Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain.

The neural mechanisms underlying the development and maintenance of chronic pain following nerve injury remain unclear. There is growing evidence that chronic neuropathic pain is associated with altered thalamic firing patterns, thalamocortical dysrhythmia and altered infra-slow oscillations in ascending pain pathways. Preclinical and post-mortem human studies have revealed that neuropathic pain is associated with prolonged astrocyte activation in the dorsal horn and we have suggested that this may result in altered gliotransmission, which results in altered resting neural rhythm in the ascending pain pathway. Evidence of astrocyte activation above the level of the dorsal horn in living humans is lacking and direct measurement of astrocyte activation in living humans is not possible, however, there is evidence that regional alterations in T2 relaxation times are indicative of astrogliosis. The aim of this study was to use T2 relaxometry to explore regional brain anatomy of the ascending pain pathway in individuals with chronic orofacial neuropathic pain. We found that in individuals with trigeminal neuropathic pain, decreases in T2 relaxation times occurred in the region of the spinal trigeminal nucleus and primary somatosensory cortex, as well as in higher order processing regions such as the dorsolateral prefrontal, cingulate and hippocampal/parahippocampal cortices. We speculate that these regional changes in T2 relaxation times reflect prolonged astrocyte activation, which results in altered brain rhythm and ultimately the constant perception of pain. Blocking prolonged astrocyte activation may be effective in preventing and even reversing the development of chronic pain following neural injury.

Bilateral activation of the trigeminothalamic tract by acute orofacial cutaneous and muscle pain in humans.

The conscious perception of somatosensory stimuli is thought to be located in the contralateral cerebral cortex. However, recent human brain imaging investigations in the spinal system report bilateral primary somatosensory cortex (SI) activations during unilateral noxious stimuli and that this ipsilateral spinal representation may be independent of transcallosal connections. In the trigeminal system, there is primate evidence for an ipsilateral somatosensory pathway through the thalamus to the face SI. However, the organization of the trigeminal nociceptive pathway in the human is not clear. The aim of this study was to determine whether noxious stimuli applied to the face are transmitted to the cerebral cortex by bilateral pathways. We used functional magnetic resonance imaging (fMRI) to compare ipsilateral and contralateral activation of the thalamus, SI and secondary somatosensory cortex (SII) during muscle and cutaneous orofacial pain and innocuous facial stimulation in healthy human subjects. We found that both muscle and cutaneous noxious stimuli, from injections of hypertonic saline into the right masseter or overlying skin, evoked bilateral increases in signal intensity in the region encompassing the ventral posterior thalamus as well as the face region of SI and SII. In contrast, innocuous unilateral brushing of the lower lip evoked a strict contralateral ventroposterior thalamic activation, but bilateral activation of SI and SII. These data indicate that, in contrast to innocuous inputs from the face, noxious information ascends bilaterally to the face SI through the ventroposterior thalamus in humans.

Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge.

Alendronate (ALN) and other bisphosphonates have been used successfully in pediatric patients with osteopenia secondary to connective tissue diseases. Loss of growth in height has not been reported, but concerns remain regarding the effect of these potent antiresorptive agents when used in children and adolescents. High-dose methotrexate (MTX) and other chemotherapy drugs have been implicated in osteoporosis and a high fracture incidence in survivors of childhood cancers and are also associated with osteopenia in adult animals. The effect of high dose MTX on bone density during rapid skeletal growth, however, has not been widely studied, nor has the potentially therapeutic effect of bisphosphonates in this setting. We examined the effects of ALN and MTX administration, alone and in combination, on bone density, morphology, mechanical strength, and longitudinal growth in normal growing rats. Sprague-Dawley rats were given ALN once weekly (0.3 mg/kg) from 5 to 11 weeks of age, with and without a course of methotrexate (MTX) given daily in weeks 1 and 3 (0.75 mg/kg/day). Twenty-four animals were randomly divided into four groups: Control (vehicle), ALN alone, ALN + MTX, and MTX alone. After 6 weeks, the femora, tibiae, and lumbar spine were studied by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, mechanical strength testing, microradiography, light microscopy, and by determination of ash weights and bone lengths. ALN treatment increased bone mineral density (BMD) by 23% to 68%. The largest increases in the femur occurred in the distal third where endochondral bone growth was greatest and included large increases in trabecular bone and total cross-sectional area. ALN + MTX produced similar effects to ALN alone. MTX only reduced BMD by 8% in the vertebrae, but not significantly at other sites. MTX also led to femoral length reductions of 2.9%. The small reductions in BMD due to MTX were overwhelmed by the increases due to ALN, whereas the length loss was unaffected. Transverse density banding corresponding to weekly ALN administrations were clearly evident radiographically throughout the growing skeleton, likely due to decreased resorption and possibly increased mineralization in the bands. ALN or ALN + MTX treatment also led to increases in mechanical strength in the femora. Although MTX administration during growth leads to some BMD reduction, ALN given with MTX eliminates this reduction and in fact bone density and strength increase above control levels.

