Specific binding of [3H]phenytoin in the human brain

Competition between cold phenytoin and [3H]phenytoin binding was observed in normal human brain. Binding was observed in all areas examined. The highest number of sites was in the amygdala (a total of 717.71 fmol/mg protein) and the lowest in the Brodman area (BA) 4 of the motor cortex (153.91 fmol/mg protein) and cerebellar cortex (154.4 fmol/mg protein). In three areas, amygdala, cortex area BA 38 (inferior parietal lobe), and cortex area BA 8 (premotor cortex), two sets of binding sites were observed. In these areas the Kd for the higher affinity sites ranged from 35 to 116 nM, and for the lower affinity site, from 328 to 866 nM. In the four areas where only one binding site was observed the KdS ranged from 164 to 311 nM and the Scatchard plot was linear.     

Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain

Mechanical probes of various sizes and shapes were used to determine thresholds for the perception of pressure, sharpness, and pain on the human finger. As force increased, perception changed from dull pressure to sharp pressure to sharp pain. With the smallest probe (0.01 mm2), sharpness threshold was very close to pressure threshold. As probe size increased, sharpness and pain threshold expressed in terms of force) increased in proportion to probe circumference (not probe area), whereas pressure threshold increased relatively little. Pain and sharpness thresholds also increased as probe angle became obtuse. There was a statistically significant increase in both thresholds with a probe angle change of 15 degrees. Thus, both size and shape are necessary to describe a mechanical stimulus adequately, and pressure (force/area) is not a sufficient metric for pain studies. Thresholds varied at different skin sites on the finger. The dorsal surface had lower thresholds than the volar surface, but the difference between the two areas was not always statistically significant. The compliance of the skin (e.g., the amount of indentation produced by a given force) exhibited no relation to sharpness or pain threshold, whether considered within subjects at various skin sites, or across subjects at the same skin site. Comparison of the perceptual thresholds with the thresholds for nociceptors determined in electrophysiological studies indicates that the sensation of nonpainful sharpness is likely to be mediated by nociceptors. Furthermore, considerably more than threshold activation of nociceptors is necessary for normal pain perception.     

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications V. Central nervous system processing of somatic and visceral sensory signals

Somatic and visceral sensation, including pain perception, can be studied noninvasively in humans with functional brain imaging techniques. Positron emission tomography and functional magnetic resonance imaging have identified a series of cerebral regions involved in the processing of somatic pain, including the anterior cingulate, insular, prefrontal, inferior parietal, primary and secondary somatosensory, and primary motor and premotor cortices, the thalamus, hypothalamus, brain stem, and cerebellum. Experimental evidence supports possible specific roles for individual structures in processing the various dimensions of pain, such as encoding of affect in the anterior cingulate cortex. Visceral sensation has been examined in the setting of myocardial ischemia, distension of hollow viscera, and esophageal acidification. Although knowledge regarding somatic sensation is more extensive than the information available for visceral sensation, important similarities have emerged between cerebral representations of somatic and visceral pain.     

Concurrent TMS-fMRI and psychophysics reveal frontal influences on human retinotopic visual cortex

BACKGROUND: Regions in human frontal cortex may have modulatory top-down influences on retinotopic visual cortex, but to date neuroimaging methods have only been able to provide indirect evidence for such functional interactions between remote but interconnected brain regions. Here we combined transcranial magnetic stimulation (TMS) with concurrent functional magnetic resonance imaging (fMRI), plus psychophysics, to show that stimulation of the right human frontal eye-field (FEF) produced a characteristic topographic pattern of activity changes in retinotopic visual areas V1-V4, with functional consequences for visual perception. RESULTS: FEF TMS led to activity increases for retinotopic representations of the peripheral visual field, but to activity decreases for the central field, in areas V1-V4. These frontal influences on visual cortex occurred in a top-down manner, independently of visual input. TMS of a control site (vertex) did not elicit such visual modulations, and saccades, blinks, or pupil dilation could not account for our results. Finally, the effects of FEF TMS on activity in retinotopic visual cortex led to a behavioral prediction that we confirmed psychophysically by showing that TMS of the frontal site (again compared with vertex) enhanced perceived contrast for peripheral relative to central visual stimuli. CONCLUSIONS: Our results provide causal evidence that circuits originating in the human FEF can modulate activity in retinotopic visual cortex, in a manner that differentiates the central and peripheral visual field, with functional consequences for perception. More generally, our study illustrates how the new approach of concurrent TMS-fMRI can now reveal causal interactions between remote but interconnected areas of the human brain.     

