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A controlled positron emission tomography study of obsessive and neutral auditory stimulation in obsessive-compulsive disorder with checking rituals.

Ten nondepressed patients with obsessive-compulsive disorder (OCD) who were characterized by predominant checking rituals were compared with 10 age- and sex-matched control subjects. Hemispheric and regional cerebral blood flow levels (rCBF) were measured with positron emission tomography (H2 15O) across four conditions: rest, auditory stimulation with idiosyncratic normal or abnormal obsession, auditory stimulation with neutral verbal stimuli, and rest. Order of neutral and obsessive stimulation was randomized. Higher subjective responses to obsessive than to neutral stimulation were found in both groups; subjective response was higher in OCD patients when obsessive stimulation was presented first. A four-way analysis of variance (group x stimulation order x hemisphere x condition [neutral or obsessive stimulation]) was performed on stimulation minus rest normalized rCBF values. Control subjects had significantly higher rCBF in the thalamus and putamen. A trend toward higher rCBF in OCD patients was found in the superior temporal regions. When neutral stimulation was presented first, rCBF was significantly higher in the caudate region of control subjects. Obsessive stimulation was associated with higher rCBF than neutral stimulation in orbitofrontal regions in both groups of subjects. Under obsessive stimulation, superior temporal and orbitofrontal activities were correlated in OCD patients but not in control subjects. Our study suggests specific abnormalities of information processing in the basal ganglia and temporal structures of compulsive checkers.

Adult↗

Temporal integration of events within and between the cerebral hemispheres.

The effect of interhemispheric transmission time (IHTT) on temporal perception was investigated by comparing simultaneity thresholds under unimanual and bimanual stimulation conditions. In the unimanual conditions the tactile stimuli were delivered to the same hand and were received by the same hemisphere, but in bimanual conditions, where stimuli were delivered to different hands, interhemispheric communication was necessary in order to compare the timing of the two stimuli. Randomised order of stimulating the fingers of the hands was compared with consistent stimulation of each hand. Previous studies have used only consistent stimulation. Thirty-two undergraduate university students (16 males and 16 females) were tested. Bimanual simultaneity thresholds were significantly higher than unimanual. Previous research showing an absence of laterality effects for simultaneity judgements was confirmed, supporting a hemispheric equivalence model of temporal processing. Simultaneity thresholds were not affected by randomisation of stimulus location, indicating that expectancy effects were not responsible for the difference between bimanual and unimanual thresholds. The implication of these findings is that temporal perceptions are affected by the process of interhemispheric transmission.

Adolescent↗

Influence of diffuse luminance flicker on choroidal and optic nerve head blood flow.

PURPOSE: In the retina there is general agreement that blood flow adapts in response to different conditions of light and darkness including diffuse luminance flicker. By contrast, regulation of choroidal blood flow in response to different light conditions is still a matter of controversy. Thus, we investigated the effect of diffuse luminance flicker on choroidal and optic nerve head blood flow. METHODS: In a group of 14 healthy volunteers, choroidal blood flow and ocular fundus pulsation amplitude were assessed with laser Doppler flowmetry and laser interferometry, respectively. Measurements were done before, during and after stimulation with diffuse luminance flicker. Furthermore, the response of optic nerve head blood flow (ONHBF) to flicker stimulation was measured. Flicker stimuli were generated by a Grass PS2 photostimulator, stimulating at a frequency of 8 Hz. Flicker light consisted of light flashes at a wavelength below 550 nm and produced a retinal irradiance of 140 microW/cm( 2). Blood pressure and pulse rate were measured non-invasively. Paired t-test was used for statistical analysis. RESULTS: ONHBF increased immediately after onset of flicker stimulation. The maximum increase in ONHBF was 30% +/- 10% (mean +/- SEM, p < 0.008). Both choroidal perfusion parameters were only slightly increased during flicker stimulation, by 2 +/- 2% (laser Doppler flowmetry, p < 0.5) and by 4 +/- 1% (laser interferometry, p < 0.12). After the end of stimulation all values returned to baseline levels. CONCLUSION: Our study clearly demonstrates that diffuse luminance flicker increases optic nerve head blood flow. In contrast, increased neural activity in the retina has no effect on choroidal blood flow. Thus, choroidal blood flow appears to be largely independent of alterations in retinal metabolism.

