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PubMed2003

Transcranial magnetic stimulation in neurology.

Transcranial magnetic stimulation (TMS) is a non-invasive tool for the electrical stimulation of neural tissue, including cerebral cortex, spinal roots, and cranial and peripheral nerves. TMS can be applied as single pulses of stimulation, pairs of stimuli separated by variable intervals to the same or different brain areas, or as trains of repetitive stimuli at various frequencies. Single stimuli can depolarise neurons and evoke measurable effects. Trains of stimuli (repetitive TMS) can modify excitability of the cerebral cortex at the stimulated site and also at remote areas along functional anatomical connections. TMS might provide novel insights into the pathophysiology of the neural circuitry underlying neurological and psychiatric disorders, be developed into clinically useful diagnostic and prognostic tests, and have therapeutic uses in various diseases. This potential is supported by the available studies, but more work is needed to establish the role of TMS in clinical neurology.

Brain↗
PubMed2001

Protein disulfide isomerase and sulfhydryl-dependent pathways in platelet activation.

The inhibition of blood platelet aggregation and secretion was studied using covalent thiol reagents, maleimides, or mercuribenzoates, or using inhibitors of protein disulfide isomerase (PDI), bacitracin or antibodies to PDI. As expected, both types of inhibitors were effective against stimulation by normal physiologic stimuli. On the other hand, when stimulation was initiated with the peptide LSARLAF, that specifically activates the integrin alphaIIbbeta3 (the fibrinogen receptor), the PDI inhibitors were without effect. LSARLAF-induced aggregation was, however, inhibited by the sulfhydryl reagents. To further investigate the role of sulfhydryl-containing proteins and alphaIIbbeta3, platelets were labeled with membrane-impermeant sulfhydryl reagents. Nine bands were found labeled on gel electrophoresis. Two of the labeled bands were identified as alphaIIb and beta3. The conclusions are that while PDI is required for platelet aggregation and secretion, an additional sulfhydryl-dependent step or protein is also required. This latter reaction occurs at the level of alphaIIbbeta3. In distinction to most literature reports, at least a subpopulation of alphaIIbbeta3 contains free sulfhydryl groups, consistent with the possibility that it is a substrate for PDI or part of the sulfhydryl-dependent response.

Blood Platelets↗
PubMed2003

Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses.

Humoral immune responses elicited after secondary exposure to immunizing Ag are characterized by robust and elevated reactivity of memory B cells that exceed those of naive B cells during the primary response. The mechanism underlying this difference in responsiveness of naive vs memory B cells remains unclear. We have quantitated the response of naive and memory human B cells after in vitro stimulation with T cell-derived stimuli. In response to stimulation with CD40 ligand alone or with IL-10, both IgM-expressing and Ig isotype-switched memory B cells entered their first division 20-30 h earlier than did naive B cells. In contrast, the time spent traversing subsequent divisions was similar. Consistent with previous studies, only memory cells differentiated to CD38(+) blasts in a manner that increased with consecutive division number. These differentiated CD38(+) B cells divided faster than did CD38(-) memory B cell blasts. Proliferation of CD40 ligand-stimulated naive B cells as well as both CD38(+) and CD38(-) cells present in cultures of memory B cells was increased by IL-10. In contrast, IL-2 enhanced proliferation of CD38(-) and CD38(+) memory B cell blasts, but not naive cells. Thus, memory B cells possess an intrinsic advantage over naive B cells in both the time to initiate a response and in the division-based rate of effector cell development. These differences help explain the accelerated Ab response exhibited by memory B cells after secondary challenge by an invading pathogen, a hallmark of immunological memory.

ADP-ribosyl Cyclase↗
PubMed1975

Adenyl cyclase activity in lymphocytes stimulated with immunologically specific and nonspecific stimuli.

