Functional Activation Studies Research Articles

Somatostatin receptor subtypes: basic pharmacology and tissue distribution

The heptahelical receptor superfamily constitutes the largest single family of transmembrane-signalling molecules that regulate a wide range of physiological processes. The five somatostatin receptors represent a distinct subgroup of this seven transmembrane receptor superfamily. They range in size from 356 to 391 amino acids with 39–57% protein identity between the subtypes with 100 residues strictly conserved among the somatostatin receptor sequences. A high grade of mRNA homology exists in somatostatin receptor subtypes cloned from different species. Following somatostatin receptor binding and functional activity studies, two alternative models of ligand-binding interaction have been hypothesised. One relies on the presence of a binding pocket within the receptor structure constituted by specific amino acids residues, the other denies the presence of such binding structures and suggests that it is the interaction of agonists with specific extracellular and/or transmembrane domains that determine stable receptor structure conformation. Somatostatin receptors, as, indeed, all G-protein-coupled receptors are able to regulate their responsiveness to agonist exposure. This agonist-specific regulation includes three main events, namely, desensitisation, receptor internalisation and receptor degradation. The cell expression of somatostatin receptor subtypes, at the mRNA level, has been characterised in rodent and in human organs with multiple subtype expression in brain and peripheral tissues.

Enhanced interictal responsiveness of the migraineous visual cortex to incongruent bar stimulation: a functional MRI visual activation study.

Since visual aura is usually described as expanding zigzag lines, neurones involved with the perception of line orientation may initiate this phenomenon. A visual incongruent line stimulation protocol was developed to obtain functional magnetic resonance images (fMRI) interictally in 5 female migraine patients with typical fortification spectra and in 5 normal matched controls. Activation in the visual cortex was present contralateral to the side of stimulation in 4 of 5 patients, notably in the extrastriate visual cortex. In 4 of 5 controls activation was observed in the medial and anterior orbitofrontal cortex. In one of them additional activation at the right nucleus accumbens/ventral striatum and right ventral pallidum was present. In the remaining control subject activation was present in the left primary visual cortex. The enhanced interictal reactivity of the visual cortex in migraineurs supports the hypothesis of abnormal cortical excitability as an important pathophysiological mechanism in migraine aura, though the role of specific regions of the visual cortex remains to be explored.

Retrosplenial cortex (BA 29/30) hypometabolism in mild cognitive impairment (prodromal Alzheimer's disease).

Previous group studies using positron emission tomography to assess resting cerebral glucose metabolism in very early Alzheimer's disease and mild cognitive impairment have identified the posterior cingulate and adjacent cingulo-parietal cortex as the first isocortical area to develop hypometabolism. We studied the profile of resting cerebral glucose metabolism in individuals with mild cognitive impairment to assess whether more specific and stereotyped regional hypometabolism would be evident across subjects. The study found that the most consistently hypometabolic region between individual subjects was a subregion of the posterior cingulate, the retrosplenial cortex (BA 29/30). This result is discussed in the context of regional connectivity, focal lesion evidence and functional activation studies of episodic memory paradigms in both normal and Alzheimer's disease groups. We propose that the retrosplenial cortex may represent a key junction between prefrontal areas involved in implementing retrieval strategies for episodic memory and hippocampal-based mnemonic processing; we therefore interpret the retrosplenial hypometabolism as a probable contributor to the memory impairment seen in mild cognitive impairment by disconnecting these two anatomical networks.

Physical and Chemical Properties of MoP, Ni2P, and MoNiP Hydrodesulfurization Catalysts: Time‐Resolved X‐Ray Diffraction, Density Functional, and Hydrodesulfurization Activity Studies.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Brain-Imaging Studies of Posttraumatic Stress Disorder

Brain-imaging studies of posttraumatic stress disorder (PTSD) have rapidly increased in recent years. Structural studies have identified potential smaller volumes of the hippocampus of traumatized and/or PTSD subjects. Functional activation studies have implicated hyperactive or altered functioning of brain regions, such as the amygdala and the insula, and a failure to engage emotional regulatory structures, such as the medial prefrontal and anterior cingulate cortex. Recent neurochemical investigations have suggested that neuromodulatory systems (eg, gamma-aminobutyric acid, micro-opioid) may underlie these aberrant brain activation patterns. This article reviews the literature on structural, functional, and neurochemical brain-imaging studies of PTSD.