Choroid↗

Chest wall stimulation for temporary suppression of competitive rhythms due to permanent pacemaker malfunction.

Chest wall stimulation by electrical stimuli was employed to suppress permanent demand (ventricular-inhibited) pacemakers in two patients with competitive ventricular rhythms. The stimuli were nor perceived by either patient, and were continued until surgical intervention was effected. In selected patients with permanent pacemaker malfunction, chest wall stimulation may be appropriate and necessary initial therapy until definitive correction is performed.

Aged↗

Role of sensory-evoked NMDA plateau potentials in the initiation of locomotion.

Reticulospinal (RS) neurons constitute the main descending motor system of lampreys. This study reports on natural conditions whereby N-methyl-D-aspartate (NMDA)-mediated plateau potentials were elicited and associated with the onset of locomotion. Reticulospinal neurons responded in a linear fashion to mild skin stimulation. With stronger stimuli, large depolarizing plateaus with spiking activity were elicited and were accompanied by swimming movements. Calcium imaging revealed sustained intracellular calcium rise upon sensory stimulation. Blocking NMDA receptors on RS neurons prevented the plateau potentials as well as the associated rise in intracellular calcium. Thus, the activation of NMDA receptors mediates a switch from sensory-reception mode to a motor command mode in RS neurons.

Animals↗

[Indirect bronchial provocation tests: a new, specific group of bronchial provocation tests for asthma].

Asthma is characterized by a variable airway obstruction, bronchial hyperresponsiveness and airway inflammation. Usually, bronchial hyperresponsiveness is measured in the clinic by provocation with non specific stimuli such as histamine or methacholine. These stimuli are called direct, as they constrict the airways by a direct stimulation of airway smooth muscle. Pharmacological stimuli such as adenosine, tachykinins and bradykinin, and physical stimuli such as exercise, isocapnic hyperventilation or hypertonic saline, are called indirect stimuli: they stimulate inflammatory cells and/or neuronal cells and the released mediator and/or neurotransmitter causes the airways to narrow. In the past 10 years the mechanisms and receptors involved in the airway narrowing caused by these indirect bronchial challenges have been characterized. It has become clear that indirect challenges form a specific group of challenges that play a role in the diagnosis and the monitoring of asthma.

Adenosine↗

Regulation of AP-1 expression and activity in antigen-stimulated mast cells: the role played by protein kinase C and the possible involvement of Fos interacting protein.

We have recently observed that protein kinase C (PKC) was involved in the regulation of the accumulation of mRNAs of the AP-1 components in cultured Abelson-transformed murine fetal-liver-derived mast cells stimulated by exocytotic stimuli. Here we analyzed the probable regulatory effect of PKC on the synthesis and DNA-binding activity of AP-1 complexes in immunologic stimulated mast cells. In this study we used the interleukin-3--dependent murine fetal-liver--derived mast cells that were not transformed by the Abelson oncogene. Study of PKC-depleted cells showed PKC dependency of c-fos mRNA accumulation and protein expression in IgE-Ag stimulated cells. In contrast, the c-jun mRNA accumulation was unaffected by PKC depletion, whereas its protein expression was dependent on this enzymatic activity. This suggests the involvement of PKC in the regulation of translation of c-Jun, a level of c-Jun regulation that was not previously described. The amount of AP-1 DNA-bound complex was also lowered in PKC-depleted cells. Therefore, PKC plays an important regulatory role in different stages of the signal transduction pathway because of IgE-Ag stimulation. Surprisingly, we have observed that although the amount of total synthesized c-Fos began to increase 15 minutes after immunologic stimulation, the amount of c-Fos associated with Juns did not increase, even after 45 minutes. This association was not affected by PKC. Using a Fos-interacting protein (FIP)-cDNA probe, an expression of 2.9 kb mRNA was detected in these cells. Furthermore, immunologic stimulation caused an increase in the amount of a Fos-containing protein complex that bound to an FIP-binding DNA oligonucleotide. Therefore, we propose that this protein complex that contains most of the immunologically induced c-Fos has an important role in IgE-Ag-stimulated signal transduction.