Adenyl cyclase activity was determined in suspensions of rat lymphocytes from animals with postadjuvant polyarthritis and from healthy animals. Adrenaline was used as activator of the enzyme. Adenyl cyclase activity was determined by the method based on synthesis of 3H-cAMP from 3H-ATP in intact cells. The influence of imidazole on blastic transformation of lymphocytes sensitized in the process of postadjuvant polyarthritis and subjected to the action of antigen, i.e. Old Tuberculin, was also studied. The response of sensitized lymphocytes to antigen in the presence of a nonspecific stimulus, adrenaline, was also investigated. In addition, the action of adrenaline on incorporation of 3H-thymidine in cultures of nonsensitized lymphocytes was observed. Adenyl cyclase activity in suspensions of lymphocytes from animals with postadjuvant polyarthritis was higher than in suspensions of lymphocytes from healthy animals. Following administration of adrenaline as activator of the enzyme, lymphocytes from healthy animals showed higher activity of the enzyme than lymphocytes from the sick rats. Imidazole inhibited the response of lymphocytes sensitized to antigen. Adrenaline had no influence on blastic transformation of lymphocytes sensitized to antigen. Adrenaline slightly inhibited incorporation of H-thymidine in cultures of sensitized lymphocytes in absence of antigen in cultures of nonsensitized lymphocytes.

Adenylyl Cyclases↗
PubMed1991

[Anti-tachycardia stimulation in supraventricular and ventricular tachycardia with and without cardioverter/defibrillator].

Reentry is the underlying electrophysiologic mechanism in most of the clinically occurring tachycardias. It has been known for 25 years that a reentrant circuit can be interrupted by correctly timed stimuli during programmed stimulation. Although there has been a continuous technological progress in pacemaker technology in the last ten years, application of pacemaker therapy for the treatment of atrial as well as of ventricular tachyarrhythmias did not increase significantly. Prophylactic permanent pacing preventing the onset of tachyarrhythmias has not become an accepted therapeutic approach and is still a matter of research. Antitachycardia pacing designed to interrupt a reentrant circuit uses single or multiple extrastimuli which invade the excitable gap of the reentrant circuit so that antegrade and retrograde conduction within the circuit becomes impossible. The excitable gap, however, is not a fixed electrophysiological parameter, but its width depends mainly on the influence of the sympathetic and parasympathetic nervous system. Therefore, a variety of stimulation programs delivered by the implanted pacemaker had to be invented in order to adapt to the constantly changing electrophysiologic parameters. It becomes obvious that application of burst stimulation is more effective than delivery of single or double extra stimuli and that tachycardia rate-related pacing is more reliable than fixed-rate pacing for tachycardia interruption. The most effective termination mode seems to be self-adaptive auto-decremental pacing with constantly decreasing intervals between multiple stimuli and addition of further impulses for each new termination attempt. The risk of acceleration of tachycardia or induction of non-clinical tachyarrhythmias is higher with burst-stimulation than with single or double extra stimuli. Fast tachycardia rates are more prone to acceleration than slower ones. Tachycardia detection algorithms are based mainly on rate, sudden onset and rate stability of the tachycardia. In order to reliably distinguish pathologic tachycardias from sinus or physiologic tachycardias, other than rate-detection parameters will be applied in the future. These are endocardial electrogram signal-analysis, frequency content of the endocardial signals as well as biological sensors. A prerequisite for successful permanent antitachycardia pacing is a thoroughly performed preoperative electrophysiologic study in order to identify the most reliable and effective tachycardia termination mode. This requires multiple induction of the clinical tachycardia under various conditions, different activity or posture states as well as under the influence of antiarrhythmic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Electric Countershock↗
PubMed1995

Reflex respiratory responses to continuous and intermittent stimulation of afferent fibres from muscles in cats.

In anaesthetized cats, reflex respiratory responses were evoked by electrically stimulating proximal ends of cut nerves to gastrocnemius-soleus muscles of the left hindlimb. The direction of these responses, in the excitatory or inhibitory sense, depended on the types of afferent fibres stimulated and on the mode of stimulation. Continuous stimulation, delivered with stimuli of 0.1 ms at 200 or 300 Hz, in all cases induced excitatory responses, consisting of increases in pulmonary ventilation, mainly caused by increases in tidal volume. Intermittent stimulation, which consisted of brief trains of stimuli repeated at 2-3 Hz, induced excitatory responses when afferent fibres with conduction velocities higher than 20 m/s were stimulated, while it induced inhibitory responses, consisting of decreases in pulmonary ventilation, tidal volume and respiratory frequency, when fibres with conduction velocities below 20 m/s were simultaneously stimulated with the high-conduction velocity fibres.

