Regional sensitivity and spatial summation in the warmth sense

The magnitude of warmth sensation aroused by heat irradiation and assessed by the method of magnitude estimation depends on the level of the irradiation, its areal extent, and the particular region of the body stimulated. Within a given body region, area and irradiation level both contribute to the magnitude of the warmth sensation (signifying generous spatial summation of neural signals), except that the proportional contribution of area diminishes gradually with increasing level of warmth and finally becomes negligible as the pain threshold is approached. Some regions of the body are far more responsive than others to low-level heating, but all regions respond more or less uniformly when the level of heating is high enough.     

Evidence for a specific influence of the nitrergic pathway on the peripheral pulse waveform in rabbits

The height of the dicrotic notch between the systolic and diastolic peaks of the peripheral pulse wave, expressed as a fraction of the overall amplitude of the wave, is sensitive to nitric oxide (NO) bioactivity. This phenomenon might form the basis of a simple, non-invasive method for determining endothelial function in vivo. We assessed whether the phenomenon is specific to the NO pathway or whether other vasoactive agents have similar effects. The relative height of the dicrotic notch (RHDN) was determined by photoplethysmography in the rabbit ear. It was dose-dependently decreased by acetylcholine, a stimulator of endothelial NO synthesis, and increased by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis. There was no effect on RHDN of the alpha-adrenergic blocker phentolamine or the beta-adrenergic blocker propranolol. The cyclo-oxygenase inhibitor indomethacin dose-dependently decreased RHDN but this effect was blocked by L-NAME, suggesting it was mediated by cross-talk with the NO pathway. Changes in RHDN appeared to be independent of heart rate and of the delay between the systolic peak and the notch, but were associated with changes in the slope of the dicrotic limb. Both L-NAME and phentolamine produced multiple diastolic peaks, indicative of wave reflections in the vasculature. These data support the view that changes in RHDN are specific to the NO pathway and provide additional information about the mechanisms involved.     

Evidence for a GABAergic nigrothalamic pathway in the rat

Extracellular recordings were made from neurones in the ventromedial and parafasicular nuclei of the rat thalamus, many of which had demonstrable capsular or caudate projections. These cells responded to electrical stimulation of the ipsilateral substantia nigra with a short latency (4 ms) inhibition presumed to be monosynaptic. This inhibitory response was often preceded by a brief period of increased excitability (latency approximately 3 ms) attributed to activation of corticofugal collaterals. Longer latency, presumably oligosynaptic excitations (latency approximately 8 ms) and inhibitions (approximately 18 ms) were also obtained, but were more commonly evoked in non-projection neurones. All units were inhibited by iontophoretically applied GABA, glycine or 5-HT. Short and long latency synaptic and GABA-induced inhibitions were selectively blocked by bicuculline. Strychnine only antagonised glycine, while 5-HT was not affected by either convulsant. Intranigral injection of muscimol greatly elevated the spontaneous discharge rate of thalamic neurones, particularly those with a striatal projection. These data are compatible with nigrothalamic neurones maintaining a tonically active, GABA-mediated inhibition of cells in the ventromedial and parafascicular nuclei of the thalamus. It is speculated that intranigral muscimol indirectly activates these thalamic cells and thereby initiates contraversive circling behaviour by suppressing this inhibitory system.     

Evidence for a retinohypothalamic pathway in the golden hamster

Evidence for a direct neural projection from the retina to the hypothalamus in the golden hamster (Mesocricetus auratus) is presented. In 25 blinded animals degeneration was followed in sections prepared according to the Wiitanen ('69) silver impregnation method. Degenerative axons were found in the optic tract, chiasm, and nerve, terminating in the lateral geniculate body and superior colliculus. A large collateral bundle of degenerating axons was observed curving medially and dorsally to enter the hypothalamus at the level of the mamillary body. This bundle turned diffusely rostrally and terminated on neurons in the ventromedial nucleus of the hypothalamus. It is proposed that two alternate pathways exist for the effect of photoperiodicity on the reproductive cycle in the hamster, one involving the pineal gland directly and the hypothalamus indirectly, and the other a direct retino-hypothalamic projection.     