Physical and Chemical Properties of MoP, Ni2P, and MoNiP Hydrodesulfurization Catalysts: Time-Resolved X-ray Diffraction, Density Functional, and Hydrodesulfurization Activity Studies

Synchrotron-based time-resolved X-ray diffraction was used to study in situ the crystalline phases present during the preparation of bulk and silica-supported MoP, Ni2P, and MoNiP by reduction of oxidic precursors in hydrogen. Independent of the type of oxidic precursor used or the presence of silica as a support, the formation of the metal phosphides occurs at temperatures between 600 and 800 °C. Since the common species in all the cases are phosphate-type groups (POx), it seems that their reduction by hydrogen is the final and determining step in the formation of MoP, Ni2P, and MoNiP. Silica-stabilized phosphide phases were detected during the synthesis of Ni2P/SiO2 and MoP/SiO2 catalysts. In the case of Ni2P/SiO2, before the appearance of the final phosphide, strong diffraction lines are observed for Ni12P5. First-principles density functional calculations for bulk MoP, Ni2P, and MoNiP indicate that the Ni−P and Mo−P bonds in these compounds have a small degree of ionic character. For MoP, Ni2P, and Mo...

Language systems in normal and aphasic human subjects: functional imaging studies and inferences from animal studies.

The old neurological model of language, based on the writings of Broca, Wernicke and Lichtheim in the 19th century, is now undergoing major modifications. Observations on the anatomy and physiology of auditory processing in non-human primates are giving strong indicators as to how speech perception is organised in the human brain. In the light of this knowledge, functional activation studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are achieving a new level of precision in the investigation of language organisation in the human brain, in a manner not possible with observations on patients with aphasic stroke. Although the use of functional imaging to inform methods of improving aphasia rehabilitation remains underdeveloped, there are strong indicators that this methodology will provide the means to research a very imperfectly developed area of therapy.

The Blushing Brain: Changes in Brain Colour Indicate the Functional State of the Cerebral Cortex

Summary Near infrared spectroscopy of the adult human head has been increasingly applied in functional activation studies. The methodological approach mostly used is based on the Beer-Lambert law and determines changes in oxygenated and deoxygenated haemoglobin from changes in attenuation at multiple wavelengths of the NIR spectrum (650–950 nm). Here we give an overview over our work to validate the method and its application in functional activation studies to better understand mechanisms of neuro-vascular coupling. Such coupling is the basis of modern imaging techniques such as PET and BOLD contrast fMRI, and is thereby of utmost interest when linking the broad knowledge on functional anatomy obtained by invasive studies in animals to the results of the ever increasing body of studies in the adult human. Besides this application in basic physiology of imaging techniques we briefly summarise our view on potential application in neurological disease especially stroke and epilepsy.

Neural Correlates of Traumatic Recall in Posttraumatic Stress Disorder

Functional activation studies of posttraumatic stress disorder (PTSD) using symptom provocation paradigms have implicated dysfunction in limbic and paralimbic brain regions. Increased or altered cerebral blood flow has been observed in amygdala and insula. Decreased or absent activity has been seen in medial prefrontal and anterior cingulate cortex (ACC). These brain regions comprise a neural circuit that has been demonstrated as important for emotional processing and emotional regulation. We studied combat veterans with PTSD (n=16), combat veterans without PTSD (combat controls, n=15 ), and age-matched healthy control subjects (n=15) with [O-15] H2O PET under a script-driven imagery paradigm of personalized traumatic/stressful and emotionally neutral events. Preliminary findings show that PTSD patients and combat controls had differential blood flow patterns during emotional recall in amygdala, insula and medial prefrontal cortex. Consistent with and extending prior findings, these preliminary results replicate differential patterns of activation in limbic and paralimbic regions of PTSD patients and trauma exposed controls suggesting that these neural substrates may be involved in the deficits in emotional processing in PTSD on one hand, and in resilience to trauma on the other.

Mapping cerebral glutamate 13C turnover and oxygen consumption by in vivo NMR.

