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PubMed2004

Impaired modulation of the vestibulo-ocular reflex in Huntington's disease.

The vestibulo-ocular reflex (VOR) stabilizes gaze during movement, in conjunction with other afferent information: visual, proprioceptive, and somaesthetic. The reflex can either be augmented or suppressed, depending on visual requirements, and undergoes long-term adaptation to compensate for physical changes in the subject. Importantly, over relatively short periods of time, the VOR should function consistently under the same circumstances. This study examines VOR function in patients with Huntington's disease (HD), with a view to investigating cortical influences on the reflex. Horizontal eye movements were recorded in 9 patients with HD and 7 normal subjects, using the scleral search coil technique, in response to high frequency, unpredictable head rotations imposed manually. To establish base VOR function, recordings were made in darkness, without instruction, before and after wearing x2 magnifying lenses for a period of 2 hours to adapt the reflex. Recordings were also made before adaptation, while fixating a stationary visual target (VOR augmentation), and while fixating a target moving with the head (VOR suppression). Although results suggest that the VOR is preserved in HD, with relatively normal gain values and appropriate augmentation and suppression of the reflex with visual input, patients were unable to adapt the VOR to altered visual conditions. This represents a novel finding in HD and suggests that cortical structures compromised in HD exert influences on the long-term adaptation of the VOR.

Adult↗
PubMed2001

4D deformation modeling of cortical disease progression in Alzheimer's dementia.

This work describes the development of a model of cerebral atrophic changes associated with the progression of Alzheimer's disease (AD). Linear registration, region-of-interest analysis, and voxel-based morphometry methods have all been employed to elucidate the changes observed at discrete intervals during a disease process. In addition to describing the nature of the changes, modeling disease-related changes via deformations can also provide information on temporal characteristics. In order to continuously model changes associated with AD, deformation maps from 21 patients were averaged across a novel z-score disease progression dimension based on Mini Mental State Examination (MMSE) scores. The resulting deformation maps are presented via three metrics: local volume loss (atrophy), volume (CSF) increase, and translation (interpreted as representing collapse of cortical structures). Inspection of the maps revealed significant perturbations in the deformation fields corresponding to the entorhinal cortex (EC) and hippocampus, orbitofrontal and parietal cortex, and regions surrounding the sulci and ventricular spaces, with earlier changes predominantly lateralized to the left hemisphere. These changes are consistent with results from post-mortem studies of AD.

Aged↗
PubMed2005

Adaptation in the rodent olfactory bulb measured by fMRI.

Effective evaluation of the odor environment necessitates the ability to attenuate responses to potent background odors in favor of novel and less robust stimuli. Olfactory receptor neuron studies suggest that some of this adaptation takes place in the primary sensory neurons, but the more extensive adaptation seen in higher cortical areas implies the involvement of additional neural mechanisms. At 7.0 T, high-resolution fMRI was used to assess the response of the rodent olfactory bulb, the most peripheral cortical structure involved in olfactory processing, to a variety of odor stimuli. The results suggest that there are additional regulatory mechanisms in the olfactory bulb that result in greater adaptation in deeper areas than that seen in sensory receptors alone and that the resultant adaptation is positively affected by increasing stimulus duration and concentration and decreasing recovery time. The implications of these findings for the integration of peripheral input with perception are discussed.

Adaptation, Physiological↗
PubMed1991

Mapping the early development of projections from the entorhinal cortex in the embryonic mouse using prenatal surgery techniques.

