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Excitation of the corticospinal tract by electromagnetic and electrical stimulation of the scalp in the macaque monkey.

1. The responses evoked by non-invasive electromagnetic and surface anodal electrical stimulation of the scalp (scalp stimulation) have been studied in the monkey. Conventional recording and stimulating electrodes, placed in the corticospinal pathway in the hand area of the left motor cortex, left medullary pyramid and the right spinal dorsolateral funiculus (DLF), allowed comparison of the actions of non-invasive stimuli and conventional electrical stimulation. 2. Responses to electromagnetic stimulation (with the coil tangential to the skull) were studied in four anaesthetized monkeys. In each case short-latency descending volleys were recorded in the contralateral DLF at threshold. In two animals later responses were also seen at higher stimulus intensities. Both early and late responses were of corticospinal origin since they could be completely collided by appropriately timed stimulation of the pyramidal tract. The latency of the early response in the DLF indicated that it resulted from direct activation of corticospinal neurones: its latency was the same as the latency of the antidromic action potentials evoked in the motor cortex from the recording site in the DLF. 3. Scalp stimulation, which was also investigated in three of the monkeys, evoked short-latency volleys at threshold and at higher stimulus intensities these were followed by later waves. The short-latency volleys could be collided from the pyramid and, at threshold, had latencies compatible with direct activation of corticospinal neurones. The longer latency volleys were also identified as corticospinal in origin. 4. The latency of the early volley evoked by electromagnetic stimulation remained constant with increasing stimulus intensities. In contrast, with scalp stimulation above threshold the latency of the early volleys decreased considerably, indicating remote activation of the corticospinal pathway below the level of the motor cortex. In two monkeys both collision and latency data suggest activation of the corticospinal pathway as far caudal as the medulla. 5. The majority of fast corticospinal fibres could be excited by scalp stimulation with intensities of 20% of maximum stimulator output. Electromagnetic stimulation at maximum stimulator output elicited a volley of between 70 and 90% of the size of the maximal volley evoked from the pyramidal electrodes. 6. Electromagnetic stimulation was also investigated in one awake monkey during the performance of a precision grip task. Short-latency EMG responses were evoked in hand and forearm muscles. The onsets of these responses were approximately 0.8 ms longer than the responses evoked by electrical stimulation of the pyramid.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

Thalamic functional tuning of the cortex in dichotic listening tasks.

In dichotic listening tasks, the (dominant) right ear's superiority in processing verbal stimuli has been attributed to its direct access to the linguistically dominant left hemisphere. The roles played by the extralinguistic factors, such as induced attentiveness and functional tuning of the auditory system, have not been carefully examined. The evidence for the facilitating effects of subcortical stimulation on processing dichotic stimuli is presented.

Dichotic Listening Tests↗

Repetitive transcranial magnetic stimulations of the rat. Effect of acute and chronic stimulations on pentylenetetrazole-induced clonic seizures.

Repetitive transcranial magnetic stimulation (RTMS) has been reported to induce epileptic seizures in normal control and in epileptic patients. Therefore we characterized the effect of acute or chronic stimulations with RTMS on the induction of pentylenetetrazole (PTZ)-induced clonic seizures in the rat. Male Wistar rats were stimulated with a 13-cm coil with a stimulus frequency of 50 Hz. The motor threshold (Tm) was determined by a single transcranial stimulus. Acute stimulation was performed with a stimulus intensity of 0.9 x Tm and 1.5 x Tm using a duration of the train of stimuli of five seconds. Chronic stimulation was performed with a duration of the train of stimuli of one and five seconds using a stimulus intensity of 1.8 x Tm, every day for 30 days. Time to onset of PTZ-induced clonic seizure was determined after the acute stimulation or the last stimulation in chronic RTMS. In the groups of rats receiving acute RTMS (0.9 and 1.5 x Tm) no seizures developed. No differences were observed in time to onset of clonic seizures after PTZ injection compared to control rats. In the group of rats receiving chronic RTMS some rats showed facial contractions, chewing or head movements during or immediately after the stimulations. None of the rats developed tonic or clonic seizures in relation to RTMS. Time to onset of PTZ clonic seizures was reduced in both groups receiving RTMS with a stimulus duration of one (P < 0.01) and five (P < 0.05) seconds compared to control rats. The results from this study suggest that acute suprathreshold stimulation with a stimulus frequency of 50 Hz does not affect the induction of clonic PTZ seizures, whereas chronic (daily) stimulations have a facilitatory effect. This indicates that chronic stimulation with RTMS may induce a kindling process in the rat. Chronic RTMS stimulation may therefore represent an interesting alternative non-invasively kindling model to chemical and electrical stimulations.