Regional rates of 13C incorporation from glucose to glutamate were detected in anesthetized rat brain in vivo at 7T with high temporal and spatial resolution using NMR method ICED PEPSI (in vivo carbon edited detection with proton echo planar spectroscopic imaging). Time courses of regional glutamate 13C turnover were fitted by a metabolic model to obtain regional tri-carboxylic acid (TCA) cycle flux and cerebral metabolic rate of oxygen consumption (CMRO2) in each voxel (8 microL) of rat cortex. CMRO2 maps obtained for rats under either alpha-chloralose or morphine anesthesia revealed average cortical values of 1.5 +/- 0.2 (n = 3) and 3.2 +/- 0.3 (n = 4) mumol/g/min, respectively. These values of CMRO2 are in good agreement with previous cortical measurements with coarser spatial resolution. The heterogeneity within each map, which depicted predominantly gray and white matter differences, was significantly greater under morphine (higher cortical activity) than under-alpha-chloralose (lower cortical activity) anesthesia. The regional variations in the basal awake state, which are expected to be even greater, should be considered to avoid partial-volume artifacts in functional activation studies of awake subjects.

Characterization of transcription factors by mass spectrometry and the role of SELDI-MS.

Over the last decade, much progress has been made in the field of biological mass spectrometry, with numerous advances in technology, resolution, and affinity capture. The field of genomics has also been transformed by the sequencing and characterization of entire genomes. Some of the next challenges lie in understanding the relationship between the genome and the proteome, the protein complement of the genome, and in characterizing the regulatory processes involved in progressing from gene to functional protein. In this new age of proteomics, development of mass spectrometry methods to characterize transcription factors promises to add greatly to our understanding of regulatory networks that govern expression. However, at this time, regulatory networks of transcription factors are mostly uncharted territory. In this review, we summarize the latest advances in characterization of transcription factors by mass spectrometry including affinity capture, identification of complexes of DNA-binding proteins, structural characterization, determination of protein-DNA and protein-protein interactions, assessment of modification sites and metal binding, studies of functional activity, and the latest chip technologies that use SELDI-MS that allow the rapid capture and identification of transcription factors.

The Mid-ventrolateral Prefrontal Cortex and Active Mnemonic Retrieval

The role of the mid-ventrolateral prefrontal cortex in memory retrieval is examined and compared with the role of the mid-dorsolateral prefrontal cortex in the monitoring of information in memory. It has been argued that the mid-ventrolateral prefrontal cortex (areas 47/12 and 45) is involved in the active retrieval of information from posterior cortical association areas. Active retrieval is required when stimuli in memory do not bear stable relations to each other and therefore retrieval cannot be automatically driven by strong, stable, and unambiguous stimulus or context relations. Data from functional activation studies with normal human subjects are presented that have demonstrated specific changes in activity within the mid-ventrolateral region of the frontal cortex in relation to the active retrieval of information from memory. By contrast, increases in activity in the mid-dorsolateral region of the frontal cortex occur when the performance of the tasks requires monitoring of information in memory.

Basic principles of optical imaging and application to the study of infant development

AbstractNew optical methods of studying the infant brain have been developed over the last 20 years. These techniques make use of a window of transparency of biological tissue to near infrared light. Using spectrophotometry new insights have been gained into mechanisms of brain damage in newborn infants undergoing intensive care, and non‐invasive functional activation studies have been pioneered in awake infants. Recently topographic mapping of activated cortex has become possible, and preliminary tomographic images of regional oxygenation in infants have been constructed. This is a rapidly changing field which offers exciting possibilities for studying both normal and abnormal child development.

Differential V gene expression detected in the immune response to Streptococcus pneumoniae capsular polysaccharide between elderly and young adults.