The purpose of this work was to study the development of specific projections from the postero-lateral cortex during the third trimester of gestation in the mouse. To do this, we labeled undifferentiated lateral cortex with the fluorescent carbocyanine dye, Dil, in the embryonic day (E) 16 mouse embryo using exo utero surgical techniques (Muneoka, Wanek, and Bryant, 1986). Embryos were allowed to develop to term (postnatal day 0, P0) at which time the fiber patterns emanating from the marked regions were studied. Dye placement in the undifferentiated postero-ventral cortex produced labeled fibers in the hippocampal formation. A robust projection of the angular bundle into the CA1 region of the hippocampus was heavily labeled. In addition, in some animals, cortical tracts, such as the anterior commissure, corpus callosum, and a corticotectal tract, were labeled. These tracts have been described previously as scaffolding pathways in the fetal cat (McConnell, Ghosh, and Shatz, 1989), and other vertebrates (Wilson, Ross, Parrett, and Easter, 1990). Dye placement in adjacent, more anterior or dorsal areas showed strong labeling in cortical structures but no labeling in the hippocampal formation. These data indicate that, by birth, the temporal cortex is subdivided along the rostro-caudal axis as entorhinal cortex and perirhinal cortex, and along the dorso-ventral axis, as entorhinal cortex and neocortex. Also, these earliest connections are similar to adult connections in their specificity of target area selection. Therefore, these early, yet specific, connections may play a role int he formation of future connections during postnatal development.

Animals↗
PubMed1999

Localization of beta-endorphin in tetrahymena by confocal microscopy. Induction of the prolonged production of the hormone by hormonal imprinting.

The unicellular Tetrahymena has hormone receptors and hormones which are characteristic of higher vertebrates, as well as similar signal transduction pathways. In the present experiments, immunocytochemistry and confocal microscopy were used to study the presence and localization of beta-endorphin in Tetrahymena pyriformis GL. Endorphin (or endorphin-like material) was localized in the cortical structures, oral field, cilia and nuclear envelope. One-hour treatment with beta-endorphin ('hormonal imprinting') increased the presence of immunocytochemically demonstrable endorphin immediately and after 24 h, and was especially strong after 96 h of treatment. Simultaneous treatment with naloxone, an opioid antagonist, did not inhibit endorphin effect, but had an additive effect on endorphin production. Naloxone alone induced a very intensive accumulation of endorphin 96 h after treatment. The results support the possibility of a hormone production being induced by the imprinting procedure, but the imprinter-like effect of naloxone also points to the importance in this case of non-discriminatory receptors also being involved in the process.

Animals↗
PubMed2001

Precuneus-prefrontal activity during awareness of visual verbal stimuli.

Awareness is a personal experience, which is only accessible to the rest of world through interpretation. We set out to identify a neural correlate of visual awareness, using brief subliminal and supraliminal verbal stimuli while measuring cerebral blood flow distribution with H(2)(15)O PET. Awareness of visual verbal stimuli differentially activated medial parietal association cortex (precuneus), which is a polymodal sensory cortex, and dorsolateral prefrontal cortex, which is thought to be primarily executive. Our results suggest participation of these higher order perceptual and executive cortical structures in visual verbal awareness.

Adult↗
PubMed1998

Analysis of molecular domains of epitope-tagged merlin isoforms in Cos-7 cells and primary rat Schwann cells.

The Neurofibromatosis 2 gene product, merlin, has striking similarity to ezrin, radixin, and moesin (ERM), members of the protein 4.1 family which have been demonstrated to connect proteins in the plasma membrane to the cytoskeletal components. The recent localization of merlin to the motile regions in cultured cells such as membrane ruffles further supports the notion that merlin represents a new class of tumor suppressors. Here we describe the localization of full-length and truncated polypeptides of merlin expressed as Flag-tagged proteins in transfected cells. Similar to endogenous merlin, the epitope-tagged full-length merlin localizes to the membrane ruffles in transfected Cos-7 cells and rat Schwann cells. In addition, the over-expressed merlin localizes to other actin-rich cortical structures, such as microvilli and filopodia. The amino-terminal half of merlin is seen dispersed throughout the cells and in membrane ruffles. Compared to the amino-terminal half of merlin, its carboxy-terminal half localizes more distinctly to membrane ruffles. The full-length and the carboxy-terminal portion of merlin co-localize with F-actin at the membrane ruffles. However, distinct from the ERM proteins, the carboxy-terminal-truncated merlin and F-actin do not co-localize with each other at the stress fibers. Our results suggest that both the amino- and the carboxy-terminal domains of merlin contribute to its membrane ruffle localization.

Animals↗
PubMed1999

Syndecan-2 induces filopodia by active cdc42Hs.

