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This article is a selective extension of a review on recombinant human erythropoietin (rHu-EPO) as an anti-anaemic drug, published in this journal in 2000. It summarises the recent advances in understanding the molecular mechanisms by which the hypoxia-inducible transcription factor 1 (HIF-1) regulates O(2)-dependent genes, including the EPO gene in brain. With respect to brain integrity, EPO exerts positive effects in two different ways. First, rHu-EPO raises the blood haemoglobin concentration and, hence, the O(2) capacity of the blood in anaemic patients. The restored O(2) supply ameliorates attention difficulties and psychomotor slowing, improves memory capacities and normalises neuroendocrine functions. Second, EPO can act as a neurotrophic and neuroprotective factor directly in brain. EPO and its receptor are expressed in the cerebral cortex, cerebellum, hippocampus, pituitary gland and spinal cord. In vitro EPO protects against glutamate-induced cell death in a dose-dependent way. In animal models it reduces volumes of brain ischaemia, protects the cortex from hypoxic damage and leads to survival of neurons and synapses. One can expect that in the near future rHu-EPO will be used therapeutically in cerebral ischaemia, brain trauma, inflammatory diseases, and neural degenerative disorders. A first clinical trial has shown the neuroprotective effectiveness of the drug in cerebral ischaemia.
Gonadotropin-releasing hormone (GnRH) is a neuropeptide that occurs in multiple structural forms among vertebrate species. Bony fishes, amphibians, reptiles, birds, and mammals express different forms of GnRH in the forebrain and endocrine regions of the hypothalamus which regulate the release of reproductive gonadotropins from the pituitary. In contrast, previous studies on bony fishes and tetrapods have localized the chicken GnRH-II (cGnRH-II) nucleus in the midbrain tegmentum and, combined with cladistic analyses, indicate that cGnRH-II is the most conserved form throughout vertebrate evolution. However, in elasmobranch fishes, the neuroanatomical distribution of cGnRH-II and dogfish GnRH (dfGnRH) cells and their relative projections in the brain are unknown. We used high-performance liquid chromatography and radioimmunoassay to test for differential distributions of various GnRH forms in tissues from the terminal nerve (TN) ganglia, preoptic area, and midbrain of the Atlantic stingray, Dasyatis sabina. These experiments identified major peaks that coelute with cGnRH-II and dfGnRH, minor peaks that coelute with lamprey GnRH-III (lGnRH-III), and unknown forms. Immunocytochemistry experiments on brain sections show that dfGnRH-immunoreactive (-ir) cell bodies are localized in the TN ganglia, the caudal ventral telencephalon, and the preoptic area. Axons of these cells project to regions of the hypothalamus and pituitary, diencephalic centers of sensory and behavioral integration, and the midbrain. A large, discrete, bilateral column of cGnRH-II-ir neurons in the midbrain tegmentum has sparse axonal projections to the hypothalamus and regions of the pituitary but numerous projections to sensory processing centers in the, midbrain and hindbrain. Immunocytochemical and chromatographic data are consistent with the presence of lGnRH-III and other GnRH forms in the TN that differ from dfGnRH and cGnRH-II. This is the first study that shows differential distribution of cGnRH-II and dfGnRH in the elasmobranch brain and supports the hypothesis of divergent function of GnRH variants related to gonadotropin control and neuromodulation of sensory function.