Animals↗

Vestibular, auditory, and somatic input to the posterior thalamus of the cat.

The responses of 157 neural units in the magnocellular (mc) and parvocellular (pc) components of the medial geniculate nucleus (MG) and other nuclei of the posterior (PO) thalamic group were recorded and analyzed. Units were tested for a response to electrical stimulation of the vestibular nerve, natural auditory and electrical cochlear nerve stimulation, and natural stimulation of joint, muscle, and cutaneous receptors of the limbs, trunk, and neck (somatic stimulation). Only 45% of the units responded to these stimuli. Twenty-four percent of the responsive units were multimodal, responding to more than one stimulus. All multimodal units were activated by auditory stimuli. More units responding to vestibular stimulation were found in mcMG than in pcMG or other components of the PO group. Potentials evoked by vestibular nerve stimulation were recorded in all 3 regions with latencies of 5--25 msec. No evidence was found for a thalamic relay from vestibular nerve to cortex in the area investigated, since the recorded latency for activity from vestibular nerve stimulation was longer than the latency of responses recorded in the cortex. This region of the thalamus appears to be important for reception of auditory information and integration with vestibular and somatic modalities.

Acoustic Stimulation↗

Energy metabolism in rat hippocampus during and following seizure activity.

The hippocampus exhibits a post-ictal phenomenon in which it is unresponsive to further stimulation. It has been suggested that this loss of excitability is the basis of post-seizure amnesia. The biochemical events associated with this phenomenon are unclear. In the present study, energy metabolites were measured in the stratum oriens, stratum pyramidale and stratum radiatum in rat hippocampus, and correlated with field potential recordings. Wistar rats were anesthetized and the calvarium removed. Following removal of the cortex by aspiration, the hippocampus was covered with oil, and stimulating and recording electrodes were placed. Stimulation consisted of a train of stimuli at 100 Hz (10-20 m Amps). This stimulation was found to be effective in evoking self-sustaining after-discharges and post-ictal depression. Tissues for metabolite analysis were taken from a series of controls, from animals during active self-sustaining seizures, and from animals which were totally unresponsive to further electrical stimulation. Hippocampal tissue for metabolite analysis was obtained by pouring liquid N2 on the exposed tissue, then removing the frozen tissue. Glucose, ATP, and phosphocreatine were measured in hippocampal layers of CA1 using fluorescence techniques and enzymatic cycling. Results showed that during seizure activity, glucose, ATP, and phosphocreatine were all decreased from 40-80% in the three layers of the hippocampus, whereas from 60 seconds after the onset of hippocampal shutdown, energy metabolites had returned toward normal. Thus, at a time when the hippocampus was unresponsive, energy metabolites were at control levels. These data suggest that the shutdown phenomenon occurs in the presence of adequate energy stores.

Animals↗

Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development?