The syndecans, a family of transmembrane heparan sulfate proteoglycans, are ubiquitous molecules whose intracellular function is still unknown. To examine the function of syndecan-2, one of the most abundant heparan sulfate proteoglycan in fibroblasts, we performed transfection studies in COS-1 and Swiss 3T3 cells. Endogenous syndecan-2 colocalized with F-actin in cortical structures. Overexpression of full-length syndecan-2 induced the formation of long filopodia-like structures. These changes correlated with a rearrangement of the actin cytoskeleton, which strongly colocalized with syndecan-2. Overexpression of syndecan-2 lacking the extracellular domain increased the number of microspikes on the cell surface but failed to induce filopodia. Addition of heparin blocked the effect of full-length syndecan-2, suggesting that heparan sulfate chains in the extracellular domain are necessary to induce filopodia. Coexpression of cdc42Hs negative-dominant N17 blocked syndecan-2-induced filopodia and cdc42Hs positive-dominant V12 had a synergic effect. This indicates that active cdc42Hs is necessary for syndecan-2 induction of filopodia. These results provide a link between syndecan-2, actin cytoskeleton, and cdc42Hs.

3T3 Cells↗
PubMed1999

Architectural dynamics of F-actin in eupodia suggests their role in invasive locomotion in Dictyostelium.

Eupodia are F-actin-containing cortical structures similar to vertebrate podosomes or invadopodia found in metastatic cells. Eupodia are rich in alpha-actinin and myosin IB/D, but not a Dictyostelium homologue of talin. In the present study, we localized other actin-binding proteins, ABP120, cofilin, coronin, and fimbrin, in the eupodia and examined the three-dimensional organization of their F-actin system by confocal microscopy and transmission electron microscopy. To examine their function, we analyzed the assembly and disassembly dynamics of the F-actin system in eupodia and its relation to lamellipodial protrusion. Actin dynamics was examined by monitoring S65T-GFP-coronin and rhodamine-actin using a real-time confocal unit and a digital microscope system. Fluorescence morphometric analysis demonstrates the presence of a precise spatiotemporal coupling between F-actin assembly in eupodia and lamellipodial protrusion. When a lamellipodium advances to invade a tight space, additional rows of eupodia are sequentially formed at the base of that lamellipodium. These results indicate that mechanical stress at the leading edge modulates the structural integrity of actin and its binding proteins, such that eupodia are formed when anchorage is needed to boost for invasive protrusion of the leading edge.

Actin Depolymerizing Factors↗
PubMed1999

Systemic hyperosmolality improves beta-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer.

Mucopolysaccharidosis VII, a classical lysosomal storage disease, is caused by deficiency of the enzyme beta-glucuronidase. Central nervous system (CNS) manifestations are severe with accumulations of storage vacuoles in all cell types. Intraventricular gene transfer can lead to transduction of the ependyma, with production and secretion of beta-glucuronidase into the cerebral spinal fluid and underlying cortex resulting in reversal of disease pathology restricted to the periventricular areas. We tested if systemic hyperosmolality would increase the distribution of beta-glucuronidase in brain parenchyma after intraventricular virus injection. Mice were administered mannitol, intraperitoneally, 20 days after gene transfer and 1 day prior to sacrifice. Mannitol-induced systemic hyperosmolality caused a marked penetration of beta-glucuronidase into the brain parenchyma. If mannitol was administered at the time of the intraventricular injection of virus, there was penetration of vector across the ependymal cell layer, with infection of cells in the subependymal region. This also resulted in increased beta-glucuronidase activity throughout the brain. Sections of brains from beta-glucuronidase-deficient mice showed correction of cellular pathology in the subependymal region plus cortical structures away from the ventricular wall. These data indicate that virus-mediated gene transfer to the brain via the ventricles, coupled with systemic mannitol administration, can lead to extensive CNS distribution of beta-glucuronidase with concomitant correction of the storage defect. Our findings have positive therapeutic implications for the treatment of CNS disorders with gene transfer vectors and recombinant proteins.

Adenoviridae↗
PubMed2000

Cocaine activation discriminates dopaminergic projections by temporal response: an fMRI study in Rat.