Early global deprivation of institutionalized children may result in persistent specific cognitive and behavioral deficits. In order to examine brain dysfunction underlying these deficits, we have applied positron emission tomography using 2-deoxy-2-[(18)F]fluoro-D-glucose in 10 children (6 males, 4 females, mean age 8.8 years) adopted from Romanian orphanages. Using statistical parametric mapping (SPM), the pattern of brain glucose metabolism in the orphans was compared to the patterns obtained from two control groups: (i) a group of 17 normal adults (9 males, 8 females, mean age 27.6 years) and (ii) a group of 7 children (5 males and 2 females, mean age 10.7 years) with medically refractory focal epilepsy, but normal glucose metabolism pattern in the contralateral hemisphere. Consistent with previous studies of children adopted from Romanian orphanages, neuropsychological assessment of Romanian orphans in the present study showed mild neurocognitive impairment, impulsivity, and attention and social deficits. Comparing the normalized glucose metabolic rates to those of normal adults, the Romanian orphans showed significantly decreased metabolism bilaterally in the orbital frontal gyrus, the infralimbic prefrontal cortex, the medial temporal structures (amygdala and head of hippocampus), the lateral temporal cortex, and the brain stem. These findings were confirmed using a region-of-interest approach. SPM analysis showed significantly decreased glucose metabolism in the same brain regions comparing the orphans to the nonepileptic hemisphere of the childhood epilepsy controls. Dysfunction of these brain regions may result from the stress of early global deprivation and may be involved in the long-term cognitive and behavioral deficits displayed by some Romanian orphans.
Recent advancements in two noninvasive transcranial neuroimaging techniques, near-infrared spectroscopy (NIRS) and transcranial magnetic stimulation (TMS), signify the increasing importance of establishing structural compatibility between transcranial methods and conventional tomographic methods, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). The transcranial data obtained from the head surface should be projected onto the cortical surface to present the transcranial brain-mapping data on the same platform as tomographic methods. Thus, we developed two transcranial projection algorithms that project given head-surface points onto the cortical surface in structural images, and computer programs based on them. The convex-hull algorithm features geometric handling of the cortical surface, while the balloon-inflation algorithm is faster, and better reflects the local cortical structure. The automatic cortical projection methods proved to be as effective as the manual projection method described in our previous study. These methods achieved perfect correspondence between any given point on the head surface or a related nearby point in space, and its cortical projection point. Moreover, we developed a neighbor-reference method that enables transcranial cortical projection of a given head-surface point in reference to three neighboring points and one additional standard point, even when no structural image of the subject is available. We also calculated an error factor associated with these probabilistic estimations. The current study presents a close topological link between transcranial and tomographic brain-mapping modalities, which could contribute to inter-modal data standardization.
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OBJECTIVE: To delineate regions involved in visual word recognition. BACKGROUND: The processes and regions involved in visual word recognition have been somewhat controversial for over 100 years. METHODS: This study used regional cerebral blood flow as assessed by functional magnetic resonance imaging to study normal subjects (N = 9) on an individual within-subject basis while they were actively engaged on-line in a visual lexical decision task. Standard analysis techniques were used for identifying regions of activation. RESULTS: Across subjects, the task activated a number of regions, including the occipital pole, lateral and basal occipitotemporal (including lingual and fusiform) regions, superior and middle temporal gyri, and supramarginal and angular gyri. Typically, these regions were activated bilaterally; when activation was unilateral, it was on the left. Some of the areas activated (e.g., inferior parietal regions) have not been previously reported to be involved in such types of processing by activation studies but have been implicated in lesion studies. CONCLUSIONS: These results broaden the areas known to be involved in visual word recognition. The bilateral activation associated with visual word recognition is in some respects analogous to the "what" system in visual recognition described in subhuman primates. In addition, the study raises several methodologic issues. The within-subject analysis showed variability in the specific regions activated when subsequently comparing across individuals, raising implications for future functional imaging studies.
A parametric functional MRI (fMRI) study with three levels of task difficulty was performed to determine the effect of practice and attentional load on brain activation during visual attention tasks. Brief practice during repeat fMRI scanning (20 min) did not change performance accuracy or reaction times (RT), but decreased activation bilaterally in the inferior, middle, and superior frontal gyri, superior temporal gyrus, thalamus, and cerebellum. Increased attentional load decreased performance accuracy but not RT, and increased activation bilaterally in the inferior, posterior, and superior parietal cortices, thalamus, cerebellum, and frontal gyri. These changes suggest that practice decreases dependency on thalamus, cerebellum, and the frontal cortices for controlled task processing possibly due to increased efficiency of the attentional network. Since short-term practice-effects in the prefrontal cortex may be similar to attentional load-effects, studies of attentional load need to take practice effects into account.
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