Pain is one of the classical signs of the inflammatory process in which sensitization of the nociceptors is the common denominator. This sensitization causes hyperalgesia or allodynia in humans, phenomena that involve pain perception (emotional component+nociceptive sensation). As this review focuses mainly on animal models, which don't allow discrimination of the emotional component, the terms nociception and hypernociception are used to describe overt behavior induced by mechanical stimulation and increase of nociceptor sensitivity, respectively. Pro- and anti-inflammatory cytokines and chemokines are endogenous small protein mediators released by local or migrating cells whose balance modulates the intensity of inflammatory response. The inflammatory stimuli or tissue injuries stimulate the release of characteristic cytokine cascades, which ultimately trigger the release of final mediators responsible for inflammatory pain. These final mediators, such as prostanoids or sympathetic amines, act directly on the nociceptors to cause hypernociception, which results from the lowering of threshold due to modulation of specific voltage-dependent sodium channels. Furthermore, a direct effect of cytokines on nociceptors is also described. On the other hand, there are also anti-inflammatory cytokines, such as interleukin (IL)-10, IL-4 and IL-13, and IL-1 receptor antagonists (IL-1ra), which inhibit the production of hypernociceptive cytokines and/or the final hypernociceptive mediators, preventing the installation of or the increase in the hypernociception. This review highlights the importance of the direct and indirect actions of cytokines and chemokines in inflammatory and neuropathic hypernociception, emphasizing the evidence suggesting these molecules are potential targets to develop novel drugs and therapies for the treatment of pain.

Analgesics↗

Force assessment of the stimulated arm flexors: quantification of contractile properties.

The primary objective was to develop equipment and evaluate protocols for non-invasive assessment of contractile properties of human arm flexors. The research design consisted of a non-randomized control trial, with repeated measures. Data from six males and two females were gathered in a clinical research laboratory. The elbow flexor torque following motor point or direct nerve stimulation was measured in response to single pulses or short trains of electrical pulses. Length--tension relationships were determined; comparative data were obtained at the identified optimal muscle lengths. Twitch waveforms and peak torques following either type of stimulation were reproducible (within 10%). Peak torques following a 4-pulse small interpulse interval stimulation were nearly identical for motor-point activation and direct nerve stimulation (15.2+/- 6.6Nm for motor point stimulation; 14.5 +/- 6.6Nm for nerve stimulation). Average perceived pain indexes associated with 4-pulse stimuli were slightly higher following nerve stimulation (782 for nerve versus 6.23 for motor-point, n=8). A reliable methodology (motor-point stimulation) has been identified to perform stimulated force assessment of human arm flexors.

Adult↗

[Disturbance in the function of the spinal centers in diffuse toxic goiter in children (electromyographic study)].

Peculiarities of the reflex and motor responses of the soleus muscle were studied in stimulation of the tibial nerve by stimuli of gradually increasing intensity, and also in double stimulation and against the background of contraction of the antagonistic muscles in children with diffuse goiter and in healthy individuals. In sick children an increase and a fall in the H-response amplitude with increase of the stimulation intensity occurred more rapidly than in healthy ones. A rapid restoration of the reflex response at the interval of 500 msec and greater was noted in studying the cycle of restoration of excitation of the motor cells of the anterior horn in sick children. Against the background of contraction of the antagonistic muscles the reciprocal inhibition of the reflex response of the muscle was weaker than in the healthy individuals. The data obtained led to a supposition that one of the causes of motor disturbances in case of an excess of the thyroid hormones in the organism could be a disturbance of the processes of the pre- and postsynaptic inhibition at the spinal level.

Adolescent↗

Chronotropic response to cardiac sympathetic nerve stimulation in spontaneously hypertensive rats.