We applied a sensitive new functional magnetic resonance imaging technique to identify the pattern and determinants of cocaine-induced brain activation in drug-naive rats. At doses greater than 0.1 mg/kg iv, cocaine produced robust activation throughout cortex with the largest magnitude increase in frontal neocortex. Additionally, we detected selective activation within dopamine-innervated subcortical regions including dorsomedial and ventrolateral striatum, nucleus accumbens region, and dorsal thalamus. Although dose response was similar among activated regions, temporal response differentiated regions along distinct anatomical boundaries with basal ganglia and limbic cortical structures, reaching maximum activation later than frontal neocortex. Pharmacological specificity was demonstrated by blocking cocaine-induced activation with SCH-23390, a selective D1 antagonist. Our data demonstrate the utility of fMRI to identify spatiotemporal patterns of cocaine-induced brain activation and implicate D1 dopaminergic mechanisms in acute cocaine action.

Animals↗
PubMed2001

Voxel-based morphometry using the RAVENS maps: methods and validation using simulated longitudinal atrophy.

Statistical analysis of anatomical maps in a stereotaxic space has been shown to be a useful tool in population-based studies for quantifying local anatomical differences or changes, without a priori assumptions about the location and extent of the regions of interest. This paper presents an extension and validation of a previously published methodology, referred to as RAVENS, for characterizing regional atrophy in the brain. A new method for elastic, volume-preserving spatial normalization, which allows for accurate quantification of very localized atrophy, is used. The RAVENS methodology was tested on images with simulated atrophy within two gyri: precentral and superior temporal. It was found to accurately determine the regions of atrophy, despite their localized nature and the interindividual variability of cortical structures. Moreover, it was found to perform substantially better than the voxel-based morphology method of SPM'99. Improved sensitivity was achieved at the expense of human effort involved in defining a number of sulcal curves that serve as constraints on the 3D elastic warping.

Atrophy↗
PubMed1977

Neurophysiology of movement disorders.

The relation of the cortex, cerebellum, and basal ganglia and their participation in movement disorders is presented. Studies have shown that lesions to the cortex will produce contralateral paralysis while damage to the basal ganglia or cerebellum will result in movement abnormalities. These data provide support for the view that subcortical but not cortical structures initiate the control movement activity. It would appear that the basal ganglia and cerebellum receive signals from the auditory, visual, and somatosensory cortex integrate this information, and relay signals back to the motor cortex, which in turn sends out efferent fibers to the motor neurons of the spinal cord. The electronic and neurophysiological basis of the somatosensory evoked responses (SER) test following peripheral nerve stimulation and sensory recording in human cortex is given. Control values of SER peak to peak latency waveforms from 66 normal volunteers show the practicality of this test. Preliminary results using SER in patients are discussed from clinical case reports. The subjects had mild to marked movement disorders secondary to Parkinson's disease, vascular occlusion, multiple sclerosis, and spino-cerebellar degeneration. The potential of the SER as a clinical and experimental tool in evaluating movement abnormalities and other neuropathological conditions is presented.

Adult↗
PubMed1977

Auditory evoked potentials recorded from chronic implanted gyrus of Heschl in man.

By means of implanted multileads electrodes, responses to clicks and prolonged sound stimulations were recorded from the Heschl gyrus of 2 human brains. These responses were strictly localized to this structure. Cortical averaged auditory evoked potentials (c.AEP) to clicks are consistent with scalp averaged auditory evoked potentials (s.AEP). So, Na Pa, Nb, P1, N1, waves have similar latencies and none of them in the s.AEP may be correlated with myogenic potentials (in opposition with the suggestions of Bickford et al. 1964 and Celesia et al. 1968). Increasing the duration of sound stimulation resulted in changes of the response. For a duration longer than 20ms, an "on-response" and an "off-response" were noted. No satisfying physiological explanation of these events is retained despite data obtained with monaural homo and heterolateral stimulations and with variation of tone of sound stimulation.

Auditory Cortex↗
PubMed1994

Treatment of vasogenic brain edema with arginine vasopressin receptor antagonist--an experimental study.

