Modulation of neuronal activity after spinal cord stimulation for neuropathic pain; H(2)15O PET study.

Spinal cord stimulation (SCS) is an effective therapy for chronic neuropathic pain. However, the detailed mechanisms underlying its effects are not well understood. Positron emission tomography (PET) with H(2)(15)O was applied to clarify these mechanisms. Nine patients with intractable neuropathic pain in the lower limbs were included in the study. All patients underwent SCS therapy for intractable pain, which was due to failed back surgery syndrome in three patients, complex regional pain syndrome in two, cerebral hemorrhage in two, spinal infarction in one, and spinal cord injury in one. Regional cerebral blood flow (rCBF) was measured by H(2)(15)O PET before and after SCS. The images were analyzed with statistical parametric mapping software (SPM2). SCS reduced pain; visual analog scale values for pain decreased from 76.1+/-25.2 before SCS to 40.6+/-4.5 after SCS (mean+/-SE). Significant rCBF increases were identified after SCS in the thalamus contralateral to the painful limb and in the bilateral parietal association area. The anterior cingulate cortex (ACC) and prefrontal areas were also activated after SCS. These results suggest that SCS modulates supraspinal neuronal activities. The contralateral thalamus and parietal association area would regulate the pain threshold. The ACC and prefrontal areas would control the emotional aspects of intractable pain, resulting in the reduction of neuropathic pain after SCS.

[Effect of Acorus tatarinowii schott on ultrastructure and permeability of blood-brain barrier].

OBJECTIVE: To explore the influence of Acorus tatarinowii schott on ultrastructure and permeability of BBB. METHOD: The ultrastructure and permeability of BBB on rats with A. tatarinowii by electron microscope were observed. The even's blue (EB) and sodium phenytoin in brain was determined by UV and HPLC-MS. RESULT: After give A. tatarinowii, tight junctions of the endothelial cell opened in cotex, and the concentration of EB and sodium phenytoin in brain are significant increased. CONCLUSION: A. tatarinowii can increase the permeability of BBB, and show its 'Kaiqiao' effect.

MicroPET study of brain neuronal metabolism under electrical and mechanical stimulation of the rat tail.

OBJECTIVE: Small-animal positron emission tomography (microPET) has been widely used for measuring various molecular processes in the rodent brain. The somatotopic projection, however, has not been identified earlier using microPET under electrical stimulation (ES) and mechanical stimulation (MS). This study aimed to utilize microPET to investigate the glucose metabolism of cortical and thalamic responses to ES and MS of the rat tail. METHODS: The rats were anesthetized by ketamine and a custom-built stereotaxic frame was used to fix the rat head to ensure that the scanned images were concordant with an atlas. [F]-fluorodeoxyglucose (FDG) was used as a radiotracer to reveal the brain metabolic changes. An activation index (AI) was calculated from microPET data o quantify the changes in local metabolic activities normalized to variations in FDG dosage between animals. RESULTS: The results showed that ES increased FDG uptake in both the contralateral thalamus (AI=18) and cortex (AI=12.5), with significant side-to-side differences (P<0.05, paired t-test). MS also significantly increased FDG uptake in both cortical and thalamic regions, although lateralization was absent in the thalamus. CONCLUSION: This study indicated that microPET can be used to elucidate the functional and quantitative neuronal activities of brain structures of rodents under peripheral stimulation, and could be applied in investigations of brain sensory functions.

Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism.

Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of apoptotic neuronal cell death. The aim of the present study was to throw the light on the role of coenzyme Q10 with or without L-dopa in an experimental model of parkinsonism induced by rotenone in rats. The present work showed that rotenone (2.5 mg/kg/day i.p. for 60 days) induced a model of parkinsonism (group II) resembling the basic findings in human characterized by bradykinesia and rigidity manifested as an increase in catalepsy score (detected after 20 days with bad prognosis after 60 days) with marked decrease in striatal dopamine levels. This model confirmed the implication of mitochondrial-apoptotic pathway in the pathogenesis of parkinsonism as there was a decrease in levels of striatal complex I activity and ATP as well as extreme overexpression of the antiapoptotic protein Bcl-2, and also exhibited the role of coenzyme Q10 where its plasma and striatal levels were found to be decreased in comparison to the normal control rats (group I). This proposed pathogenesis was evidenced by the significant correlation between catalepsy score and the neurochemical parameters obtained in the current work. The treated groups started to receive the drug(s) after 20 days from induction of parkinsonism and continued to complete for 60 days. Oral administration of Co Q10 in a low dose 200 mg/kg/day (group III) or a high dose 600 mg/kg/day (group IV), resulted in amelioration of the mitochondrial induced apoptosis by dose-dependent restoration of striatal complex I activity, ATP levels with temperate increase in expression of Bcl-2 as well as decrease in catalepsy score. Although both low and high doses of Co Q10 resulted in significant increase in its plasma and striatal levels, but only the high dose was shown to reach the recommended therapeutic levels. As a current replacement therapy, oral administration of levodopa 10 mg/kg/day (group V), caused symptomatic improvement in the form of reduction of catalepsy score with restoration of striatal dopamine levels, but it did not show any significant effects on either striatal complex I activity, ATP levels or the expression of Bcl-2, pointing to the lack of its disease-modifying role. On the other hand, its administration with high dose of coenzyme Q10 caused the most marked symptomatic improvement in catalepsy score when compared to its administration with low dose of coenzyme Q10, or when compared to either coenzyme Q10 high dose or L-dopa, respectively. Moreover, administration of high dose coenzyme Q10 with L-dopa provided a significant increase in striatal complex I activity, ATP levels and Bcl-2 expression in comparison to group administered coenzyme Q10 low dose with L-dopa, in addition to the significant restoration of striatal dopamine levels and both plasma and striatal Co Q10 levels. Regarding that L-dopa is viewed as a replacement therapy in parkinsonism, it could be concluded that addition of coenzyme Q10 in a high dose in early parkinson's disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity and intervention with neuronal apoptosis. A further research to investigate other apoptosis-targeted compounds will open a new era in the treatment of parkinsonism.