Neural plasticity in high-level visual cortex underlying object perceptual learning

With intensive training, human can achieve impressive behavioral improvement on various perceptual tasks. This phenomenon, termed perceptual learning, has long been considered as a hallmark of the plasticity of sensory neural system. Not surprisingly, high-level vision, such as object perception, can also be improved by perceptual learning. Here we review recent psychophysical, electrophysiological, and neuroimaging studies investigating the effects of training on object selective cortex, such as monkey inferior temporal cortex and human lateral occipital area. Evidences show that learning leads to an increase in object selectivity at the single neuron level and/or the neuronal population level. These findings indicate that high-level visual cortex in humans is highly plastic and visual experience can strongly shape neural functions of these areas. At the end of the review, we discuss several important future directions in this area.     

Distinct Parietal and Temporal Pathways to the Homologues of Broca's Area in the Monkey

The homologues of the two distinct architectonic areas 44 and 45 that constitute the anterior language zone (Broca's region) in the human ventrolateral frontal lobe were recently established in the macaque monkey. Although we know that the inferior parietal lobule and the lateral temporal cortical region project to the ventrolateral frontal cortex, we do not know which of the several cortical areas found in those regions project to the homologues of Broca's region in the macaque monkey and by means of which white matter pathways. We have used the autoradiographic method, which permits the establishment of the cortical area from which axons originate (i.e., the site of injection), the precise course of the axons in the white matter, and their termination within particular cortical areas, to examine the parietal and temporal connections to area 44 and the two subdivisions of area 45 (i.e., areas 45A and 45B). The results demonstrated a ventral temporo-frontal stream of fibers that originate from various auditory, multisensory, and visual association cortical areas in the intermediate superolateral temporal region. These axons course via the extreme capsule and target most strongly area 45 with a more modest termination in area 44. By contrast, a dorsal stream of axons that originate from various cortical areas in the inferior parietal lobule and the adjacent caudal superior temporal sulcus was found to target both areas 44 and 45. These axons course in the superior longitudinal fasciculus, with some axons originating from the ventral inferior parietal lobule and the adjacent superior temporal sulcus arching and forming a simple arcuate fasciculus. The cortex of the most rostral part of the inferior parietal lobule is preferentially linked with the ventral premotor cortex (ventral area 6) that controls the orofacial musculature. The cortex of the intermediate part of the inferior parietal lobule is linked with both areas 44 and 45. These findings demonstrate the posterior parietal and temporal connections of the ventrolateral frontal areas, which, in the left hemisphere of the human brain, were adapted for various aspects of language production. These precursor circuits that are found in the nonlinguistic, nonhuman, primate brain also exist in the human brain. The possible reasons why these areas were adapted for language use in the human brain are discussed. The results throw new light on the prelinguistic precursor circuitry of Broca's region and help understand functional interactions between Broca's ventrolateral frontal region and posterior parietal and temporal association areas.     

Brain monoamines following castration of aggressive muricidal rats

The effect of castration on the levels of brain monoamines and their metabolites has been investigated in rats which became or did not become muricidal following long-term isolation. Fourteen brain areas were explored: olfactory bulbs (OB), olfactory tubercles (OT), septum (Se), striatum (Sr), amygdala (A), thalamus (Th), hypothalamus (Hy), hippocampus (Hi), superior colliculus (SC), inferior colliculus (IC), raphe (Ra), pons-medulla (PM), frontal cortex (FC), temporal cortex (TC) and parietal cortex (PC). Except in the raphe of non muricidal rats and in the striatum of muricidal animals, all other areas examined demonstrate some changes of monoamines neurotransmitter or their metabolites after castration. The strongest changes, always increases, were found in the thalamus. In several brain areas, the changes occurring after castration, differ quantitatively and qualitatively in muricidal and non-muricidal rats.Special issue dedicated to Dr. Claude Baxter.Prof. P. Mandel passed away on October 6th, 1992.     