We determined the effect of a centrally administered V1 receptor antagonist of arginine vasopressin on the brain water content in an animal model of vasogenic brain edema. Using adult rats, a cold injury was induced in the left hemisphere of the brain by applying a frozen copper rod. 50 ng of V1 receptor antagonist was administered into the left lateral ventricle 10 minutes prior to and/or 1 hour after injury. Twenty four hours after the cold injury, the brain water and sodium contents and plasma osmolality were measured. The V1 receptor antagonist significantly suppressed the increase of the brain water and sodium contents in the cortical structure adjacent to the lesion without any changes in plasma osmolality. Our results demonstrate the effectiveness of a V1 receptor antagonist of vasopressin on vasogenic brain edema.

Animals↗
PubMed1996

Vertical signal flow and oscillations in a three-layer model of the cortex.

A model of vertical signal flow across a layered cortical structure is presented and analyzed. Neurons communicate through spikes, which evoke an excitatory or inhibitory postsynaptic potential (spike response model). The layers incorporate two anatomical features-dendritic and axonal arborization patterns and distance-dependent time delays. The vertical signal flow through the network is discussed for various stimulus conditions using two different, but typical, axonal arborization patterns. We find stationary as well as oscillatory response, but the oscillatory response may be restricted to a single layer. Confronted with conflicting stimuli the network separates the patterns through phase-shifted oscillations. We also discuss two hypothetical animals, to be called "cat" and "mouse." These have different axonal arborizations, which give rise to a different oscillatory response (if any) of the various layers.

Axons↗
PubMed1991

Functional organization of auditory cortical fields in the Mongolian gerbil (Meriones unguiculatus): binaural 2-deoxyglucose patterns.

Unilaterally deafened (cochlear destruction) gerbils were exposed to white noise after injection of 14-C-2-deoxyglucose. The labelling patterns were compared to those of unstimulated operated animals, noise stimulated control animals and bilaterally ear plugged animals. Serial transverse, horizontal and tangential autoradiographs through the cortex were analysed. In lesioned animals, labelling was strongly reduced on the side contralateral to the lesion in the high frequency regions of A1 and the anterior auditory field (AAF). We assume that these regions correspond to the high frequency EI cell areas. Fine banding could be seen superimposed on this pattern in transverse and tangential sections. We suggest that this may be due to alternating strips of EI and EE cells orthogonal to iso-frequency contours. In the low frequency regions of A1 and AAF, labelling asymmetries were also present, but were less pronounced. We assume that these effects are due to low frequency EE cells. In sub-cortical structures, labelling was reduced in the inferior colliculus and ventral part of the medial geniculate body contralateral to the lesioned ear, but no labelling pattern was visible. We presume that the spatial separation of EE and EI inputs to these structures is not marked enough to allow labelling patterns to be seen. In the superior olivary complex, labelling was reduced on the side contralateral to the lesioned ear in the medial dendritic field of the medial superior olivary nucleus and in the nucleus of the trapezoid body. Ipsilateral to the lesioned ear, labelling was reduced in the lateral dendritic field of the medial superior olive.

Acoustic Stimulation↗
PubMed1994

In vivo microelectrode localization in the brain of the alert monkey: a combined radiographic and magnetic resonance imaging approach.

A technique is described for in vivo localization of microelectrodes during single-unit recording in the alert monkey. Four hollow glass spheres filled with copper sulfate and iohexol were affixed to the surface of the animal's skull prior to the acquisition of a series of coronal magnetic resonance (MR) images. These reference beads were visible in both X-ray and MR images. Cranial recording chambers were then implanted bilaterally over the amygdaloid complex. A microelectrode was advanced to various depths in the subject's brain. At each selected microelectrode site, five radiographs were obtained and a small electrolytic lesion was made. Based on the data from the radiographs, we computed the position of the microelectrode tip at each site relative to the reference beads. With a precision of 625 microns, this method was used to predict the neuroanatomical location of ten microlesions placed in both subcortical and cortical structures. Postmortem histological analysis revealed that the actual location of the lesions closely matched predictions arrived at using the X-ray/MRI localization technique. This technique thus provides an accurate, reliable and noninvasive method for in vivo localization of microelectrode recording sites.

Animals↗