Streptococcus pneumoniae is one of the major causative agents of respiratory infections in the elderly population. The 23-valent pneumococcal polysaccharide vaccine is recommended for use in this age group. However, research has indicated that the protective efficacy of the vaccine declines with age. Although similar levels of antibody induction are seen in both young and elderly adults, following immunization with this vaccine, recent studies have indicated that the elderly possess antibodies with lower opsonophagocytic activity and avidity than young adults. We investigated whether a shift in V(H) gene usage may be responsible for this observation. To this end we utilized anti-idiotypic determinants to detect V(H)1 and V(H)3 gene usage by antibodies to pneumococcal capsular polysaccharides in both young and elderly subjects by enzyme-linked immunosorbent assay (ELISA). We found no significant difference in V(H)3 idiotypic expression in antibody responses to capsular polysaccharide from serotype 14 (PPS14). In response to PPS14 a significant higher level of V(H)1 idiotypic expressing antibodies was detected in the elderly as compared with young adults. V(H)1 idiotypic expression in response to capsular polysaccharide from serotype 4 (PPS4) was identical in young and elderly individuals. V(H)3 idiotypic expression in the elderly response to PPS4 was significantly lower than that seen in young individuals. These patterns of idiotypic expression are discussed in relation to recent studies of functional activity of pneumococcal reactive antibodies from young and aged humans.

Women and men exhibit different cortical activation patterns during mental rotation tasks

The strongest sex differences on any cognitive task, favoring men, are found for tasks that require the mental rotation of three-dimensional objects. A number of studies have explored functional brain activation during mental rotation tasks, and sex differences have been noted in some. However, in these studies there was a substantial confounding factor because male and female subjects differed in overall performance levels. In contrast, our functional brain activation study examined cortical activation patterns for males and females who did not differ in overall level of performance on three mental rotation tasks. This allowed us to eliminate any confounding influences of overall performance levels. Women exhibited significant bilateral activations in the intraparietal sulcus (IPS) and the superior and inferior parietal lobule, as well as in the inferior temporal gyrus (ITG) and the premotor areas. Men showed significant activation in the right parieto-occitpital sulcus (POS), the left intraparietal sulcus and the left superior parietal lobule (SPL). Both men and women showed activation of the premotor areas but men also showed an additional significant activation of the left motor cortex. No significant activation was found in the inferior temporal gyrus. Our results suggest that there are genuine between-sex differences in cerebral activation patterns during mental rotation activities even when performances are similar. Such differences suggest that the sexes use different strategies in solving mental rotation tasks.

MRI-Guided Diffuse Optical Spectroscopy of Malignant and Benign Breast Lesions

We present the clinical implementation of a novel hybrid system that combines magnetic resonance imaging (MRI) and near-infrared (NIR) optical measurements for the noninvasive study of breast cancer in vivo. Fourteen patients were studied with a MR-NIR prototype imager and spectrometer. A diffuse optical tomographic scheme employed the MR images as a priori information to implement an image-guided NIR localized spectroscopic scheme. All patients who entered the study also underwent gadolinium-enhanced MRI and biopsy so that the optical findings were crossvalidated with MR readings and histopathology. The technique quantified the oxy-and deoxyhemoglobin of five malignant and nine benign breast lesions in vivo. Breast cancers were found with decreased oxygen saturation and higher blood concentration than most benign lesions. The average hemoglobin concentration ([H]) of cancers was 0.130±0.100 mM, and the average hemoglobin saturation (Y) was 60±9% compared to [H]=0.018±0.005 mM and Y=69±6% of background tissue. Fibroadenomas exhibited high hemoglobin concentration [H]=0.060±0.010 mM and mild decrease in oxygen saturation Y=67±2%. Cysts and other normal lesions were easily differentiated based on intrinsic contrast information. This novel optical technology can be a significant add-on in MR examinations and can be used to characterize functional parameters of cancers with diagnostic and treatment prognosis potential. It is foreseen that the technique can play a major role in functional activation studies of brain and muscle as well.

Variability and asymmetry in the human precentral motor system. A cytoarchitectonic and myeloarchitectonic brain mapping study.