Evidence for a GABAergic nigrothalamic pathway in the rat

Summary Unilateral stereotaxic microinjection of muscimol into the caudal region of the substantia nigra (SN) evoked tight, dose-related contralateral locomotor asymmetry and stereotypy. These behaviours were partially attenuated by various pre-treatments, including 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway, intraperitoneal (i.p.) haloperidol, and inhibition of thalamic GABA-transaminase activity by local intrathalamic injection of ethanolamine-O-sulphate. Electrolytic or kainic acid lesions of the medial thalamic nuclei (MTN) partially reduced the contraversive rotation to intranigral muscimol, and completely abolished the similar behaviour elicited by apomorphine (25 g) injected into the ipsilateral caudate nucleus. Contraversive turning to intranigral muscimol was completely inhibited by kainic acid lesions of the ipsilateral SN, but potentiated by intrathalamic injection of picrotoxin. Muscimol (40 ng-4 g) administered to the MTN complex in one hemisphere stimulated rats to move in ipsilateral circles that were unaffected by haloperidol. The results of these behavioural experiments suggest that the nigrostriatal dopamine pathway, the nigrothalamic projection and possibly other non-dopaminergic SN efferents all play important roles in mediating the influences of the SN on motor and stereotyped behaviours. Disruption of the nigrothalamic pathway following electrical or chemical injury to the SN was accompanied by falls in GABA and its synthesising enzyme in the corresponding MTN. These data, together with the findings of our electrophysiological study presented in the following paper, are consistent with the nigrothalamic system having a GABAergic inhibitory function.This work was partly supported by an M.R.C. programme grant awarded to Prof. D.W. StraughanI.C. Kilpatrick and A. Fletcher are respectively M.R.C. and S.R.C. scholars     

Evidence of a nonlinear human magnetic sense

Human subjects respond to low-intensity electric and magnetic fields. If the ability to do so were a form of sensory transduction, one would expect that fields could trigger evoked potentials, as do other sensory stimuli. We tested this hypothesis by examining electroencephalograms from 17 subjects for the presence of evoked potentials caused by the onset and by the offset of 2 G, 60 Hz (a field strength comparable to that in the general environment). Both linear (time averaging) and nonlinear (recurrence analysis) methods of data analysis were employed to permit an assessment of the dynamical nature of the stimulus/response relationship. Using the method of recurrence analysis, magnetosensory evoked potentials (MEPs) in the signals from occipital derivations were found in 16 of the subjects (P<0.05 for each subject). The potentials occurred 109-454 ms after stimulus application, depending on the subject, and were triggered by onset of the field, offset of the field, or both. Using the method of time averaging, no MEPs were detected. MEPs in the signals from the central and parietal electrodes were found in most subjects using recurrence analysis, but no MEPs were detected using time averaging. The occurrence of MEPs in response to a weak magnetic field suggested the existence of a human magnetic sense. In distinction to the evoked potentials ordinarily studied, MEPs were nonlinearly related to the stimulus as evidenced by the need to employ a nonlinear method to detect the responses.     

Evidence for a crossed nigrostriatal pathway in rats

In order to characterize further the origin of striatal afferents, adult rats underwent a unilateral intrastriatal infusion of 30% Evans Blue solution (0.2–0.5 μl). Labeled neurons were observed in ipsilateral substantia nigra, thalamus, cortex, ventromedial mesencephalic tegmentum and dorsal raphe. Several labeled neuronal somata, albeit considerably fewer than seen ipsilaterally, were found also in the contralateral substantia nigra and ventral tegmental area, a result contrary to previously reported findings in the rat. Control injections restricted to cortex overlying striatal target site did not result in similar labeling, and corpus callosum transection prior to intrastriatal injection did not prevent labeling of contralateral substantia nigra. These findings indicate that rats, like cats, have a sparse crossed nigrostriatal pathway.     

Evidence for a GABAergic inhibitory nigrotectal pathway in the rat

The aim of the present study was to test the GABAergic nature of the inhibitory projection from substantia nigra, pars reticulata (SNr) to superior colliculus (SC) in the rat, through the use of extracellular recordings and microiontophoresis. The effect of SN stimulation on the spontaneous or glutamate-evoked firing of SC units was analyzed. Among 28 SC cells inhibited by SNr stimulation, 27 decreased their firing rate following iontophoretic application of either GABA or glycine. The effect of the iontophoretic administration of bicuculline on SNr-evoked inhibition was studied on 14 of these GABA- and glycine-sensitive neurons. Bicuculline reversibly blocked nigral inhibition on 12 neurons, with iontophoretic current which did not affect glycine depression.These results are consistent with the hypothesis that GABA is the inhibitory transmitter of the nigrotectal projection.     

Topographical distribution of warmth, burning and itch sensations in healthy humans

To gain information on the topographical distribution of warmth, burning and itch sensations in healthy humans, we delivered laser stimuli to elicit sensations of warmth, applied capsaicin cream for burning, and pricked histamine for itch on the skin of the face, shoulder, hand, thigh and foot in 12 healthy subjects. We found that whereas warm and burning sensations progressively increased from foot to face, itch sensation increased from face to foot (P<0.0001). Hence our findings indicate that unlike thermal and pain receptors, itch receptors are denser at distal than at proximal body sites. Our psychophysical study provides new information supporting the idea that specific unmyelinated neuronal pathways mediate sensations of warmth, burning and itch.     