Alteration of neural activity and neuroinflammatory factors in the insular cortex of mice with corneal neuropathic pain

Dry eye disease (DED) affects nearly 55% of people worldwide; several studies have proposed that central sensitization and neuroinflammation may contribute to the developing corneal neuropathic pain of DED, while the underlying mechanisms of this contribution remain to be investigated. Excision of extra orbital lacrimal glands established the dry eye model. Corneal hypersensitivity was examined through chemical and mechanical stimulation, and open field test measured the anxiety levels. Restingstate fMRI is a method of functional magnetic resonance imaging (rs-fMRI) was performed for anatomical involvement of the brain regions. The amplitude of low-frequency fluctuation (ALFF) determined brain activity. Immunofluorescence testing and Quantitative real-time polymerase chain reaction were also performed to further validate the findings. Compared with the Sham group, ALFF signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were increased in the dry eye group. This change of ALFF in the insular cortex was linked with the increment in corneal hypersensitivity (p < 0.01), c-Fos (p < 0.001), brain-derived neurotrophic factor (p < 0.01), TNF-α, IL-6, and IL-1β (p < 0.05). In contrast, IL-10 levels (p < 0.05) decreased in the dry eye group. DED-induced corneal hypersensitivity and upregulation of inflammatory cytokines could be blocked by insular cortex injection of Tyrosine Kinase receptor B agonist cyclotraxin-B (p < 0.01) without affecting anxiety levels. Our study reveals that the functional activity of the brain associated with corneal neuropathic pain and neuroinflammation in the insular cortex might contribute to dry eye-related corneal neuropathic pain.     

慢性疼痛与皮层-边缘系统

慢性疼痛作为最常见的临床症状之一,已被认为是全球性的公共健康问题.然而,目前急性疼痛转化为慢性疼痛(即疼痛慢性化)的机制尚不清楚,如何防治急性疼痛转化为慢性疼痛仍然是临床亟待解决的问题.影像学研究表明,编码疼痛情绪、动机和记忆的脑区涉及皮层-边缘系统,而编码持续性疼痛的脑区也主要涉及该系统.基于此,本文概述了慢性疼痛患者在情绪、动机和记忆等方面的行为异常,并详细讨论了慢性疼痛患者皮层-边缘系统的结构和功能变化.其次,本文以慢性腰背痛为例,总结了可能预测疼痛慢性化的影像学指标,如内侧前额叶皮层与伏隔核以及海马的功能连接、背内侧前额叶皮层-杏仁核-伏隔核之间的功能连接均可预测1年后腰背痛疼痛慢性化的发展.此外,基于现有的疼痛慢性化理论模型,本文指出疼痛慢性化可能涉及患者对负面情绪的强化学习以及奖赏和应激系统的功能失调.最后,根据目前研究仍存在的问题和局限,本文对未来的研究方向和方法提出了建议.     

Motor and cognitive functions of the ventral premotor cortex

Recent data show that the ventral premotor cortex in both humans and monkeys has motor and cognitive functions. The cognitive functions include space perception, action understanding and imitation. The data also show a clear functional homology between monkey area F5 and human area 44. Preliminary evidence suggests that the ventral part of the lateral premotor cortex in humans may correspond to monkey area F4. A tentative map of the human lateral premotor areas founded on the reviewed evidence is presented.     

The modification of cortical reorganization and chronic pain by sensory feedback

Recent neuroscientific evidence has revealed that the adult brain is capable of substantial plastic change in areas such as the primary somatosensory cortex that were formerly thought to be modifiable only during early experience. We discuss research on phantom limb pain as well as chronic back pain that revealed functional reorganization in both the somatosensory and the motor system in these chronic pain states. In phantom limb pain patients, cortical reorganization is correlated with the amount of phantom limb pain; in low back pain patients the amount of reorganizational change increases with chronicity. We present a model of the development of chronic pain that assumes an important role of somatosensory pain memories. In phantom limb pain, we propose that those patients who experienced intense pain prior to the amputation will later likely develop enhanced cortical reorganization and phantom limb pain. We show that cortical plasticity related to chronic pain can be reduced by behavioral interventions that provide feedback to the brain areas that were altered by somatosensory pain memories.     

Emotional regulation of pain: the role of noradrenaline in the amygdala

The perception of pain involves the activation of the spinal pathway as well as the supra-spinal pathway,which targets brain regions involved in affective and cognitive processes.Pain and emotions have the capacity to influence each other reciprocally;negative emotions,such as depression and anxiety,increase the risk for chronic pain,which may lead to anxiety and depression.The amygdala is a key-player in the expression of emotions,receives direct nociceptive information from the parabrachial nucleus,and is densely innervated by noradrenergic brain centers.In recent years,the amygdala has attracted increasing interest for its role in pain perception and modulation.In this review,we will give a short overview of structures involved in the pain pathway,zoom in to afferent and efferent connections to and from the amygdala,with emphasis on the direct parabrachio-amygdaloid pathway and discuss the evidence for amygdala’s role in pain processing and modulation.In addition to the involvement of the amygdala in negative emotions during the perception of pain,this brain structure is also a target site for many neuromodulators to regulate the perception of pain.We will end this article with a short review on the effects of noradrenaline and its role in hypoalgesia and analgesia.     