Afferent Pathways↗
PubMed1999

Chemosensory event-related potentials to trigeminal stimuli change in relation to the interval between repetitive stimulation of the nasal mucosa.

Event-related potentials (ERPs) to olfactory and trigeminal stimuli have been used commonly to evaluate chemosensory dysfunction. The aim of the present study was to investigate how ERPs could be modified by repetitive stimulations of the intranasal trigeminal nerve using 52% v/v CO2 stimuli for 200 ms periods. Nine subjects were exposed to 6 sessions each during which trains of 16 stimuli were applied. The interval between stimuli was constant for each experiment, but varied between experiments (10, 20, 30, 40, 60, and 90 s). Trigeminal ERPs were obtained from three positions on the skull. Both intensity ratings and ERP amplitudes decreased as the interstimulus interval (ISI) shortened. Specifically, ratings and response amplitudes were most strongly reduced by approximately 30-50% at the shortest ISI used (10 s) and were largest at an ISI of 90 s. The decrease of amplitudes was strongest for the P46 amplitude. Our findings suggest that this may be the result of both habituation and stimulus predictability. We hypothesize that the ISI dependence of chemosensory ERPs may also be a function of an interaction between Adelta and C fibers.

Adult↗
PubMed1977

The site and receptors responsible for the inhibition by sympathetic nerves of intestinal smooth muscle and its parasympathetic motor nerves.

1. The effects of three inhibitory stimuli, sympathetic nerve stimulation, noradrenaline (NA) and isoprenaline have been examined on three forms of motor activity in the rabbit colon, the response to pelvic (parasympathetic) nerve stimulation, acetylcholine (ACh) and spontaneous tone.2. The response to pelvic nerve stimulation is most effectively inhibited by sympathetic nerve stimulation, much less effectively by NA and hardly at all by isoprenaline. The sympathetic nerves can inhibit the pelvic response at frequencies of stimulation which do not affect spontaneous tone. The inhibitory effect of sympathetic stimulation, and of NA, on the pelvic response is reduced by phentolamine 5 x 10(-6)M and unaffected by propranolol 5 x 10(-6)M suggesting the effect is mediated via alpha receptors.3. The response to ACh is inhibited by all three stimuli equally. The inhibitory effect of sympathetic nerve stimulation and of isoprenaline is reduced by propranolol 5 x 10(-6)M. The inhibitory effect of NA is also reduced by propranolol but to a lesser extent. Phentolamine 5 x 10(-6)M has a small effect in reducing the inhibitory effect of sympathetic nerve stimulation or of NA. This effect of phentolamine is lost if the participation of motor nerves in the response to ACh is excluded by either tetrodotoxin 10(-7) g/ml. or cold storage for 10-14 days. These results suggest that inhibition of the ACh response takes place mainly at the muscle by activation of beta receptors but that ACh may have a small indirect stimulant action through motor nerves and this is susceptible to inhibition through alpha receptors.4. All three stimuli are equally effective in lowering smooth muscle tone. This inhibitory effect of sympathetic nerve stimulation and of isoprenaline is reduced by propranolol 5 x 10(-6)M and unaffected by phentolamine 5 x 10(-6)M. The inhibitory effect of NA is reduced by propranolol but again is less sensitive to block than the other two inhibitory stimuli. Phentolamine is without effect on the inhibitory action of NA and the combination of phentolamine with propranolol is no more effective than propranolol alone. These results suggest that NA liberated by sympathetic nerves and isoprenaline inhibit myogenic tone in the smooth muscle by an action on beta receptors but the action of NA added to the bath cannot be fully explained in this way.

Acetylcholine↗
PubMed1983

Synaptic activation of phasic bursting in rat supraoptic nucleus neurones recorded in hypothalamic slices.

