Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain

The extracellular signal-regulated kinase (ERK) cascade has been shown to be a key modulator of pain processing in the central nucleus of the amygdala (CeA) in mice. ERK is activated in the CeA during persistent inflammatory pain and this activation is both necessary and sufficient to induce peripheral tactile hypersensitivity. Interestingly, biochemical studies show that inflammation-induced ERK activation in the CeA only occurs in the right, but not the left hemisphere. This inflammation-induced ERK activation in the right CeA is independent of the side of peripheral inflammation, suggesting that there is a dominant role of the right hemisphere in the modulation of pain by ERK activation in the CeA. However, the functional significance of this biochemical lateralization has yet to be determined. In the present study, we tested the hypothesis that modulation of pain by ERK signaling in the CeA is functionally lateralized. We acutely blocked ERK activation in the CeA by infusing the MEK inhibitor U0126 into the right or the left hemisphere and then measured the behavioral effects on inflammation-induced mechanical hypersensitivity in mice. Our results show that blockade of ERK activation in the right, but not the left CeA, decreases inflammation-induced peripheral hypersensitivity independent of the side of peripheral injury. These findings demonstrate that modulation of pain by ERK signaling in the CeA is functionally lateralized to the right hemisphere, suggesting a dominant role of the right amygdala in pain processing.     

Mapping the Effects of SI Cortex Stimulation on Somatosensory Relay Neurons in the Rat Thalamus: Direct Responses and Afferent Modulation

We have used single-unit recording techniques to map the spatial distribution of the primary somatosensory (SI) cortical influences on thalamic somatosensory relay nuclei in the rat. A total of 193 microelectrode penetrations were made to record single neurons in tracks through the medial and lateral ventroposterior (VPL and VPM), ventrolateral (VL), posterior (Po), and reticular (nRt) thalamic nuclei. Single units were classified according to their (1) location within the nuclei, (2) receptive fields, and (3) response to standardized microstimulation in deep layers of the SI cortical forepaw areas. The SI stimulation produced short-latency (1- to 7-msec) excitatory responses in different percentages of neurons recorded in the following thalamic nuclei: VPL, 42.0%; Po, 25.0%; nRt, 16.4%; VL, 13.6%; and VPM, 9.9%. Within the VPL, the highest proportion of responsive neurons was found in the anterior region. Although most of the VL region was unresponsive, the caudal subregion bordering the rostral VPL showed some responsiveness (13.6% of neurons). In general, the spatial pattern of corticothalamic influences appeared to reciprocate the known thalamocortical connection patterns, but with a heterogeneity that was unpredicted.

The same parameters of SI cortical stimulation were used in studies of corticofugal modulation of afferent transmission through the VPL thalamus. A condition—test (C-T) paradigm was implemented in which the cortical stimulation (C) was delivered at a range of time intervals before test (T) mechanical vibratory stimulation was applied to digit 4 of the contralateral forepaw. The time course of cortical effects was analyzed by measuring the averaged evoked unit responses of thalamic neurons to the T stimuli, and plotting them as a function of C-T intervals from 5 to 50 msec. Of the 20 VPL neurons tested during SI stimulation, the average response to T stimulation was decreased a mean of 36%, with the suppression peaking (at 49% inhibition of the afferent response) about 15 msec after the C stimulus. Considerable rostrocaudal variation was observed, however. Whereas neurons in the rostral VPL (near VL) were strongly inhibited (-69%), neurons in the middle and caudal VPL exhibited facilitations at long and short C-T intervals, respectively. This study establishes a specific projection system from the forepaw region of SI cortex to different subregions of the VPL thalamus, producing specific temporal patterns of sensory modulation.     