In Sprague-Dawley rats, we attempted to develop an experimental model to stimulate the cardiac sympathetic nerve. After transverse thoracotomy under anesthesia, a miniature, bipolar electrode was placed on the right ansa subclavia and it was stimulated electrically. The nerve stimulation at 2, 4, and 8.3 Hz (2 ms in duration, 5 V) increased heart rate by 21.2 +/- 4.19, 34.2 +/- 5.33, and 47.8 +/- 9.25 beats min-1, respectively (p < 0.05). Tetrodotoxin abolished the chronotropic response evoked by nerve stimulation at 4 Hz (p < 0.05). The beta-adrenergic receptor antagonist propranolol abolished the chronotropic response (p < 0.005). These results indicate that the cardiac sympathetic nerve secretes norepinephrine as a neurotransmitter and that the electrical stimuli did not directly stimulate the cardiac tissues. Thus, our preparation is appropriate for stimulation of the cardiac sympathetic nerve. We then determined the extent of the positive chronotropic responses evoked by electrical stimulations of the cardiac sympathetic nerve in spontaneously hypertensive rats (SHR) and compared the results with those in Wistar-Kyoto rats (WKY). At 5-7 weeks of age, the extent of positive chronotropic responses at 2, 4, and 8.3 Hz in SHR was 16.1 +/- 3.5, 25.2 +/- 3.8, 32.2 +/- 4.3 beats.min-1, respectively, and the extent was not different from results in WKY at the same age. At 15-17 weeks of age, the positive chronotropic responses at 2, 4, and 8.3 Hz in SHR were 6.6 +/- 1.6, 15.7 +/- 2.8, and 22.3 +/- 4.0 beats.min-1, respectively, and were significantly less than those in WKY at the same age (p < 0.05). Also, responses in SHR at 15-17 weeks were significantly less than in SHR at 5-7 weeks (p < 0.05). The same degree of positive chronotropic response evoked by peripheral cardiac sympathetic nerve stimulation in both SHR and WKY at 5-7 weeks during the developmental phase of hypertension suggests that the overactivity of the sympathetic nerve known to occur during this phase in SHR may not be produced by the postganglionic nerve fiber per se, but rather by increased activity in the central nervous system. The reduced positive chronotropic response as hypertension is established may indicate that it is developed in the course of a high blood pressure state, but it is not the inherent nature of hypertension.

Animals↗

Temporo-spatial analysis of cortical activation by phasic innocuous and noxious cold stimuli--a magnetoencephalographic study.

Clinical findings and recent non-invasive functional imaging studies pinpoint the insular cortex as the crucial brain area involved in cold sensation. By contrast, the role of primary (SI) and secondary (SII) somatosensory cortices in central processing of cold is controversial. So far, temporal activation patterns of cortical areas involved in cold processing have not been examined. Using magnetoencephalography, we studied, in seven healthy subjects, the temporo-spatial dynamics of brain processes evoked by innocuous and noxious cold stimulation as compared to tactile stimuli. For this purpose, a newly designed and magnetically silent cold-stimulator was employed. In separate runs, cold and painful cold stimuli were delivered to the dorsum of the right hand. Tactile afferents were stimulated by pneumatic tactile stimulation.Following innocuous cold stimulation (DeltaT=5+/-0.3 degrees C in 50+/-2ms), magnetic source imaging revealed an exclusive activation of the contra- and ipsilateral posterior insular cortex. The mean peak latencies were 194.3+/-38.1 and 241.0+/-31.7ms for the response in the ipsi- and contralateral insular cortex, respectively. Based on the measurement of onset latencies, the estimated conduction velocity of peripheral nerve fibres mediating cold fell in the range of Adelta-fibres (7.4+/-0.8 m/s). Noxious cold stimulation (DeltaT=35+/-5 degrees C in 70+/-12ms) initially activated the contra- and ipsilateral insular cortices in the same latency ranges as innocuous cold stimuli. Additionally, we found an activation of the contra- and ipsilateral SII areas (peak latencies 304+/-22.7 and 310.1+/-19.4ms, respectively) and a variable activation of the cingulate cortex. Notably, neither cold- nor painful cold stimulation produced an activation of SI. By contrast, the evoked cortical responses following tactile stimulation could be located to the contralateral SI cortex and bilateral SII. In conclusion, this study strongly corroborates the posterior insular cortex as the primary somatosensory area for cortical processing of cold sensation. Furthermore, it supports the role of SII and the cingulate cortex in mediating freeze-pain. Therefore, these results suggest different processing of cold, freeze-pain and touch in the human brain.

Adult↗

[Variations of neuronal responses in cat cerebral cortex to somatic stimulation in the presence of additional stimulants].

Neuronal responses (areas 3, 4, 5) were registered in awake cats after electric stimulation of the contralateralis limb. External stimuli, food and defensive motivation inhibit short-latency neuronal reactions which were registered in control. When in the experiment there was electric stimulation of another limb instead of an external stimuli the neuronal reaction did not change. If subthreshold electric stimulation (SES) was given with a perceptible stimulation of such modality the spike neuronal responses appeared in either cases. This SES may be used as a conditional signal during defensive conditioning. It is established that the neuronal pattern under somatic stimulation is not constant. Its character is connected with fluctuation of cat's exteroceptive attention under external stimuli and internal motivational condition.