The morphology of the region of the primary motor cortex in the human brain is variable, and putative asymmetries between the hemispheres have been noted since the beginning of last century. Such variability may confound the results of clinical lesion or functional activation studies. We measured Brodmann area (BA) 4 and the identifiable precentral component of the pyramidal tract (PRPT) in 11 human post-mortem brains using techniques of quantitative cytoarchitectonic and myeloarchitectonic image analysis. Topography and variability in the localization of architectonic borders were analysed and mapped to a computerized spatial reference system, which consists of an individual in vivoMRI brain. All maps were superimposed to produce probabilistic maps of BA 4 and PRPT which can be co-registered with any image of brain structure or function that has also been transformed to Talairach coordinates. These maps can be readily applied to future brain mapping studies. We observed a considerable degree of variability between hemispheres (intra-individual) and between brains (inter-individual). The variation zones of BA 4 and PRPT differ from the templates of the Talairach atlas. Voxel-based morphometry shows significant side differences with larger volumes of PRPT in the left hemisphere than in the right hemisphere. This larger volume of the descending cortical motor fibres may be related to the known left-hemisphere dominance for handedness in >90% of the population. In contrast, BA 4 was symmetrically organized. The lack of a significant correlation between the size of BA 4 and the size of PRPT may relate to the fact that additional non-primary motor and sensory cortices contribute to the origins and size of the pyramidal tract proper.

Analysis of the temporal dynamics of event-related functional MRI activation studies

Analysis of the temporal dynamics of event-related functional MRI activation studies

Stable, polarised, functional expression of Kir1.1b channel protein in Madin-Darby canine kidney cell line.

1. The family of Kir1.1 (ROMK) channel proteins constitute a secretory pathway for potassium in principal cells of cortical collecting duct and thick ascending limb of Henle's loop. Mutations in Kir1.1 account for some types of Bartter's syndrome. 2. Here we report that stable transfection of Kir1.1b (ROMK2) in Madin-Darby canine kidney (MDCK) cell line results in expression of inwardly rectifying K+ currents and transmonolayer electrical and transport properties appropriate to Kir1.1 function. When grown on permeable supports, transfected monolayers secreted K+ into the apical solution. This secretion was inhibited by application of barium to the apical membrane, or by reduction in expression temperature from 37 to 26 C. However, whole-cell voltage clamp electrophysiology showed that K+ conductance was higher in cells expressing Kir1.1b at 26C. 3. To investigate this further, Kir1.1b was tagged with (EGFP), a modification that did not affect channel activity. Protein synthesis was inhibited with cycloheximide. Spectrofluorimetry was used to compare protein degradation at 37 and 26 C. The increased level of Kir1.1b at the plasma membrane at 26 C was due to an increase in protein stability. 4. Confocal microscopic investigation of EGFP-Kir1. 1b fluorescence in transfected cells showed that the channel protein was targeted to the apical domain of the cell. 5. These results demonstrate that Kir1.1b is capable of appropriate trafficking and function in MDCK cell lines at physiological temperatures. In addition, expression of Kir1.1b in MDCK cell lines provides a useful and convenient tool for the study of functional activity and targeting of secretory K+ channels.

Acute carotid occlusion alters the activation flow coupling response to forepaw stimulation in a rat model.

To determine whether the hemodynamic response to functional stimulation is sensitive to proximal arterial occlusion, we measured the activation flow coupling response in a rat model of acute reversible vascular occlusion. In alpha-chloralose-anesthetized rats (n=18), laser Doppler measurements were made through a thinned skull over the somatosensory cortex in response to electrical forepaw stimulation. Signal-averaged responses to 4 and 8 seconds of electrical forepaw stimulation were obtained before, during, and shortly after acute unilateral or bilateral carotid occlusion produced with the use of a surgically placed snare. Baseline cerebral blood flow was significantly decreased over the forepaw region of the somatosensory cortex after both occlusion of the carotid contralateral to the stimulated forepaw and bilateral occlusion compared with preocclusion (P<0.05). Postocclusion and ipsilateral occlusion led to a nonsignificant increase in baseline cerebral blood flow compared with preocclusion. Contralateral carotid occlusion and bilateral occlusion significantly prolonged the temporal characteristics of the flow response, especially the delay to peak (P<0.05), compared with preocclusion, whereas ipsilateral carotid occlusion significantly shortened the delay to peak (P<0.05). Only contralateral carotid occlusion produced a significant reduction in the peak amplitude of the flow response compared with preocclusion (P<0.05). These findings suggest that temporal characteristics of functional activation responses are sensitive to alterations in the proximal arterial supply and, conversely, that functional activation studies must be interpreted with consideration of proximal arterial disease.