Extensive dual innervation and mutual inhibition by forelimb and hindlimb inputs to ventroposterolateral nucleus projection neurons in the rat

The stimulation of brachial plexus and sciatic nerve resulted in a precisely timed, synchronous volley of inputs to ventroposterolateral (VPL) neurons from either forelimb or hindlimb. Such stimulation activated sensory fibers of all modalities and was therefore modality-nonspecific. Extracellular recordings of modality-nonspecific single-unit evoked responses from VPL showed that 13% of VPL projection neurons responded to both forelimb and hindlimb inputs. We also demonstrated mutually inhibitory interactions between inputs from forelimb and hindlimb in 45% of VPL units. Unlike the somatotopic map produced by others using modality-specific inputs, the modality-nonspecific evoked response map of VPL had a broadly overlapping distribution of evoked responses. This was especially true for the more caudal aspects of VPL. When the delivery of stimuli was appropriately timed, forelimb inputs caused the inhibition of responses to forelimb stimulation; similarly, hindlimb inputs inhibited responses to forelimb stimulation. The inhibition had a variable duration that may reflect a combination of processes, including recurrent inhibitory collateral input from the thalamic reticular nucleus (TRN) or an intrinsic hyperpolarizing inhibitory afterpotential of the VPL neuron. The presence of an extensive converging input on VPL neurons and an inhibitory correlate to this overlapping of inputs may explain the shifting of VPL maps following lesions of peripheral nerve, spinal cord, or dorsal column nuclei (DCN).     

Mapping the effects of SI cortex stimulation on somatosensory relay neurons in the rat thalamus: direct responses and afferent modulation

We have used single-unit recording techniques to map the spatial distribution of the primary somatosensory (SI) cortical influences on thalamic somatosensory relay nuclei in the rat. A total of 193 microelectrode penetrations were made to record single neurons in tracks through the medial and lateral ventroposterior (VPL and VPM), ventrolateral (VL), posterior (Po), and reticular (nRt) thalamic nuclei. Single units were classified according to their (1) location within the nuclei, (2) receptive fields, and (3) response to standardized microstimulation in deep layers of the SI cortical forepaw areas. The SI stimulation produced short-latency (1- to 7-msec) excitatory responses in different percentages of neurons recorded in the following thalamic nuclei: VPL, 42.0%; Po, 25.0%; nRt, 16.4%; VL, 13.6%; and VPM, 9.9%. Within the VPL, the highest proportion of responsive neurons was found in the anterior region. Although most of the VL region was unresponsive, the caudal subregion bordering the rostral VPL showed some responsiveness (13.6% of neurons). In general, the spatial pattern of corticothalamic influences appeared to reciprocate the known thalamocortical connection patterns, but with a heterogeneity that was unpredicted. The same parameters of SI cortical stimulation were used in studies of corticofugal modulation of afferent transmission through the VPL thalamus. A condition-test (C-T) paradigm was implemented in which the cortical stimulation (C) was delivered at a range of time intervals before test (T) mechanical vibratory stimulation was applied to digit 4 of the contralateral forepaw. The time course of cortical effects was analyzed by measuring the averaged evoked unit responses of thalamic neurons to the T stimuli, and plotting them as a function of C-T intervals from 5 to 50 msec. Of the 20 VPL neurons tested during SI stimulation, the average response to T stimulation was decreased a mean of 36%, with the suppression peaking (at 49% inhibition of the afferent response) about 15 msec after the C stimulus. Considerable rostrocaudal variation was observed, however. Whereas neurons in the rostral VPL (near VL) were strongly inhibited (-69%), neurons in the middle and caudal VPL exhibited facilitations at long and short C-T intervals, respectively. This study establishes a specific projection system from the forepaw region of SI cortex to different subregions of the VPL thalamus, producing specific temporal patterns of sensory modulation.     

Activation of thalamic ventroposteriolateral neurons by phrenic nerve afferents in cats and rats.

