Direct recording of somatosensory evoked potentials in the vicinity of the dorsal column nuclei in man: their generator mechanisms and contribution to the scalp far-field potentials

Somatosensory evoked potentials (SEPs) in the vicinity of the dorsal column nuclei in response to electrical stimulation of the median nerve (MN) and posterior tibial nerve (PTN) were studied by analyzing the wave forms, topographical distribution, effects of higher rates of stimulation and correlation with components of the scalp-recorded SEPs. Recordings were done on 4 patients with spasmodic torticollis during neurosurgical operations for microvascular decompression of the eleventh nerve. The dorsal column SEPs to MN stimulation (MN-SEPs) were characterized by a major negative wave (N1; 13 msec in mean latency), preceded by a small positivity (P1) and followed by a large positive wave (P2). Similar wave forms (P1′-N1′-P2′) were obtained with stimulation of PTN (PTN-SEPs), with a mean latency of N1′ being 28 msec. Maximal potentials of MN-SEPs and PTN-SEPs were located in the vicinity of the ipsilateral cuneate and gracile nuclei, respectively, at a level slightly caudal to the nuclei. The latencies of P1 and N1 increased progressively at more rostral cervical cord segments and medulla, but that of P2 did not. A higher rate of stimulation (16 Hz) caused no effects on P1 and N1, while it markedly attenuated the P2 component. These findings suggest that P1 and N1 of MN-SEPs, as well as P1′ and N1′ of PTN-SEPs, are generated by the dorsal column fibers, and P2 and P2′ are possibly of postsynaptic origin in the respective dorsal column nuclei.The peak latency of N1 recorded on the cuneate nucleus was identical with the scalp-recorded far-field potential of P13–14 in all patients, while no scalp components were found which corresponded to P2. These findings support the previous assumption that the scalp-recorded P13–14 is generated by the presynaptic activities of the dorsal column fibers at their terminals in the cuneate nucleus.     

Investigation of the mechanism of temperature sensitivity of the electroreceptors of ampullae of lorenzini

In experiments on Black Sea skates (Raja clavata), the potential of the receptor epithelium of the ampullae of Lorenzini and spike activity of single nerve fibers connected to them were investigated during electrical and temperature stimulation. Usually the potential within the canal was between 0 and –2 mV, and the input resistance of the ampulla 250–400 k. Heating of the region of the receptor epithelium was accompanied by a negative wave of potential, an increase in input resistance, and inhibition of spike activity. With worsening of the animal's condition the transepithelial potential became positive (up to +10 mV) but the input resistance of the ampulla during stimulation with a positive current was nonlinear in some cases: a regenerative spike of positive polarity appeared in the channel. During heating, the spike response was sometimes reversed in sign. It is suggested that fluctuations of the transepithelial potential and spike responses to temperature stimulation reflect changes in the potential difference on the basal membrane of the receptor cells, which is described by a relationship of the Nernst's or Goldman's equation type.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. I. M. Sechenov, Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of the USSR, Leningrad. Pacific Institute of Oceanology, Far Eastern Scientific Center, Academy of Sciences of the USSR, Vladivostok. Translated from Neirofiziologiya, Vol. 12, No. 1, pp. 67–74, January–February, 1980.     

Impulse propagation and muscle activation in long maximal voluntary contractions

With fatigue, force generation may be limited by several factors, including impaired impulse transmission and/or reduced motor drive. In 5-min isometric maximal voluntary contraction, no decline was seen in the peak amplitude of the tibialis anterior compound muscle mass action potential (M wave) either during or immediately after the voluntary effort, provided maximal nerve stimulation was retained. For first dorsal interosseous (FDI) muscle, M wave amplitudes declined by 19.4 +/- 1.6% during the first 2 min but did not change significantly thereafter, despite the continued force reduction (up to 94% in 5 min for both muscles). The duration of the FDI M waves increased (greater than 30%), suggesting that the small decline in amplitude was the result of increased dispersion between the responses of different motor units. Some subjects kept FDI maximally activated throughout, but when they used tibialis anterior, twitch occlusion and tetanic muscle stimulation showed that most subjects were usually only able to do so for the first 60 s and thereafter only during brief "extra efforts." Thus force loss during isometric voluntary contractions sustained at the highest intensities results mainly from failure of processes within the muscle fibers.     

Motor skill training and strength training are associated with different plastic changes in the central nervous system.