Animals↗

Programmed electrical stimulation at potential ventricular reentry circuit sites. Comparison of observations in humans with predictions from computer simulations.

The purpose of this study was to define specific types of resetting responses to programmed electrical stimulation during human ventricular tachycardia and to use computer simulations of reentry circuits to assess the possible mechanisms and pacing site location relative to the reentry circuit for each type of response. The effects of scanning single stimuli at 35 left ventricular endocardial sites during sustained monomorphic ventricular tachycardia in 12 patients were studied. In considering alterations in QRS configuration and the delay between the stimulus and the advanced QRS, we identified three types of resetting responses to scanning stimuli consistent with stimulation at sites in or near the reentry circuit at 12 abnormal endocardial sites in eight patients. Type 1: all capturing stimuli were followed after a delay by early QRS complexes that had the same configuration as the tachycardia complexes. Type 2: late stimuli reset tachycardia as in type 1 but early stimuli reset the tachycardia after altering the QRS configuration. Type 3: late stimuli reset tachycardia as in type 1, but early stimuli advanced tachycardia with a short stimulus to QRS delay without altering the QRS configuration. In the simulations, premature depolarization of sites in the circuit produced orthodromic and antidromic wavefronts. The orthodromic wavefront propagated through the circuit and exited the circuit at the same site as did the previous tachycardia wavefronts and advanced the tachycardia without altering the configuration of the advanced QRS. The antidromic wavefront of relatively late stimuli was confined within or near the circuit by collision with the orthodromic wavefront of the preceding tachycardia beat and failed to alter ventricular activation distant from the circuit. Therefore, the QRS configuration after the stimulus was unchanged. A type 1 response occurred when all capturing stimuli produced this effect. However, with increasing stimulus prematurity, the antidromic wavefront propagated farther before colliding with an orthodromic wavefront, and under some conditions, it exited the circuit from a site other than the original circuit "exit," and altered the ventricular activation sequence distant from the circuit and, therefore, the QRS configuration, producing a type 2 pattern. The type 3 pattern occurred when the antidromic wavefront of early premature beats captured the original circuit exit. The effect of a stimulus was dependent on the stimulus prematurity, the relative conduction times from the stimulation site to the potential sites of "exit" from the circuit, and the timing of the excitable gap at the stimulation site.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiac Pacing, Artificial↗

Effects of flunarizine on electrical and mechanical responses of smooth muscle cells in basilar and ear arteries of the rabbit.

The effects of flunarizine on electrical and mechanical responses of smooth muscle tissues of the rabbit basilar and ear arteries to transmural stimulation, high-potassium solution (high-K), 5-hydroxytryptamine and noradrenaline were studied. In the basilar artery, 10(-6) M flunarizine (69 min application) blocked spike potentials generated by outward current stimuli or transmural stimulation without change in the resting-membrane potential or membrane resistance. The spike potentials generated in the ear artery were attenuated by a long exposure (up to 2 h) to a high concentration of flunarizine (10(-6) M). Membrane depolarizations produced by high-K, noradrenaline or 5-hydroxytryptamine were not blocked by flunarizine. Flunarizine inhibited smooth muscle contractions produced by transmural stimuli, high-K, noradrenaline or 5-hydroxytryptamine in both arteries, however the inhibition developed slowly, and the ear artery required a longer period of incubation with flunarizine than the basilar artery. The inhibitory effects of flunarizine on basilar artery were more marked against transmural stimulation or high-K induced contractions than against agonist-induced contractions.