It has been demonstrated that phrenic nerve afferents project to somatosensory cortex, yet the sensory pathways are still poorly understood. This study investigated the neural responses in the thalamic ventroposteriolateral (VPL) nucleus after phrenic afferent stimulation in cats and rats. Activation of VPL neurons was observed after electrical stimulation of the contralateral phrenic nerve. Direct mechanical stimulation of the diaphragm also elicited increased activity in the same VPL neurons that were activated by electrical stimulation of the phrenic nerve. Some VPL neurons responded to both phrenic afferent stimulation and shoulder probing. In rats, VPL neurons activated by inspiratory occlusion also responded to stimulation on phrenic afferents. These results demonstrate that phrenic afferents can reach the VPL thalamus under physiological conditions and support the hypothesis that the thalamic VPL nucleus functions as a relay for the conduction of proprioceptive information from the diaphragm to the contralateral somatosensory cortex.     

Model approach to neurological variants of visuo-spatial neglect

Neglect is a neurological disorder of spatial attention with reduced awareness of visual stimuli in the hemifield contralateral to an acute temporo-parietal lesion mainly of the right hemisphere. There is a close association of multisensory orientation centers (MSO) and vestibular tonus imbalance. A lesion of the dominant right MSO causes a left-sided neglect due to a lack of ipsilateral activation of the visual cortex, which is further enhanced by increasing inhibition from the contralateral visual cortex. The nondominant MSO in the left hemisphere might be involved in the manifestation of the less frequent and more transient right-sided neglect and in the plastic mechanisms of gradual recovery from left-sided neglect or extinction. There is evidence that a vestibular tonus inbalance due to peripheral or central vestibular pathway lesions may also induce a neglect. In a first model approach using an attractor network and assuming that there is only one MSO in the right hemisphere, it is possible to simulate attentional shifts into a visual hemifield and to induce a neglect. The neural network model consists of four layers of neurons: retina, MSO, visual cortex V1, and superior colliculus. The superior colliculus layer is modeled as a recurrent attractor network with one inhibitory interneuron and synaptic weights chosen to implement a winner-take-all network that centers the hill of activity on the strongest input. We are well aware of the simplifications used in the conceptual drawings and the computational model, but nevertheless hope that they will serve as an inspiration for further modeling and clinical studies.     

Reflection of evolutionary trends in the recovery pattern of the electrical activity in the human brain after unilateral electroshock]

After unilateral electroshocks the following stages of the recovery of EEG may be defferentiated in man: residual seizure activity, flat EEG, low-amplitude polyform arrhythmia, monoform delta-rhythm, synchronized teta- and alpha-rhythms. It is assumed that changes of these stages reflect the migration of EEG pacemakers within the system of hierarchically interrelated brain structures, which provide for various forms of regulation of the electrical activity of the cortex. It was shown that in each of the hemispheres, pacemakers operate relatively independently and that electrical stimulation of the dominant (left) hemisphere affects brain activity to a greater extent than stimulation of nondominant (right) hemisphere. The ascending influences of desynchronizing systems of the brain stem are less lateral as compared to the ascending pathways of hypothalamic and thalamic structures.     

Higher density of mental capacities in the left cerebral hemisphere of man: a quantitative investigation in children with localized cerebral lesions

51 children with localized cerebral lesions were investigated with the British Ability Scales, Wechsler test, Porteus Mazes, Conners Teacher Rating Scale, and computerized tomography. The extent of the lesions was quantitatively determined. The IQ was 10 points lower in the left hemispheric lesions, although the right hemispheric lesions were larger. When corrected for size of lesions, the IQ is 17 points higher (p less than 0.05) in children with right than with left hemispheric early lesions. The children with left hemispheric lesions had also significantly more behavioural problems (Conners Scale). Children with bilateral lesions had 15 points lower IQ than those with unilateral lesions, although from the slightly larger extent one could expect only 3 points difference. There was no influence of hemiparesis or of epilepsy of the IQ independent of the extent of lesion. There was more plasticity of the hemisphere than of the lobes as shown by Wisconsin Card Sorting data. The higher density of mental capacities in the left cerebral hemisphere of man is explained by more efficient programs, and more dense packing of functions due to more training of the left cerebral hemisphere.     