Shaping appropriate locomotive motor output through interlimb neural pathway within spinal cord in humans

Direct evidence supporting the contribution of upper limb motion on the generation of locomotive motor output in humans is still limited. Here, we aimed to examine the effect of upper limb motion on locomotor-like muscle activities in the lower limb in persons with spinal cord injury (SCI). By imposing passive locomotion-like leg movements, all cervical incomplete (n = 7) and thoracic complete SCI subjects (n = 5) exhibited locomotor-like muscle activity in their paralyzed soleus muscles. Upper limb movements in thoracic complete SCI subjects did not affect the electromyographic (EMG) pattern of the muscle activities. This is quite natural since neural connections in the spinal cord between regions controlling upper and lower limbs were completely lost in these subjects. On the other hand, in cervical incomplete SCI subjects, in whom such neural connections were at least partially preserved, the locomotor-like muscle activity was significantly affected by passively imposed upper limb movements. Specifically, the upper limb movements generally increased the soleus EMG activity during the backward swing phase, which corresponds to the stance phase in normal gait. Although some subjects showed a reduction of the EMG magnitude when arm motion was imposed, this was still consistent with locomotor-like motor output because the reduction of the EMG occurred during the forward swing phase corresponding to the swing phase. The present results indicate that the neural signal induced by the upper limb movements contributes not merely to enhance but also to shape the lower limb locomotive motor output, possibly through interlimb neural pathways. Such neural interaction between upper and lower limb motions could be an underlying neural mechanism of human bipedal locomotion.     

Evidence for adult lung growth in humans

A 33-year-old woman underwent a right-sided pneumonectomy in 1995 for treatment of a lung adenocarcinoma. As expected, there was an abrupt decrease in her vital capacity, but unexpectedly, it increased during the subsequent 15 years. Serial computed tomographic (CT) scans showed progressive enlargement of the remaining left lung and an increase in tissue density. Magnetic resonance imaging (MRI) with the use of hyperpolarized helium-3 gas showed overall acinar-airway dimensions that were consistent with an increase in the alveolar number rather than the enlargement of existing alveoli, but the alveoli in the growing lung were shallower than in normal lungs. This study provides evidence that new lung growth can occur in an adult human.     

Evidence for the involvement in the baroreceptor reflex of a descending inhibitory pathway

1. The onset and time course of baroreceptor inhibition of pre- and post-ganglionic sympathetic reflex activity has been examined in the anaesthetized cat.2. The shortest time to the onset of inhibition of an intercostal evoked reflex response in cardiac and renal nerve was less than 90 msec following a rise in pressure in a carotid sinus blind sac, and around 55 msec following stimulation of the ipsilateral sinus nerve. The cardiac nerve response was completely inhibited before the renal nerve response.3. Because of the long delays in the somato-sympathetic reflex pathway it is argued that these minimum times will be much less than the real central delay of baroreceptor inhibition. These were estimated by adding on the central times for the somato-sympathetic reflexes to give latencies of 94-143 msec for the inhibition.4. A spinal sympathetic reflex was inhibited by 30-75% following a rise in pressure in a carotid sinus blind sac or sinus nerve stimulation. The minimum time for this inhibition was around 100 msec.5. The baroreceptor inhibition of the spinal sympathetic reflex was abolished following section of a restricted region in the dorsolateral part of the lateral funiculus of the cervical spinal cord.6. Both pre- and post-ganglionic reflexes could be inhibited when stimulating within three regions of the medulla oblongata. The latency to inhibition elicited from the ventromedial reticular formation was short, some 5-30 msec, whereas that elicited from a ventrolateral region or the mid line raphe nucleus was long, some 90-160 msec.7. The possibility is discussed that the baroreceptor inhibition of both the pre- and post-ganglionic reflexes examined in this study is occurring at the spinal level via a pathway from either the raphe nuclei or ventrolateral medulla.     

Evidence for a vestigial pinna‐orienting system in humans

Although some people can voluntarily move their ears, overt reflexive control of the pinnae has been lost during the course of primate evolution. Humans and apes do not move their ears to express emotion, they do not defensively retract them when startled, and they do not point them at novel, salient, or task‐relevant stimuli. Nevertheless, it is the thesis of this review that neural circuits for pinna orienting have survived in a purely vestigial state for over 25 million years. There are three lines of evidence: (1) Shifting the eyes hard to one side is accompanied by electromyographic (EMG) activity in certain ear muscles and by a barely visible (2–3 mm) curling of the dorsal edge of the pinna. (2) The capture of attention by a novel, unexpected sound emanating from behind and to one side has been found to trigger a weak EMG response in the muscle behind the corresponding ear. (3) Reflexive EMG bursts recorded during a selective attention task suggested that subjects were unconsciously attempting to orient their ears toward the relevant sounds. In addition to pinna orienting, the possibility that pinna startle might have survived in a vestigial state is also considered. It is suggested that the postauricular reflex to sudden, intense sounds constitutes a vestigial startle response, but that the reflex arc is dominated by a pathway that bypasses the main organizing center for startle.     