Action Potentials↗

Photochemically induced transient spinal ischemia induces behavioral hypersensitivity to mechanical and cold stimuli, but not to noxious-heat stimuli, in the rat.

Pain-like sensory disorders lasting several days were observed in rats after transient ischemia in the lumbar region of the spinal cord. The ischemia was induced with a recently developed photochemical technique. Rats exhibited strong allodynia, a pain-like reaction to innocuous stimuli, to mechanical stimulation of the caudal trunk, hind limbs, and hind paws, which were areas innervated by the ischemic spinal segments. The rats also expressed hypersensitivity to cold stimuli. However, no changes in sensitivity to noxious heat could be detected with the hot-plate test. Furthermore, no morphological damage could be observed in the spinal cord at the light microscopic level in the majority of rats after transient spinal cord ischemia. The present results indicate that allodynia-like symptoms to mechanical stimuli after spinal ischemia may be mediated by myelinated afferents and could be associated with dysfunction of inhibitory transmission in the spinal cord. We suggest that this pain-related syndrome after spinal ischemia could be considered as an animal model of painful states of spinal origin.

Animals↗

The role of the glycine sensitive area of the ventral medulla in cardiovascular responses to carotid chemoreceptor and peripheral nerve stimulation.

The present study on cats anaesthetised with Althesin, which unlike more commonly used anaesthetics does not prevent reflex activation of the brain-stem defence areas, reaffirmed that carotid chemoreceptor stimulation and radial nerve stimulation can evoke the visceral components of the alerting stage of the defence response (visceral alerting response). This includes tachycardia, mesenteric vasoconstriction but vasodilatation in skeletal muscle which is not secondary to the hyperventilation. However, mild chemoreceptor stimulation which evoked but a weak hyperventilation elicited bradycardia and vasoconstriction is mesentery and in muscle i.e. a response comparable with that evoked by chemoreceptor stimulation under chloralose or barbiturate anaesthesia. This suggests that chemoreceptor stimulation can evoke two separate patterns of response, the visceral alerting response predominating when the defence areas are strongly activated. The efferent pathway from the defence areas is known to synapse in the 'glycine sensitive area' of the ventral medulla which contains neurones whose activity seems to provide the main sympatho-excitatory drive for normal arterial pressure. Bilateral application of glycine to that area produces a pronounced fall in arterial pressure, apnoea and greatly attenuates the response to defence area stimulation, the vasoconstrictor components being abolished. In the present study bilaterally applied glycine abolished the muscle vasodilatation of the visceral alerting response evoked by chemoreceptor and radial nerve stimulation but both stimuli evoked vasoconstriction in mesenteric and muscle vasculature at least until arterial pressure was very low. It is proposed that both chemoreceptor and peripheral nerve stimulation can activate the defence areas to produce a visceral alerting response which is relayed via neurones of the glycine sensitive area.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

Evidence for two different afferent pathways carrying stress-related information (noxious and amygdala stimulation) to the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) is an important nucleus involved in mediating amygdala-regulated endocrine effects. Since the amygdala is important in mediating the endocrine response to noxious somatosensory stimuli and olfactory stimulation, this experiment studies whether noxious input (tail pinch, TP) and stress-related input (amygdala stimulation, AmygS) will modulate BNST neuronal activity. One hundred and fifty-eight BNST neurons were studied following AmygS, TP and cutaneous stroke. AmygS was effective in 66% of BNST neurons and produced one of the following five responses: oligosynaptic excitation (43%), polysynaptic excitation (5%), time-locked inhibition (4%), generalized increase in firing rate (8%), or generalized decrease in firing rate (6%). TP produced an increase in firing rate in 27% of BNST neurons tested. Analysis of a contingency table constructed to determine the degree of correspondence between neurons responsive to AmygS and neurons responsive to TP showed that the distributions of reactivity to these stimuli in BNST neurons are independent of each other. This suggests that although AmygS and TP are both capable of altering the firing rate of BNST neurons, the pathways by which they reach BNST differ.