Ultradian rhythms in processing speed of laterally exposed words and pictures

The study was designed to find out the cerebral hemispheres oscillations in stimuli processing during the 24-hour period of wakefulness in isolated subjects remaining in a monotonous environment. Stimuli processing speed from the 24-hour constant routine periods (06.00-06.00 h) of a larger experiment were analysed for the purpose of this paper. Parallel sets of words and pictures were exposed laterally using a purpose-designed computer program. The subjects reacted to pictures or words by pressing appropriate buttons. The significant dominant ultradian rhythms (around 4 h) in the processing speed of words addressed to the right hemisphere were found and of pictures addressed to the left hemisphere. Longer significant dominant periodicities (around 12 h) appeared in the processing speed of words addressed to the left hemisphere and of pictures (around 8 h) addressed to the right hemisphere. Ultradian rhythmicity of the central nervous system functioning is suggested.     

Participation of the neocortical and reticulo-hypothalamic apparatuses in the regulation of recurrent inhibition in the thalamic relay nucleus]

In acute experiments on cats a study was made into the development of the field potential of the recurrent inhibition wave (P-wave) in VPL in response to the stimulation of the somatosensory cortex. It has been found that high-frequency stimulation of the posterior medial hypothalamus results in the reduction of the thalamic P-wave brought about antidromically and in a decrease of the number of waves in the series. The effect of stimulation of the posterior hypothalamus on the processes of recurrent inhibition in the relay thalamus is to a great extent mediated through mechanisms of the branstem reticular formation. It has been shown that the dynamics of amplitude characteristics of primary sensory responses in the VPL depends on the phases of development of P-wave in the nucleus. Functional switching off of the cortex by means of loci toxic action reduces the amplitude of P-wave produced by stimulation of a point of the poisoned cortex. Spatial non-coincidence between the topography of foci of maximal activity of primary thalamo-cortical responses and the foci of maximal influences of the stimulated cortex on recurrent inhibition in VPL points to the likely involvement of the neocortical apparatus proper in recurrent thalamic inhibition.     

Effect of the unilateral activation of brain hemispheres on visceral pain sensitivity in BALB/c mice

A hemispheric asymmetry of the visceral pain sensitivity control was revealed in the BALB/c mice: animals with the left hemisphere inactivation did not differ from sham-operated control mice in respect to the pain response parameters. A right hemisphere inactivation reduced or suppressed the pain response. This suggests that the right hemisphere domineers in the visceral pain control.     

The Intrinsic Organization of the Ventroposterolateral Nucleus and Related Reticular Thalamic Nucleus of the Rat: A Double-Labeling Ultrastructural Investigation with γ-Aminobutyric Acid Immunogold Staining and Lectin-Conjugated Horseradish Peroxidase

An electron-microscopic investigation of the synaptic organization of the rat's ventroposterolateral nucleus (VPL) and of a reticular thalamic nucleus (RTN) area related to somatosensory thalamic nucleus was performed. In a group of 11 rats, wheatgerm agglutinin conjugated to horseradish peroxidase (WGA:HRP) was injected either in the first somatosensory area of cortex (SI) or in the dorsal column nuclei (DCN). The retrogradely and/or anterogradely transported enzyme was visualized using paraphenylenediamine-pyrocatechol (PPD-PC) as substrate. In a second series of six experiments, an immunocytochemical procedure using a specific anti-γ-aminobutyric acid (anti-GABA) was employed. Postembedding localization of GABA was performed for ultrastructural observation by means of the colloidal gold immunostaining procedure. Thin sections of recognized VPL and RTN areas from WGA:HRP-injected animals were further processed for immunocytochemistry in order to localize simultaneously, at the electron-microscopic level, the transported enzyme and GABA.

