that high-resolution functional magnetic resonance imaging is capable of functional mapping of suborganizations in small nuclei together with cortical activation. This will have an impact for studying the thalamocortical networks in the human brain.

Dissociation of response conflict, attentional selection, and expectancy with functional magnetic resonance imaging

Two different attentional networks have been associated with visuospatial attention and conflict resolution. In most situations either one of the two networks is active or both are increased in activity together. By using functional magnetic resonance imaging and a flanker task, we show conditions in which one network (anterior attention system) is increased in activity whereas the other (visuospatial attention system) is reduced, showing that attentional conflict and selection are separate aspects of attention. Further, we distinguish between neural systems involved in different forms of conflict. Specifically, we dissociate patterns of activity in the basal ganglia and insula cortex during simple violations in expectancies (i.e., sudden changes in the frequency of an event) from patterns of activity in the anterior attention system specifically correlated with response conflict as evidenced by longer response latencies and more errors. These data provide a systems-level approach in understanding integrated attentional networks.

Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: Identification of functional themes

The genetic basis for virulence in influenza virus is largely unknown. To explore the mutational basis for increased virulence in the lung, the H3N2 prototype clinical isolate, A/HK/1/68, was adapted to the mouse. Genomic sequencing provided the first demonstration, to our knowledge, that a group of 11 mutations can convert an avirulent virus to a virulent variant that can kill at a minimal dose. Thirteen of the 14 amino acid substitutions (93%) detected among clonal isolates were likely instrumental in adaptation because of their positive selection, location in functional regions, and/or independent occurrence in other virulent influenza viruses. Mutations in virulent variants repeatedly involved nuclear localization signals and sites of protein and RNA interaction, implicating them as novel modulators of virulence. Mouse-adapted variants with the same hemagglutinin mutations possessed different pH optima of fusion, indicating that fusion activity of hemagglutinin can be modulated by other viral genes. Experimental adaptation resulted in the selection of three mutations that were in common with the virulent human H5N1 isolate A/HK/156/97 and that may be instrumental in its extreme virulence. Analysis of viral adaptation by serial passage appears to provide the identification of biologically relevant mutations.