Afferent Pathways↗

Cerebral cortical somatosensory evoked responses, multiple unit activity and current source-densities: their interrelationships and significance to somatic sensation as revealed by stimulation of the awake monkey's hand.

In awake monkeys, electrical pulse stimuli which mimic touch stimulation were delivered to the thenar eminence while electrophysiologic recordings were made from surface to depth in postcentral gyrus. Cortical depth profiles of somatosensory evoked responses (SEPs), multiple unit activity (MUA) and current source-densities (CSDs) were analyzed to gain insight into the neural process underlying the SEP and somatic sensation. The following was found: The thenar stimulus evoked four main SEP components which were seen over wide regions of postcentral gyrus: P1 at 12 ms, the primary evoked response; P1a, near 20 ms; N1, near 50 ms; and P2, around 120 ms after the stimulus. MUA was observed during the P1, P1a and N1 temporal intervals whose vigor changed as a function of the respective SEP component's amplitude. CSD analysis showed that during P1 a current sink and source appeared within the middle and superficial cortical layers, respectively. During P1a, a sink just above that of P1 and a superficial source became evident. During N1, a large superficial sink and one or two deep sources appeared. Evoked MUA during P1 and P1a was most prominent at the level of their current sinks while MUA during N1 appeared at the level of the current sources, in general. When stimulation was moved from the thenar portion of the hand to a region which most closely matched the receptive field of the cortical recording site, P1 and P1a increased amplitude while N1 both increased in amplitude and decreased in peak latency. Also, MUA activity during the early temporal intervals become more vigorous. These changes were similar to those observed with thenar stimuli as the recording site approached the thenar cortical representation. Over repeated trials at a single stimulus intensity, the spontaneous changes in SEP amplitude were found to be directly correlated with MUA and CSD measures within the same temporal interval. In contrast, SEP, MUA or CSD measures within the early temporal intervals (i.e., P1 or P1a) were uncorrelated or less frequently, inversely correlated with the same measures in the late temporal interval (i.e. N1). The multiple measures complemented one another which led to a descriptive model of the neural process underlying the evoked cortical response in postcentral gyrus of awake monkey.

Animals↗

Peripheral origins and central modulation of subcutaneous formalin-induced activity of rat dorsal horn neurones.

Extracellular recordings of single convergent dorsal horn neurones in the spinal cord region L1-L3 were made in rats anaesthetised with halothane in a gaseous mix of N2O and O2. Subcutaneous formalin (5%, 50 microliters) has previously been found to produce a prolonged distinct biphasic response of dorsal horn convergent neurones in the same preparation. The present study demonstrates that the second period of neuronal excitation which occurs at about 20 min and lasts for at least another 40 min, could be abolished by lignocaine (2%, 50 microliters) injected into the site of the formalin injection (n = 5). The inhibition of formalin-evoked activity lasted for about 10-20 min and was followed by complete recovery of the neuronal response. The same dose of i.v. lignocaine had no effect on the formalin-induced neuronal activity (n = 4). Profound inhibitions of the second phase were also produced by tactile segmental stimulation and noxious stimuli applied to widespread areas of the body (diffuse noxious inhibitory controls). These findings are discussed with regard to the peripheral and central consequences of prolonged noxious stimuli.

Animals↗

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inflammatory stimuli up-regulate secretion of the soluble GM-CSF receptor in human monocytes: evidence for ectodomain shedding of the cell surface GM-CSF receptor alpha subunit.