The results obtained with this procedure demonstrated that HRP-labeled terminals from DCN contacted the soma and proximal dendrites of VPL neurons, while the terminals labeled after SI cortical injections were predominantly localized to the distal portion of the dendrites. The same cortical injection also determined the presence of labeled synaptic boutons contacting the soma, and both proximal and distal dendrites of RTN neurons. GABA-immunolabeled terminals were observed in VPL in a number larger than those observed with other methods, since not only typical F terminals were labeled but also terminals containing round and/or pleomorphic vesicles. GABA-ergic terminals contacted the soma and the proximal and distal dendrites of VPL neurons, while in RTN cells they made synaptic contact mainly with the soma and proximal dendrites. In the double-labeling experiments, terminals containing both HRP and specific immunogold GABA staining were never observed.

The present data provide a direct demonstration of the presence of a strong inhibitory input from RTN upon VPL neurons and of the existence of autoinhibition within RTN neurons.     

Interhemispheric asymmetry of the hippocampal damage after bilateral ligation of common carotid arteries

Permanent bilateral occlusion of common carotid arteries in rats with different behaviour types led to non-uniform structural alterations in the hippocampus. In the majority of animals, morphological changes were diffuse (i.e. having no clear localisation in a definite region of the brain structure) and symmetrical (i.e. having no evident prevalence in one of the brain hemispheres). In 6.6% of survived animals, apart from diffuse structural changes, local and asymmetrical sites of lesions occurred in the hippocampus and mostly in the dorso-lateral thalamic nuclei of the right brain hemisphere. These local zones of strongly pronounced pathology corresponded to ischemic insults which were described earlier by other authors under transient cerebral ischemia. It is supposed that the occurrence of unilateral ischemic insults in a definite region of hippocampus and thalamus after bilateral occlusion of common carotid arteries is due to individual features of the anatomy of the vascular brain system which are found more frequently in rats with passive type of behaviour and in rats of the middle group than in rats with active type of behaviour.     

Intercentral relations of the electrical processes of the rabbit brain with a polarization dominant

The dynamics of changes in intercentral relations of electrical activity of the sensorimotor and premotor zones of both hemispheres and the ventroposterolateral (VPL) nucleus of the left and right thalamus at formation of motor dominant under the action of the DC anode in the rabbit sensorimotor cortex was studied by the method of spectral-correlation analysis. It is shown that in the much less than dominant much greater than motor analyzer (the sensorimotor cortex and VPL) highly coherent connections of electrical processes are formed in the delta-range with conjugated lowering of biopotential connections between the structures of the motor analyzer of the much less than nondominant much greater than part of the brain. At the same time differently directed connections of electrical processes are formed between the structures of the motor analyzer, and between the premotor cortex and focus area. Thus, during formation of the much less than polarization much greater than dominant, a new structure of the intercentral relations of electrical processes is established not only in the much less than dominant much greater than but also in the other half of the brain.     

Functional assymmetry of the cerebral cortex in cats during formation of a conditioned reflex

During elaboration of a symmetric active defensive reflex, the animal is given the opportunity to make instrumental movements with the right or left paw. On the first day of elaboration, the cats can be subdivided into three approximately equal groups: with the right preferred paw, with the left preferred paw and ambidexters. After stabilization of the reflex, motor asymmetry increases in both preferred groups, while the number of ambidexters diminishes. Unilateral electric shock producing seizures, which is applied to the "dominant" or "subdominant" hemisphere, exerts correspondingly differing influences on the subsequent reproduction of the reflex. Suppression of reproduction is more pronounced when the shock is applied to the "dominant" hemisphere. The result of repetitive application of electroshock to one and the same hemisphere is that the functions of the "dominant" hemisphere are effected by the hemisphere which was not subjected to direct electrical stimulation.     