Using slices of rat hypothalamus (400-500 micron thick), intracellular and extracellular recordings were made of activity from eight-eight neurones in the supraoptic nucleus (s.o.n.). Electrical stimulation with single stimuli dorsolateral to s.o.n. was excitatory to fifty-nine phasically firing cells (67% of total, 95% of phasic cells). In intracellularly recorded cells, such stimulation reliably evoked excitatory post-synaptic potentials which often gave rise to action potentials. Trains of stimuli reliably triggered bursts of action potentials which continued after stimulation had ceased. Stimulation more dorsal or more lateral to the critical region or in the optic tract adjacent to the s.o.n. did not evoke responses. Stimulation dorsomedial to the nucleus produced only direct, probably antidromic, activation of s.o.n. neurones. Application of acetylcholine (ACh) by microperifusion in the s.o.n. region mimicked the effect of electrical stimulation by evoking prolonged discharge in eight of eight tested phasically firing s.o.n. neurones. Non-phasic, continuously firing neurones were either inhibited or unaffected by electrical stimulation in the critical region. The discharge pattern of unaffected cells (six cells) was not modified by locally applied ACh, although they were excited by local application of sodium glutamate. The excitatory, synaptically mediated, responses to stimulation in the dorso-lateral region were blocked reversibly by the nicotinic blockers, d-tubocurarine chloride and hexamethonium bromide (in seven of seven cells tested), but were unaffected by the muscarinic blocker, atropine, even at high concentrations (two of two cells tested). Thus, this activation appears to be mediated by nicotinic receptors. In separate experiments with the position of stimulating and recording electrodes reversed, s.o.n. stimulation was effective in antidromically activating one cell of sixty-eight recorded extracellularly in the dorsolateral region. Some slowly firing s.o.n. neurones (less than 4 Hz) were inhibited by electrical stimulation in the same area in which phasically active cells were excited. In these cases, stimulation produced large summating i.p.s.p.s. and/or inhibition of ongoing activity for the duration of the stimulus train. These results support evidence from earlier studies that the cholinergic input to s.o.n. neurones originates from cells in its close proximity, and suggests this input to be via a monosynaptic pathway.

Acetylcholine↗
PubMed1999

Effects of ginseng saponins on responses induced by various receptor stimuli.

We investigated the effects of four ginseng saponins, ginsenoside-Rb1, -Rg2, -Rg3 and -Ro, on the responses induced by receptor stimulation of various stimuli. Ginsenoside-Rg2 (1-100 microM) reduced the secretions of catecholamines from bovine adrenal chromaffin cells stimulated by acetylcholine and gamma-aminobutyric acid but not by angiotensin II, bradykinin, histamine and neurotensin. In guinea-pig, the ginsenoside also diminished the nicotine-induced secretion of catecholamines from the adrenal chromaffin cells, but it did not affect the muscarine- and the histamine-induced ileum contractions. On the other hand, ginsenoside-Rg3 (1-100 microM) reduced not only the acetylcholine-, the gamma-aminobutyric acid- and the neurotensin-induced secretions but also, at a higher concentration (100 microM), the angiotensin II-, the bradykinin- and the histamine-induced secretions from the bovine chromaffin cells. Furthermore, the saponin (3-100 microM) significantly inhibited the muscarine- and the histamine-induced ileum contractions of the guinea-pig. Ginsenoside-Rb1 and -Ro had no marked effect on their responses. These results strongly suggest that ginsenoside-Rg2 is a potent selective blocker of nicotinic acetylcholine and gamma-aminobutyric acid receptors (ionotropic receptors) and ginsenoside-Rg3 is not only a blocker of ionotropic receptors but also an antagonist of muscarinic or histamine receptors.

Adrenal Glands↗
PubMed1995

Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation.

In vivo somatosensory stimuli evoked the release of substance P from primary afferent neurons that terminate in the spinal cord and stimulated endocytosis of substance P receptors in rat spinal cord neurons. The distal dendrites that showed substance P receptor internalization underwent morphological reorganization, changing from a tubular structure to one characterized by swollen varicosities connected by thin segments. This internalization and dendritic structural reorganization provided a specific image of neurons activated by substance P. Thus receptor internalization can drive reversible structural changes in central nervous system neurons in vivo. Both of these processes may be involved in neuronal plasticity.

Animals↗
PubMed2002

Effect of H1-antagonist Dithiaden on human PMN-leukocyte aggregation and chemiluminescence is stimulus-dependent.