Animals↗

Predicting the dynamics of antiviral cytotoxic T-cell memory in response to different stimuli: cell population structure and protective function.

This paper examines the numerical and functional consequences of various stimuli on antiviral CD8+ T-cell memory using a mathematical model. The model is based upon biological evidence from the murine model of infection with lymphocytic choriomeningitis virus (LCMV) that the phenotype of immunological memory represents low-level responses driven by various stimuli, and the memory CTL population is partitioned between resting, cycling and effector cells. These subpopulations differ in their lifespan, their potential to mediate antiviral protection and in the stimuli needed for their maintenance. Three types of maintenance stimuli are examined: non-antigen-specific (bystander) stimulation, persisting antigen stimulation and reinfection-mediated stimulation. The modelling predicts that: (i) stable persistence of CTL memory requires the presence of either bystander or antigen-specific stimulation above a certain threshold depending on the sensitivity of memory CTL to stimulation and their life-span; (ii) a relatively low level of stimuli (approximately 10(4) fold less on a per CTL basis compared to acute infection) is needed to stabilize the expanded memory CTL population; (iii) the presence of CTL subsets in the memory pool of different activation states and lifespans ensures the robustness of memory persistence in the face of temporal variation in the low-level stimuli and; (iv) an 'optimal' population structure of the memory CTL pool, in terms of immediate protection, requires the presence of both activated cycling and effector CTL. For this, persisting antigen alone or synergistically with bystander signals provide the appropriate stimulation, so that the stimuli equivalent to approximately 30 p.f.u. of LCMV in the spleen are sufficient to maintain approximately 10(5)-10(6) specific CTL in the memory pool. These observations are relevant both to our understanding of natural protective immunity and to vaccine design.

Animals↗

Regulatory effect of recombinant interleukin (IL)3 and IL4 on cytokine gene expression of bone marrow and peripheral blood mononuclear cells.

This study shows that both recombinant human interleukin (rhIL)3 and rhIL4 induced proliferation in bone marrow (BM) cells of myelogenous leukemia patients in a manner similar to that reported using normal BM cells. However, we additionally found that these cytokines also influenced expression of other cytokines. Namely, using a reproducible dot blot hybridization technique we observed on the one hand that BM cells were capable of constitutively expressing low levels of cytokine mRNA coding for IL3, IL4, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte (G)-CSF and IL 1 beta, and on the other hand that in normal peripheral blood mononuclear cells rhIL4 inhibited mRNA expression coding for GM-CSF, G-CSF, IL3 and IL 1 beta, while IL4 mRNA and 28S rRNA was not affected. In contrast, rhIL3 marginally enhanced mRNA coding for IL3, GM-CSF, G-CSF and IL 1 beta and counteracted the inhibitory effect of IL4. In long-term cultures rhIL3 and rhIL4 had no significant effect on spontaneous cytokine gene expression of myelogenous leukemia-derived peripheral blood or BM cells, but made these cells more sensitive for subsequent stimulation with different polyclonal stimuli. Thus, IL3 and IL4 already modulate cytokine gene expression during the initiation of cell culture and differentiate BM cells into populations of cells which are capable of responding with an enhanced cytokine gene expression after polyclonal stimulation.

Biological Factors↗

Clinical anti-aging hormetic strategies.

Hormesis is a term describing the beneficial effects of mild and repeated stimulation or stress, which ultimately bolsters defences against deleterious processes. Although hormetic influences are clearly encountered at the cellular and molecular level, little is known about the effects of hormesis at a clinical level. This paper examines the suggestion that mild stimulation or appropriately timed challenges may be used clinically in order to influence the impact of age-related disease and dysfunction. Examples of stimulation or challenges that may exhibit hormetic effects include dietary restriction, physical and mental exercise, and even social and spiritual stimulation. Dietary restriction places the organism under nutritional stress, stimulating several biochemical repair pathways that may counteract certain age-related changes. Physical and mental challenges, if appropriately timed and sufficiently varied, are directed at increasing the complexity and integration of interacting muscular, cardiovascular, and neural stimuli. Social and spiritual stimulation aimed at reversing age-related loss of dynamical complexity acts upon even higher levels to ensure a reduced risk of social problems in aging.