Changes in corticospinal excitability induced by 4 wk of heavy strength training or visuomotor skill learning were investigated in 24 healthy human subjects. Measurements of the input-output relation for biceps brachii motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation were obtained at rest and during voluntary contraction in the course of the training. The training paradigms induced specific changes in the motor performance capacity of the subjects. The strength training group increased maximal dynamic and isometric muscle strength by 31% (P < 0.001) and 12.5% (P = 0.045), respectively. The skill learning group improved skill performance significantly (P < 0.001). With one training bout, the only significant change in transcranial magnetic stimulation parameters was an increase in skill learning group maximal MEP level (MEP(max)) at rest (P = 0.02) for subjects performing skill training. With repeated skill training three times per week for 4 wk, MEP(max) increased and the minimal stimulation intensity required to elicit MEPs decreased significantly at rest and during contraction (P < 0.05). In contrast, MEP(max) and the slope of the input-output relation both decreased significantly at rest but not during contraction in the strength-trained subjects (P < or = 0.01). No significant changes were observed in a control group. A significant correlation between changes in neurophysiological parameters and motor performance was observed for skill learning but not strength training. The data show that increased corticospinal excitability may develop over several weeks of skill training and indicate that these changes may be of importance for task acquisition. Because strength training was not accompanied by similar changes, the data suggest that different adaptive changes are involved in neural adaptation to strength training.     

Comparison of human transcallosal responses evoked by magnetic coil and electrical stimulation

Human transcallosal responses (TCRs) were elicited by focal magnetic oil (MC) stimulation of homologous sites in contralateral frontal cortex and compared with those to focal anodic stimulation. With MC stimulation, the TCR consisted of an initially positive wave with an onset latency of 8.8–12.2 msec, a duration of 7–15 msec, and an amplitude which reached up to 20 μV, sometimes followed by a broad low amplitude negative wave. With anodic stimulation, a similar response was obtained in which the positive wave was similar in latency and maximum amplitude, but had a greater duration. With anodic stimulation, not only was the TCR threshold below that for contralateral movement, but it reached substantial size at intensities below motor threshold. With MC stimulation, contralateral arm movement and scalp corticomotor potentials were observed when the MC was displaced posteriorly towards the central sulcus. Unlike with anodic stimulation, the MC evoked TCR was usually not preceded by a prominent EMG potential from temporalis muscle and was not associated with subject discomfort.The TCR provides unique information concerning the functional integrity of callosal projection neurons, their axons and transsynaptic processes in recipient cortex. This information may prove useful in the evaluation of intrinsic cerebral mechanisms and in establishing cortical viability.     

Hemispheric asymetry of the evoked electrical activity of the cerebral cortex to letter and non-verbal stimuli]

Average evoked potentials (AEP) were recorded in practically healthy subjects to "meaningless" figures and letters, presented to different halves of the visual field. Analysis of the amplitudes of AEP late components to verbal and non-verbal stimuli reveals hemispheric asymmetry. A higher amplitude of the late positive evoked response (P300) to a "direct" stimulation both by verbal and non-verbal stimuli (in the contralateral field of vision) is recorded in the left hemisphere than in the right one. Similar stimulation of the right hemisphere does not reveal sucha difference. In the left hemisphere the P300 wave is of a clearly greater amplitude to a "direct" stimulation (contralateral visual field) than to an "indirect" one (ipsilateral visual field), regardless of the nature of the stimulus. No such difference is observed in the right hemisphere. The magnitude of the late negative wave (component N200) to non-verbal stimuli is greater in the right hemisphere both in response to "direct" and "indirect" stimulations. No intrahemispheric difference has been found in the amplitude of late evoked responses of the cerebral cortex to verbal and non-verbal stimuli.     

Agonist-selective, receptor-specific interaction of human P2Y receptors with beta-arrestin-1 and -2

Interaction of G-protein-coupled receptors with beta-arrestins is an important step in receptor desensitization and in triggering "alternative" signals. By means of confocal microscopy and fluorescence resonance energy transfer, we have investigated the internalization of the human P2Y receptors 1, 2, 4, 6, 11, and 12 and their interaction with beta-arrestin-1 and -2. Co-transfection of each individual P2Y receptor with beta-arrestin-1-GFP or beta-arrestin-2-YFP into HEK-293 cells and stimulation with the corresponding agonists resulted in a receptor-specific interaction pattern. The P2Y(1) receptor stimulated with ADP strongly translocated beta-arrestin-2-YFP, whereas only a slight translocation was observed for beta-arrestin-1-GFP. The P2Y(4) receptor exhibited equally strong translocation for beta-arrestin-1-GFP and beta-arrestin-2-YFP when stimulated with UTP. The P2Y(6), P2Y(11), and P2Y(12) receptor internalized only when GRK2 was additionally co-transfected, but beta-arrestin translocation was only visible for the P2Y(6) and P2Y(11) receptor. The P2Y(2) receptor showed a beta-arrestin translocation pattern that was dependent on the agonist used for stimulation. UTP translocated beta-arrestin-1-GFP and beta-arrestin-2-YFP equally well, whereas ATP translocated beta-arrestin-1-GFP to a much lower extent than beta-arrestin-2-YFP. The same agonist-dependent pattern was seen in fluorescence resonance energy transfer experiments between the fluorescently labeled P2Y(2) receptor and beta-arrestins. Thus, the P2Y(2) receptor would be classified as a class A receptor when stimulated with ATP or as a class B receptor when stimulated with UTP. The ligand-specific recruitment of beta-arrestins by ATP and UTP stimulation of P2Y(2) receptors was further found to result in differential stimulation of ERK phosphorylation. This suggests that the two different agonists induce distinct active states of this receptor that show differential interactions with beta-arrestins.     