The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies.

Histamine neurons are exclusively located in the posterior hypothalamus, and project their fibers to almost all regions of the human brain. Although a significant amount of research has been done to clarify the functions of the histaminergic neuron system in animals, a few studies have been reported on the roles of this system in the human brain. In past studies, we have been able to clarify some of the functions of histamine neurons using different methods, such as histamine-related gene knockout mice or human positron emission tomography (PET). The histaminergic neuron system is known to modulate wakefulness, the sleep-wake cycle, appetite control, learning, memory and emotion. Accordingly we have proposed that histamine neurons have a dual effect on the CNS, with both stimulatory and suppressive actions. As a stimulator, neuronal histamine is one of the most important systems that stimulate and maintain wakefulness. Brain histamine also functions as a suppressor in bioprotection against various noxious and unfavorable stimuli of convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress susceptibility. This review summarizes our works on the functions of histamine neurons using human PET studies, including the development of radiolabeled tracers for histamine H1 receptors (H1R: (11)C-doxepin and (11)C-pyrilamine), PET measurements of H1R in depression, schizophrenia, and Alzheimer's disease (AD), and studies on the sedative effects of antihistamines using H(2)(15)O and H1R occupancy in the human brain. These molecular and functional PET studies in humans are useful for drug development in this millennium.

Manganese-enhanced magnetic resonance imaging of mossy fiber plasticity in vivo.

Mn(2+)-enhanced magnetic resonance imaging (MEMRI) was used to characterize activity-dependent plasticity in the mossy fiber pathway after intraperitoneal kainic acid (KA) injection. Enhancement of the MEMRI signal in the dentate gyrus and the CA3 subregion of the hippocampus was evident 3 to 5 days after injection of MnCl(2) into the entorhinal cortex both in control and KA-injected rats. In volume-rendered three-dimensional reconstructions, Mn(2+)-induced signal enhancement revealed the extent of the mossy fiber pathway throughout the septotemporal axis of the dentate gyrus. An increase in the number of Mn(2+)-enhanced pixels in the dentate gyrus and CA3 subfield of rats with KA injection correlated (P < 0.05) with histologically verified mossy fiber sprouting. These data demonstrate that MEMRI can be used to detect specific changes at the cellular level during activity-dependent plasticity in vivo. The present findings also suggest that MEMRI signal changes can serve as an imaging marker of epileptogenesis.

Cerebral perfusion changes in mesial temporal lobe epilepsy: SPM analysis of ictal and interictal SPECT.

We examined cerebral perfusion changes in mesial temporal lobe epilepsy (mTLE) by the statistical parametric mapping of brain single photon emission computed tomography (SPECT) images of 38 mTLE patients and 19 normal controls. Ictal and interictal SPECTs were compared with control SPECTs by independent t test, and ictal and interictal SPECTs by paired t test. We evaluated the number of heterotopic neurons in temporal lobe white matter, white matter changes of the anterior temporal lobe (WCAT) and ictal hyperperfusion of the temporal stem (IHTS). Left mTLE showed interictal hypoperfusion in the ipsilateral hippocampus, bilateral thalami, and paracentral lobules. Right mTLE showed hypoperfusion in bilateral hippocampi, contralateral insula, bilateral thalami, and paracentral lobules. Both mTLEs showed ictal hyperperfusion in bilateral temporal lobes with ipsilateral predominance, and in the anterior frontal white matter bilaterally. By paired t test, ictal hyperperfusion was found in the ipsilateral temporal lobe, temporal stem, hippocampus, thalamus, putamen, insula, and bilateral precentral gyri, whereas ictal hypoperfusion was found in bilateral frontal poles and middle frontal gyri. Fifteen patients showed WCAT and 19 showed IHTS, a weak correlation was observed between WCAT and IHTS (r = 0.377, P = 0.02). WCAT was found to correlate with an early seizure onset age. In 35 patients, heterotopic neurons were found in the white matter of the resected temporal lobe, but the number of heterotopic neurons did not correlate with WCAT or IHTS. In summary, the cerebral perfusion patterns of mTLE suggest interictal hypofunction and ictal activation of the cortico-thalamo-hippocampal-insular network and ictal hypoperfusion of the anterior frontal cortex.