Parallel processing in cerebral cortex of the marmoset monkey: effect of reversible SI inactivation on tactile responses in SII.

1. Responsiveness within the hand region of the second somatosensory area of cortex (SII) was investigated in the marmoset monkey (Callithrix jacchus) in association with cooling-induced, reversible inactivation of the primary somatosensory area, SI. The aims were to determine whether thalamocortical systems in this primate species are organized according to a serial scheme in which tactile information is conveyed from the thalamus to SI and thence to SII as the next hierarchical level of processing and to establish whether primates are fundamentally different, in this respect, from mammals in which tactile information is conveyed in parallel from the thalamus to both SI and SII. 2. Inactivation of the SI had area was achieved when the temperature at the face of the silver cooling block over this SI region was lowered to < or = 13 degrees C. Inactivation was confirmed by abolition of the SI surface potential evoked by a brief tap stimulus to the hand and by the abolition of responsiveness in single SI neurons located beneath and around the edge of the block. 3. The effect of SI inactivation on SII-evoked potentials was investigated in 20 experiments by simultaneous recording of the SI- and SII-evoked potentials. The SII response was never abolished and was unchanged in the majority (12/20) of experiments. In the remainder, the SII-evoked potentials underwent a reduction in amplitude that was usually < 30% but never > 50%. 4. Tactile responsiveness was examined quantitatively in 47 individual SII neurons of different functional classes before, during, and after the inactivation of SI. Controlled tactile stimuli consisted of trains of sinusoidal vibration or rectangular pulses delivered to the glabrous or hairy skin of the hand. 5. Thirteen of the 47 SII neurons (28%) were unaffected in their response levels in association with SI inactivation. The remaining 34 SII neurons underwent some reduction in responsiveness, but in only 6% (3/47) was responsiveness abolished by SI inactivation. As the same range of functional classes of tactile neurons were represented among the affected and unaffected SII neurons, there was no evidence for a differential susceptibility among SII tactile neurons to the effect of SI inactivation. 6. Where reductions in amplitude of the SII-evoked potential or in response levels of SII neurons were observed, the effects were not attributable to direct spread of cooling from SI to the SII hand area as there was no cooling-induced prolongation of either the evoked potential or spike waveform in SII, an effect that is known to precede cooling-induced reductions in responsiveness. 7. These lines of evidence indicate that reductions in SII responsiveness in association with SI inactivation may be attributable to a loss of a background facilitatory influence rather than to a blockage of a component of peripheral input that comes over a putative serial path to SII via SI. First, as SI was cooled, there was a progressive increase in latency and time course of the SI responses before their disappearance, but no comparable delay in the SII responses as might be expected if SI were placed earlier than SII in a strict hierarchical scheme of thalamocortical processing. Second, SI inactivation failed to bring about a tightening in the phase-locking of SII responses to vibrotactile stimuli as might have been expected if the inputs to the SII neurons come via both a direct path from the thalamus and an indirect intracortical path via SI. Blockage of the indirect intracortical pathway through SI might be expected to reduce temporal dispersion in the input to SII neurons and result in an improvement in phase-locking in the SII responses to skin vibration. Third, the background activity of some SII neurons was reduced during SI inactivation along with the reduction in their responses to tactile stimulation.

Corticothalamic influences on transmission of tactile information in the ventroposterolateral thalamus of the cat: effect of reversible inactivation of somatosensory cortical areas I and II.

The influence of the corticothalamic projections from somatosensory areas I and II (SI and SII) on the transmission of tactile information through the ventroposterolateral (VPL) thalamus was investigated by examining the effects of cooling-induced, reversible inactivation of SI and/or SII on the responsiveness of 32 VPL neurons to controlled tactile stimulation of the distal forelimb in anaesthetized cats. Both the response levels and spontaneous activity were unaffected in 21 (66%) of the VPL neurons as a result of inactivation of SI or SII singly, or both SI and SII simultaneously. In the remaining 11 neurons, 10 displayed a reduction in response level, an effect observed over the whole of the stimulus-response relations for the neurons studied at different stimulus amplitudes, and one neuron displayed an increase in response level in association with cortical inactivation. When responses in VPL neurons were affected by inactivation of one cortical somatosensory area, they were not necessarily affected by inactivation of the other. Of 14 neurons studied for the effects of the separate inactivation of SI alone and of SII alone, 7 were affected, one from both areas, but the remaining 6 were affected by inactivation of only one of these areas. Phaselocking, and therefore the precision of impulse patterning in the responses of VPL neurons to skin vibration, was unchanged by the cortical inactivation irrespective of whether the response level was affected. The results suggest that SI and SII may exert a facilitatory influence on at least a third of VPL neurons and in this way may modulate the gain of transmission of tactile signalling through the thalamus.