OBJECTIVE AND DESIGN: Contradictory data published on histamine-PMN leukocyte interactions stimulated us to study to the role of histamine and H1-antagonist Dithiaden in generation of reactive oxygen species (ROS) and aggregation of human neutrophils. METHODS AND MATERIALS: Whole blood or isolated PMN-leukocytes were exposed in a dose-dependent way to histamine or H1-antagonist Dithiaden and subsequently stimulated. Whole blood was stimulated with opsonised zymosan (OZ). Isolated cells were stimulated with membrane stimuli (OZ, N-formyl-methionyl-leucyl-phenylalanine--fMLP), or membrane bypassing stimuli (Ca2+-ionophore A23187, phorbol-myristate-acetate--PMA). The luminol-enhanced chemiluminescence (CL) was measured separately (whole blood) in a luminometer or simultaneously with neutrophil aggregation in a whole blood lumiaggregometer. RESULTS: Depending on the concentration used, Dithiaden" was 1.5- to 25.0-times more effective in inhibiting activated CL of whole blood than histamine. In isolated neutrophils both histamine and Dithiaden inhibited OZ- and A23187-stimulated CL dose-dependently, with potentiation observed after stimulation with PMA and fMLP. Histamine did not alter aggregation with any of the stimuli tested. Dithiaden inhibited A23187-, OZ- and PMA-stimulated PMN-leukocytes but potentiated fMLP-induced aggregation of isolated neutrophils. Simultaneous application of Dithiaden and histamine abolished the effect of Dithiaden on fMLP-stimulated CL. CONCLUSIONS: Dithiaden, depending on the stimuli applied, inhibited human neutrophils, both isolated or in whole blood, more markedly than histamine. The inhibition of aggregation and CL was dose- and stimulus-dependent. Histamine administered simultaneously abolished the effect of Dithiaden on fMLP-stimulated PMN-leukocytes. It seems likely that the interaction of Dithiaden with neutrophils operated both at an extra- and intracellular level.

Benzothiepins↗
PubMed1986

Tectal neurons of the frog: intracellular recording and labeling with cobalt electrodes.

With the aid of cobalt-filled intracellular electrodes, responses evoked by electrical and visual stimulation were recorded from tectal neurons. Diffuse light and "edge" and "spot" stimuli were used for visual stimulation; electrical stimuli were delivered by means of bipolar electrodes to the optic tract. The cells were subsequently filled with cobalt for a correlative histological study. The following types of neurons were distinguished: (1) Pear-shaped neurons with restricted and broad dendritic fields occurring in tectal layers 8, 6, 4, and 2. In one group, the dendrites bore beads and small protrusions and the short axon arborized within, or close to, the dendritic arbor. They responded mostly with inhibitory postsynaptic potentials to the various stimulations. This type of neuron was interpreted to be a tectal interneuron. In the second group the dendrites were smooth, the dendritic arbor was large, and the axon could be followed to layer 7 in a few cases. Excitatory activities with frequent spike discharges prevailed in their responses. They were regarded as efferent neurons of the tectum. (2) Large ganglionic neurons showed a greater variation in form than has been described in previous Golgi studies. Their responses to the different stimulations were also very variable. The axons of five neurons could be followed to the dorsal part of the thalamus, to the postoptic commissural system, and to the direct and crossed tectobulbar tract. These axons emitted several collaterals to tectal, pretectal, and tegmental structures. (3) A single stellate neuron was impaled in layer 9. It responded only to electrical stimulation with excitation. (4) Deep bipolar neurons were not mentioned in earlier works. Their somata were found in layer 6; the vertically oriented dendrites arborized in plexiform layers 7, 5, and 3, over a distance of more than 1 mm. These cells were sensitive only to electrical stimulation.

Animals↗
PubMed1991

Fusimotor reflexes influencing secondary muscle spindle afferents from flexor and extensor muscles in the hind limb of the cat.