Cortical orofacial motor representation in Old World monkeys, great apes, and humans. II. Stereologic analysis of chemoarchitecture.

This study presents a comparative stereologic investigation of neurofilament protein- and calcium-binding protein-immunoreactive neurons within the region of orofacial representation of primary motor cortex (Brodmann's area 4) in several catarrhine primate species (Macaca fascicularis, Papio anubis, Pongo pygmaeus, Gorilla gorilla, Pan troglodytes, and Homo sapiens). Results showed that the density of interneurons involved in vertical interlaminar processing (i.e., calbindin- and calretinin-immunoreactive neurons) as well pyramidal neurons that supply heavily-myelinated projections (i.e., neurofilament protein-immunoreactive neurons) are correlated with overall neuronal density, whereas interneurons making transcolumnar connections (i.e., parvalbumin-immunoreactive neurons) do not exhibit such a relationship. These results suggest that differential scaling rules apply to different neuronal subtypes depending on their functional role in cortical circuitry. For example, cortical columns across catarrhine species appear to involve a similar conserved network of intracolumnar inhibitory interconnections, as represented by the distribution of calbindin- and calretinin-immunoreactive neurons. The subpopulation of horizontally-oriented wide-arbor interneurons, on the other hand, increases in density relative to other interneuron subpopulations in large brains. Due to these scaling trends, the region of orofacial representation of primary motor cortex in great apes and humans is characterized by a greater proportion of neurons enriched in neurofilament protein and parvalbumin compared to the Old World monkeys examined. These modifications might contribute to the voluntary dexterous control of orofacial muscles in great ape and human communication.

Differential regulation of thalamic and cortical axonal growth by hepatocyte growth factor/scatter factor.

The initial axonal projections between the cerebral cortex and thalamus are established during embryogenesis. Chemoattractants and repellents are thought to provide specific guidance cues for directional growth of these pathways. Hepatocyte growth factor/scatter factor (HGF/SF) serves as an attractant for developing motor neurons, and its distribution in embryonic pallidum, pallium and thalamus suggests a similar role in forebrain development. We examined the effectiveness of HGF/SF in regulating thalamic and cortical neuronal growth using in vitro assays. HGF/SF increased neurite outgrowth of thalamic, but not cortical neurons, grown in dissociated cultures or as explants. HGF/SF also exhibited a chemoattractant property for thalamic axons, promoting the extension of neurites towards an HGF/SF source. These experiments demonstrate HGF/SF has the capacity to selectively direct thalamocortical projections into an intermediate target, the pallidum, and eventually to their final cortical destination.

The distribution and morphological characteristics of serotonergic cells in the brain of monotremes.

The distribution and cellular morphology of serotonergic neurons in the brain of two species of monotremes are described. Three clusters of serotonergic neurons were found: a hypothalamic cluster, a cluster in the rostral brainstem and a cluster in the caudal brainstem. Those in the hypothalamus consisted of two groups, the periventricular hypothalamic organ and the infundibular recess, that were intimately associated with the ependymal wall of the third ventricle. Within the rostral brainstem cluster, three distinct divisions were found: the dorsal raphe nucleus (with four subdivisions), the median raphe nucleus and the cells of the supralemniscal region. The dorsal raphe was within and adjacent to the periaqueductal gray matter, the median raphe was associated with the midline ventral to the dorsal raphe, and the cells of the supralemniscal region were in the tegmentum lateral to the median raphe and ventral to the dorsal raphe. The caudal cluster consisted of three divisions: the raphe obscurus nucleus, the raphe pallidus nucleus and the raphe magnus nucleus. The raphe obscurus nucleus was associated with the dorsal midline at the caudal-most part of the medulla oblongata. The raphe pallidus nucleus was found at the ventral midline of the medulla around the inferior olive. Raphe magnus was associated with the midline of the medulla and was found rostral to both the raphe obscurus and raphe pallidus. The results of our study are compared in an evolutionary context with those reported for other mammals and reptiles.