Mirroring Pain in the Brain: Emotional Expression versus Motor Imitation

Perception of pain in others via facial expressions has been shown to involve brain areas responsive to self-pain, biological motion, as well as both performed and observed motor actions. Here, we investigated the involvement of these different regions during emotional and motor mirroring of pain expressions using a two-task paradigm, and including both observation and execution of the expressions. BOLD responses were measured as subjects watched video clips showing different intensities of pain expression and, after a variable delay, either expressed the amount of pain they perceived in the clips (pain task), or imitated the facial movements (movement task). In the pain task condition, pain coding involved overlapping activation across observation and execution in the anterior cingulate cortex, supplementary motor area, inferior frontal gyrus/anterior insula, and the inferior parietal lobule, and a pain-related increase (pain vs. neutral) in the anterior cingulate cortex/supplementary motor area, the right inferior frontal gyrus, and the postcentral gyrus. The ‘mirroring’ response was stronger in the inferior frontal gyrus and middle temporal gyrus/superior temporal sulcus during the pain task, and stronger in the inferior parietal lobule in the movement task. These results strongly suggest that while motor mirroring may contribute to the perception of pain expressions in others, interpreting these expressions in terms of pain content draws more heavily on networks involved in the perception of affective meaning.     

In vitro interaction of premazepam with benzodiazepine receptors in rat brain regions

Premazepam (PRZ) in vitro competitively displaced 3H-diazepam (DIA), 3H-flunitrazepam (FLU) and 3H-RO 15-1788 from their binding sites on rat brain synaptosomes, with a potency intermediate to other benzodiazepines (BDZs), and Hill coefficients near 1 in different brain regions. Incubation at 37 degrees C reduced premazepam's affinity for BDZ receptors to a lower extent than other benzodiazepines and had no effect on the Hill coefficient. The IC50 of PRZ on 3H-RO 15-1788 and 3H-FLU binding was markedly reduced by GABA in rat cortex, like those of reference classical BDZs, but was GABA-independent in the cerebellum. The IC50 of the BDZ antagonist, RO 15-1788 was unaffected by GABA in both brain areas. The possibility that PRZ behaves as a partial agonist in the cortex and as an antagonist in the cerebellum is discussed.     

Evidence for Distinct 5-Hydroxytryptamine2 Binding Site Subtypes in Cortical Membrane Preparations

5-Hydroxytryptamine (5-HT) displays a sixfold higher affinity for 5-HT2 binding sites labeled by [3H]ketanserin in rat (IC50 = 200 +/- 40 nM) and human (IC50 = 190 +/- 50 nM) cortex than for 5-HT2 sites in bovine cortex (IC50 = 1,200 +/- 130 nM). The Hill slopes of the 5-HT competition curves are 0.67 +/- 0.04 in rat, 0.69 +/- 0.08 in human, and 0.96 +/- 0.02 in bovine cortex. Scatchard analysis of (+/-)-[3H]4-bromo-2,5-dimethoxyamphetamine ([3H]DOB) binding in the rat indicates a population of binding sites with a KD of 0.38 +/- 0.04 nM and a Bmax of 1.5 +/- 0.05 pmol/g tissue. In contrast, specific [3H]DOB binding cannot be detected in bovine cortical membranes. These data indicate that species variations exist in 5-HT2 binding site subtypes and that [3H]ketanserin appears to label a homogeneous population of 5-HT2 binding site subtypes in bovine cortex.     

Binding sites for melanin-concentrating hormone in the human brain

Binding sites for melanin-concentrating hormone (MCH) in human brain were investigated and characterized by radioligand binding. Specific binding sites for MCH were present in every region of human brain (cerebral cortex, cerebellum, thalamus, hypothalamus, pons, and medulla oblongata) obtained at autopsy. alpha-Melanocyte stimulating hormone or ACTH was a poor inhibitor of (125)I-MCH binding (IC(50) 1 microM) compared with MCH (IC(50) = 0.3 +/- 0.07 nM, mean +/- SEM, n = 3). Scatchard plots of (125)I-MCH binding in human brain (thalamus) gave a dissociation constant of 0.2 +/- 0.06 nM and maximal binding of 5.8 +/- 0.3 fmol/mg protein (n = 3). These findings suggest that specific MCH binding sites that differ from the melanocortin receptors exist in human brain.     