Aging↗

Stimulation in the NICU: is more necessarily better?

Animal studies and studies with human full-term infants suggest that the stimulation present in utero affects postnatal preferences and levels of response. The premature infant does not necessarily benefit from a re-creation of the in utero environment. Each aspect of the in utero environment should be assessed independently as a potential source of added stimulation in the NICU to determine its possible effects on the development of the premature infant. The NICU environment cannot be accurately labeled by global descriptors of "deprivation" or "overstimulation." When compared with the home environments of full-term infants from lower SES homes, different aspects of the NICU environment were recorded more often, less often, or equally as often as in the full-term infants' homes. Baseline levels of stimulation should be recorded in any NICU environment prior to the institution of an intervention program. NICU caregivers tended to respond contingently to their premature patients' behaviors. However, the prematures provided few opportunities for the nurses to respond, when visual and vocal behaviors used by full-term infants were employed as the expected norm. Perhaps both the medical staff and parents should be trained to recognize and respond to the more subtle, different cues described by Als et al. as being prevalent in the behavioral repertoire of the premature infant. Based on ecologic descriptions of NICU's, researchers have suggested that an inappropriate pattern of stimulation may characterize the environment, rather than an inappropriate amount of stimulation. The NICU environment has been characterized as providing little cross-modal stimulation, few temporally patterned stimuli, and little diurnal rhythmicity. In addition, the premature infant may have few opportunities to control the environment, contrary to the full-term infant's experiences. There is evidence of some negative effects of added NICU stimulation. Individual infants should be assessed prior to intervention for their level of behavioral maturation. Interventions should be individualized for the particular needs of each infant, rather than subjecting all infants assigned to a treatment condition with a stimulation "package." The worthy goal of promoting the development of premature infants carries with it the responsibility of ensuring that no harmful effects could befall any one infant.

Acoustic Stimulation↗

Posterior cingulate cortex: sensory and oculomotor properties of single neurons in behaving cat.

The posterior cingulate cortex of the cat is strongly linked to cortical areas with sensory and oculomotor functions. We have now recorded from feline posterior cingulate neurons in order to determine whether they are active in conjunction with sensory events and eye movements. The results described here are based on monitoring the electrical activity of 195 single neurons in the posterior cingulate cortex of three cats equipped with surgically implanted scleral search coils and trained to fixate visual targets. Posterior cingulate neurons carry tonic orbital position signals and are phasically active in conjunction with saccadic eye movements. Activity related to eye movements and gaze is attenuated but not abolished by the elimination of visual feedback. Posterior cingulate neurons also are responsive to visual, auditory, and somatosensory stimulation. Systematic testing with visual stimuli revealed that responses are sharply reduced due to refractoriness at rates of stimulation greater than a few per second. These results conform to the theory that posterior cingulate cortex is involved in processes underlying visuospatial cognition.

Acoustic Stimulation↗

[Convergence and interaction of reticulofugal and afferent impulses on caudate nucleus neurons in the cat].

In chronic experiments on cats the activity of 269 striatal neurons was investigated extracellularly under direct electrical stimulation of the midbrain reticular formation and using different sensory stimuli: auditory, mechanical, visual. The same striatal neuron responded to reticular and peripheral stimulations. The responses to reticular stimulation recorded in 53% of striatal neurons were orthodromic with high probability of appearance. 23% of striatal neurons responded to reticular stimulation and to stimuli of a single modality. 14% of neurons exhibited polymodal responses. Under all kinds of stimulation excitatory reactions prevailed. Interaction between reticular and acoustic inputs was revealed with paired stimulation in 100 striatal neurons. The reticular formation stimulation caused both facilitatory (predominantly) and inhibitory influences on striatal neurons.

Afferent Pathways↗