Evidence for multi-site closure of the neural tube in humans

Four separate initiation sites for neural tube (NT) fusion have been demonstrated recently in mice and other experimental animals. We evaluated the question of whether the mult-site model vs. the traditional single-site model of NT closure provided the best explanation for neural tube defects (NTDs) in humans. Evidence for segmental vs. continuous NT closure was obtained by review of our recent clinical cases of NTDs and previous medical literature. With the multi-site NT closure model, we find that the majority of NTDs can be explained by failure of fusion of one of the closures or their contiguous neuropores. We hypothesize that: Anencephaly results from failure of closure 2 for meroacranium and closures 2 and 4 for holoacranium. Spina bifida cystica results from failure of rostral and/or caudal closure 1 fusion. Craniorachischisis results from failure of closures 2,4, and 1. Closure 3 non-fusion is rare, presenting as a midfacial cleft extending from the upper lip through the frontal area (“facioschisis”). Frontal and parietal cephaloceles occur at the sites of the junctions of the cranial closures 3-2 and 2–4 (the prosencephalic and mesencephalic neuropores). Occipital cephaloceles result from incomplete membrane fusion of closure 4. In humans, the most caudal NT may have a 5th closure site involving L2 to S2. Closure below S2 is by secondary neurulation. Evidence for multi-site NT closure is apparent in clinical cases of NTDs, as well as in previous epidemiological studies, empiric recurrence risk studies, and pathological studies. Genetic variations of NT closures sites occur in mice and are evident in humans, e.g., familial NTDs with Sikh heritage (closure 4 and rostral 1), Meckel-Gruber syndrome (closure 4), and Walker-Warburg syndrome (2–4 neuropore, closure 4). Environmental and teratogenic exposures frequently affect specific closure sites, e.g., folate deficiency (closures 2, 4, and caudal 1) and valproic acid (closure 5 and canalization). Classification of NTDs by closure site is recommended for all studies of NTDs in humans. We conclude that (1) multi-site NT closure provides the best explanation for NTDs in humans; (2) closure sites are most likely controlled by separate genes expressed during embryogenesis, and variations in rate and location of closures would make embryos more susceptible to environmental and other factors; (3) homologies between the mouse and human genomes may allow linkage studies to be done for families with recurrence of NTDs; and (4) recurrence risks and associated anomalies vary between closure sites, so that more accurate genetic counselling can be given based on the location of the NTD(s) in the proband(s). © 1993 Wiley-Liss, Inc.     

Long-latency spinal reflexes in humans

Stretching human muscles with a mechanical device gave rise to multiple peaks in the rectified and averaged electromyogram. In the first dorsal interosseous the latency of the first peak (M1) was 32.4 +/- 2.4 ms (SD) and the latency of the second peak (M2) was 55.1 +/- 11.3 ms, in both cases measured from the time of the stimulus to the take-off point of the peak. Often a third peak (M3) was seen, having a considerably longer latency. The origin of peak M1 was considered to be in the stretch reflex arc because of its latency and its invariable association with muscle movement. Peak M2 was due to stimulation of afferent terminals in the skin and/or subcutaneous tissues by the mechanical device producing the muscle stretch. The conduction velocity of the pathway involved in the generation of the M1 component is the same as that for M2. This implies that central processing in the spinal cord delays the M2 response. The M2 mechanism does not involve a transcortical (long-loop) pathway because in foot muscles the M1-M2 delay remains the same as is found for hand muscles, although M1 latency is prolonged (to 39.4 +/- 6.2 ms for extensor digitorum longus). This indicates that there is not time for M2 impulses to traverse a pathway any longer than that passing to and from the spinal cord.     

Evidence for a branched pathway in the polarized cell division of Saccharomyces cerevisiae

Cells of Saccharomyces cerevisiae can choose a bud site in one of two different spatial patterns (axial or bipolar) determined by their mating type. Genes important for bud-site selection have been identified and a linear model describing the hierarchy of these genes was proposed. We have uncovered a new class of genes which is required only for the bipolar pattern. The phenotype of the corresponding mutants coupled with epistasis experiments with some budding mutants already described suggest the existence of specific genes for the bipolar pathway.