Influence of age on NMDA receptor complex in rat brain studied by in vitro autoradiography

N-methyl-D-aspartate (NMDA) receptors are known to play an important role in learning and memory and to be involved in neuron cell death accompanying cerebral ischemia, seizures, and Alzheimer's disease. The NMDA receptor complex has been considered to consist of an L-glutamate recognition site, a strychnine-insensitive glycine modulatory site, and a voltage-dependent cation channel. In the present study, effects of age on an L-glutamate recognition site and a glycine site were examined in rat brain by quantitative in vitro autoradiography with [3H]-CPP and [3H]-glycine. Both [3H]-glycine and [3H]-CPP binding sites were most abundant in the hippocampus and cerebral cortex, and they showed a similar distribution pattern throughout the brain. [3H]-glycine binding sites were severely decreased in the telencephalic regions, including the hippocampus and cerebral cortex, in aged brain. Conversely, [3H]-CPP binding sites were well preserved in these brain areas. In the mid-brain regions and cerebellum, neither [3H]-glycine nor [3H]-CPP binding sites changed in the aged brain. Our results indicate that within the NMDA receptor complex, glycine receptors are primarily affected in the aging process.     

Functional brain mapping of pain perception

In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes were almost exclusively the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been confirmed with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area which amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only--and not in other brain areas--was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief is taken into account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the PAG, and, at least in some instances, with the involvement of endogenous opioids.     

Differences between D- and L-aspartate binding to the Na+-dependent binding sites on glutamate transporters in frozen sections of rat brain

The Na+-dependent, "high-affinity" transport of L-glutamate (GluT) in brain tissue has become a significant focus of interest, particularly since it has been revealed that abnormalities of GluT may be associated with serious neurological disorders. Using quantitative autoradiography on 3H-sensitive films, we have studied, in thaw-mounted sections of rat brain, the distribution and pharmacology of radioligand binding to sites with characteristics of the substrate-recognition/binding locus on GluT. The technique makes it possible to determine not only the intensity of binding in brain regions but, with a high level of precision, pharmacological constants such as IC50 or nH. [3H]L-aspartate and [3H]D-aspartate are two classical radioligands used in studies of GluT. We have determined IC50 values for the inhibition of [3H]L- and [3H]D-aspartate binding by their non-radioactive counterparts in the cerebral neocortex. hippocampus, striatum, septal nuclei and the cerebellar cortex. The two radioligands did not appreciably differ from each other in their interactions with the binding sites in the forebrain, consistent with all Na+-dependent GluT binding sites in that region having no stereoselectivity for aspartate enantiomers. In the cerebellar cortex, however, the data indicated the presence of a GluT binding site that preferred L- over D-aspartate. These findings contrast with many previous observations and suggest that the pharmacological characteristics of the ligand binding sites on GluT in the mammalian cerebellar cortex may have to be re-assessed and/or a possibility of an existence of (a) hitherto unknown molecule(s) with properties of a glutamate transporter be considered.     

臂丛神经撕脱伤后慢性疼痛患者脑区葡萄糖代谢的研究

臂丛神经撕脱伤后慢性疼痛是一种临床上顽固性神经病理性疼痛.然而,对于其潜在的中枢机制还知之甚少.为了进一步探讨臂丛神经撕脱伤后慢性疼痛的相关脑区活动,利用18F-脱氧葡萄糖(FDG)正电子断层扫描(PET)技术观察臂丛神经撕脱后慢性疼痛患者的脑葡萄糖代谢.选择左侧臂丛神经撕脱伤后慢性疼痛行脊髓后根入髓区(DREZ)切开术后疼痛减轻>75%的患者,共5例,分别在术前和术后14天行PET扫描采集数据,同时行视觉模拟评分(VAS),汉密尔顿(Hamilton)抑郁和焦虑评分.用统计参数图(SPM2)软件分析数据.与术前疼痛状态下相比,术后葡萄糖代谢明显减低的脑区有双侧尾状核,眶额回(OFC)(BA11),对侧扣带下回(BA25)和同侧前额叶背外侧区域(DLPFC)(BA46/47).葡萄糖代谢明显增高的脑区有对侧丘脑,枕核和同侧项叶(BA7).研究结果提示,涉及情绪、注意和疼痛内在调节的脑区在臂丛神经撕脱伤后慢性疼痛的调制中发挥重要作用.