The purpose of this study was to investigate secondary muscle spindle afferents from the triceps-plantaris (GS) and posterior biceps and semitendinosus (PBSt) muscles with respect to their fusimotor reflex control from different types of peripheral nerves and receptors. The activity of single secondary muscle spindle afferents was recorded from dissected and cut dorsal root filaments in alpha-chloralose anaesthetized cats. Both single spindle afferents and sets of simultaneously recorded units (2-3) were investigated. The modulation and mean rate of firing of the afferent response to sinusoidal stretching of the GS and PBSts muscle were determined. Control measurements were performed in the absence of any reflex stimulation, while test measurements were made during reflex stimulation. The reflex stimuli consisted of manually performed movements of the contralateral hind limb, muscle stretches, ligament tractions and electrical stimulations of cutaneous afferents. Altogether 21 secondary spindle afferents were investigated and 20 different reflex stimuli were employed. The general responsiveness (i.e. number of significant reflex effects/number of control-test series) was 52.4%, but a considerable variation between different stimuli was found, with the highest (89.9%) for contralateral whole limb extension and the lowest (25.0%) for stretch of the contralateral GS muscle. The size of the response to a given stimulus varied considerably between different afferents, and, in the same afferent, different reflex stimuli produced effects of varying size. Most responses were characterized by an increase in mean rate of discharge combined with a decrease in modulation, indicative of static fusimotor drive (Cussons et al., 1977). Since the secondary muscle spindle afferents are part of a positive feedback loop, projecting back to both static and dynamic fusimotor neurones (Appelberg Et al., 1892 a, 1983 b; Appelberg et al., 1986), it is suggested that the activity in the loop may work like an amplified which, during some circumstances, enhance the effect of other reflex inputs to the system (Johansson et al., 1991 b).

Afferent Pathways↗
PubMed1978

[Hemodynamic changes upon nociceptive stimulation and stimulation of the amygdaloid complex following catecholamine administration].

In cats, changes in arterial pressure (AP), intracardiac pressure (ICP), and blood flow volume rate following a nociceptive stimulus, stimulation of the amygdala and the combination of these before and after adrenaline (A) and norepinephrine (NE) administration into the lateral nucleus of amygdala, were studied. Nociceptive stimuli and electric stimulation of amygdala increased AP and ICP. The combination of these increased the pressor reaction. The blood flow volume rate was not altered by the nociceptive stimulus while decreasing at amygdalar stimulation. After A and NE administration the stimulation of amygdala plus the nociceptive stimulus suppressed the pressor reaction; a nociceptive stimulus was followed by the same changes as in intact cats; a nociceptive stimulus plus the stimulation of the amygdala increased the pressor reaction. The blood flow volume rate response to the stimuli was the same as in the control group. But the stimulation of amygdala after NE and a nociceptive stimulus plus amygdala stimulation (20 min after A) increased the blood flow volume rate, while the stimulation of amygdala alone with A administration reduced the blood flow.

Amygdala↗
PubMed1990

Possible role of Ca2(+)-independent protein kinase C isozyme, nPKC epsilon, in thyrotropin-releasing hormone-stimulated signal transduction: differential down-regulation of nPKC epsilon in GH4C1 cells.

Protein kinase C (PKC) molecular species of GH4C1 cells were analyzed after separation by hydroxyapatite column chromatography. A novel Ca2(+)-independent PKC, nPKC epsilon, was identified together with two conventional Ca2(+)-dependent PKCs, PKC alpha and beta II by analysis of kinase and phorbol ester-binding activities, immunoblotting using isozyme-specific antibodies, and Northern blotting. These PKCs are down-regulated differently when cells are stimulated by outer stimuli; phorbol esters deplete PKC beta II and nPKC epsilon from the cells more rapidly than PKC alpha, whereas thyrotropin-releasing hormone (TRH) at 200 nM depletes nPKC epsilon exclusively with a time course similar to that induced by phorbol esters. However, translocation of PKC alpha and beta II to the membranes is elicited by both TRH and phorbol esters. These results suggest that TRH and phorbol ester activate PKC alpha and beta II differently but that nPKC epsilon is stimulated similarly by both stimuli. Thus, in GH4C1 cells, Ca2(+)-independent nPKC epsilon may play a crucial role distinct from that mediated by Ca2(+)-dependent PKC alpha and beta II in a cellular response elicited by both TRH and phorbol esters.

Animals↗