Soluble GM-CSF receptor alpha subunit (sGMRalpha) is a soluble isoform of the GMRalpha that is believed to arise exclusively through alternative splicing of the GMRalpha gene product. The sGMRalpha mRNA is expressed in a variety of tissues, but it is not clear which cells are capable of secreting the protein. We show here that normal human monocytes, but not lymphocytes, constitutively secrete sGMRalpha. Stimulation of monocytes with GM-CSF, LPS, PMA, or A23187 rapidly up-regulates the secretion of sGMRalpha in a dose-dependent manner, demonstrating that secretion is also regulated. To determine whether sGMRalpha arose exclusively through alternative splicing of the GMRalpha gene product, or whether it could also be generated through ectodomain shedding of GMRalpha, we engineered a murine pro-B cell line (Ba/F3) to express exclusively the cDNA for cell surface GMRalpha (Ba/F3.GMRalpha). The Ba/F3.GMRalpha cell line, but not the parental Ba/F3 cell line, constitutively shed a sGMRalpha-like protein that bound specifically to GM-CSF, was equivalent in size to recombinant alternatively spliced sGMRalpha (60 kDa), and was recognized specifically by a mAb raised against the ectodomain of GMRalpha. Furthermore, a broad-spectrum metalloprotease inhibitor (BB94) reduced constitutive and PMA-, A23187-, and LPS-induced secretion of sGMRalpha by monocytes, suggesting that shedding of GMRalpha by monocytes may be mediated in part through the activity of metalloproteases. Taken together, these observations demonstrate that sGMRalpha is constitutively secreted by monocytes, that GM-CSF and inflammatory mediators up-regulate sGMRalpha secretion, and that sGMRalpha arises not only through alternative splicing but also through ectodomain shedding of cell surface GMRalpha.

Alternative Splicing↗

Intracellular recording from a spider vibration receptor.

The present study introduces a new preparation of a spider vibration receptor that allows intracellular recording of responses to natural mechanical or electrical stimulation of the associated mechanoreceptor cells. The spider vibration receptor is a lyriform slit sense organ made up of 21 cuticular slits located on the distal end of the metatarsus of each walking leg. The organ is stimulated when the tarsus receives substrate vibrations, which it transmits to the organ's cuticular structures, reducing the displacement to about one tenth due to geometrical reasons. Current clamp recording was used to record action potentials generated by electrical or mechanical stimuli. Square pulse stimulation identified two groups of sensory cells, the first being single-spike cells which generated only one or two action potentials and the second being multi-spike cells which produced bursts of action potentials. When the more natural mechanical sinusoidal stimulation was applied, differences in adaptation rate between the two cell types remained. In agreement with prior extracellular recordings, both cell types showed a decrease in the threshold tarsus deflection with increasing stimulus frequency. Off-responses to mechanical stimuli have also been seen in the metatarsal organ for the first time.

Action Potentials↗

Pain threshold changes following acupuncture, measured with cutaneous argon laser and electrical tooth pulp stimulation, a comparative study.

1. The present study compared the argon laser technique for pain threshold measurements with the previously often used threshold measurements with electrical tooth pulp (TP) stimulation. 2. Conditioning stimuli with acupuncture was given since it previously has been shown to induce pain threshold changes. Acupuncture needles were inserted in the hands and arms and electrically stimulated. 3. The experiments were performed in a single blind fashion comparing pain threshold effects after either acupuncture or placebo. Pain threshold measurements with a method of limits were used with both electrical TP and the argon laser method. 4. In comparison to placebo the pain thresholds increased after acupuncture, both on the face and on the hand, with the argon laser method, while the TP thresholds were not influenced. No significant pain threshold change was detected with either the argon laser or the TP method following placebo treatment. 5. The results indicate that the argon laser used for sensory testing with a method of limits is a useful method for pain threshold measurements. The difference in pain threshold effects induced by acupuncture measured with the argon laser and the TP stimulation, are discussed and related to mechanisms that may differ between the two types of pain threshold measurements.

Acupuncture Therapy↗