Age-related dynamics of thalamic-cortical evoked potentials in the rabbit in the early period of life

Data have been obtained on development of evoked potentials in the sensorimotor cortex to electrical stimulation of the thalamic ventroposterolateral nucleus (VPL) in rabbits in early ontogeny. In 3-5 days rabbits, under four times increase of threshold electric stimulation of VPL the thalamocortical response (TCR) is presented by a positive-negative potential with a long latency and minimum amplitude parameters. Second and third TCR positive components to increasing of threshold value of electric stimulation 4 times, are differentiated from 7-8 days age. Age dynamics of TCR amplitude-temporal parameters is characterized by a shortening of latency and an increase of oscillations amplitude, most expressed at 2-3 weeks of postnatal life. TCR of one month rabbit to increased threshold electrical stimulation of VPL is presented by short-latency positive-negative oscillation with a positive phase consisting of three components with successively increasing amplitudes.     

Assessment of recognition of emotions by healthy persons and patients with focal brain pathology

To assess the involvement of different structures of the human brain into successive stages of the recognition of the principal emotions by facial expression, we examined 48 patients with local brain lesions and 18 healthy adult subjects. It was shown that at the first (intuitive) stage of the recognition, premotor areas of the right hemisphere and temporal areas of the left hemisphere are of considerable importance in the recognition of both positive and negative emotions. In this process, the left temporal areas are substantially involved into the recognition of anger, and the right premotor areas predominantly participate in the recognition of fear. In patients with lesions of the right and left brain hemispheres, at the second (conscious) stage of recognition, the critical attitude to the assessment of emotions drops depending on the sign of the detected emotion. We have confirmed the hypothesis about a correlation between the personality features of the recognition of facial expressions and the dominant emotional state of a given subject.     

The structural-functional characteristics of the rostral sections of the neocortex in Chiroptera]

Studies have been made on the connections of rostral neocortex in bats in order to reveal connections with the structures of the auditory sensory system the existence of which is indicated by evident specific responses to ultrasound in the form of synchronization reaction. It was shown that dorsolateral parts of the rostral neocortex receive topically organized projections from the thalamic nuclei VPL and VL. Connections with the auditory cortex and suprageniculate nucleus are not evident. Afferents of the medial wall of the rostral cortex originate from the thalamic nuclei MD and AM. Possible pathways of auditory afferentation to the dorso-lateral part of rostral neocortex are discussed.     

丘脑网状核及其GABAB受体在癫痫小发作形成中的作用

目的和方法：实验选用ＳＤ大鼠戊四氮（ＰＴＺ）模型,结合电刺激或电解毁损丘脑网状核、丘脑接替核（丘脑腹后外侧核）、丘脑前核（丘脑前内侧核）,并用蝇蕈醇、氯苯氨丁酸、３疏基丙酸等药物在丘脑网状核内微量注射或腹腔注射后观察棘慢波的变化。结果：电刺激丘脑网状核可增强癫痫小发作,毁损丘脑网状核可抑制癫痫小发作,ＧＡＢＡＢ受体的激活不利于小发作的消除     

Changes in somatosensory evoked potentials following an experimental focal ischaemic lesion in thalamus

Experiments have been performed to produce localized thalamic ischaemia in baboons anaesthetised with alpha-chloralose. Somatosensory evoked potentials to median nerve stimulation were recorded in the medial lemniscus. VPL of thalamus and the primary somatosensory cortex. Local blood flow was also recorded by the hydrogen clearance technique in these regions. The early potential recorded in thalamus has been shown to be generated from 3 sources: (i) a positivity generated outside the VPL, (ii) local wavelets, most likely from synaptic activity close to the recording electrode, and (iii) a local overall negativity. The first of these potentials alone remains after thalamic ischaemia. It arises below the level of the thalamus, being very likely generated by the afferent volley in the medial lemniscus, and is seen in the surface-recorded response as the early component P8 (corresponding to P15 in the human).