Auditory brain-stem evoked potentials in cat after kainic acid induced neuronal loss. II. Cochlear nucleus

Auditory brain-stem potentials (ABRs) were studied in cats for up to 6 weeks after kainic acid had been injected unilaterally into the cochlear nucleus (CN) producing extensive neuronal destruction. The ABRcomponents were labeled by the polarity at the vertex (P, for positive) and their order of appearance (the arabic numerals 1,2, etc.). Component P1 can be further subdivided into 2 subcomponents, P1a and P1b. The assumed correspondence between the ABR components in cat and man is indicated by providing human Roman numeral designations in parentheses following the feline notation, e.g., P2 (III). To stimulation of the ear ipsilateral to the injection, the ABR changes consisted of a loss of components P2 (III) and P3 (IV), and an attenuation and prolongation of latency of components P4 (V) and P5 (VI). The sustained potential shift from which the components arose was not affected. Wave P1a (I) was also slightly but significantly attenuated compatible with changes of excitability of nerve VIII in the cochlea secondary to cochlear nucleus destruction. Unexpectedly, to stimulation of the ear contralateral to the injection side, waves P2 (III), P3 (IV), and P4 (V) were also attenuated and delayed in latency but to a lesser degree than to stimulation of the ear ipsilateral to the injection. Changes in binaural interaction of the ABR following cochlear nucleus lesions were similar to those produced in normal animals by introducing a temporal delay of the input to one ear. The results of the present set of studies using kainic acid to induce neuronla loss in auditory pathway when combined with prior lesion and recording experiments suggest that each of the components of the ABR requires the integrity of an anatomically diffuse system comprising a set of neurons, their axons, and the neurons on which they terminate. Disruption of any portion of the system will alter the amplitude and/or the latency of that component.     

Early scalp responses evoked by stimulation of the supraorbital nerve in man

In 25 healthy volunteers the supraorbital nerve was stimulated and evoked potentials were recorded. Leads were placed on the scalp and along the ipsilateral eyebrow-mastoid line and were either referred to a non-cephalic reference (on the neck, or Cv7) or linked to form bipolar derivations. As template wave form was chosen the one obtained from derivation Cz-Cv7, which had an initial triphasic component with negative (SW1a), positive (SW1b), negative (SW1c) polarity (mean latencies 0.63, 0.95 and 1.43 msec), followed by 2 negative waves (SW2 and SW3, mean latencies of 2.20 and 2.89 msec). A final positive wave could be observed in most cases (SP4, mean latency of 4.08 msec). The records collected from the various derivations showed that each component (SW1, SW2, SW3 and SP4) had a different behaviour, thus suggesting separate origins. SW1 would originate from a volley travelling from the point of stimulation towards the mastoid, probably across the ophthalmic branch of the trigeminal nerve. The subsequent components would be generated by deeply situated structures: double pulse stimulation suggests that SW1, SW2 and SW3 are generated before the first synapse, whereas SP4 is a postsynaptic event. A strong similarity exists between the components evoked by stimulation of the supraorbital and the infraorbital nerves. Local anaesthetic block of the frontal nerve on the stimulated side and monitoring of the EMG activity of m. orbicularis oculi and m. frontalis ruled out any muscle contamination of the responses described in this paper.     

Auditory brain-stem evoked potentials in cat after kainic acid induced neuronal loss. I. Superior olivary complex

Auditory brain-stem potentials (ABRs) were studied in cats for up to 45 days after kainic acid had been injected unilaterally or bilaterally into the superior olivary complex (SOC) to produce neuronal destruction while sparing fibers of passage and the terminals of axons of extrinsic origin connecting to SOC neurons. The components of the ABR in cat were labeled by their polarity at the vertex (P, for positive) and their order of appearance (the arabic numerals 1, 2, etc.). Component P1 can be further subdivided into 2 subcomponents labeled P1a and P1b. The correspondences we have assumed between the ABR components in cat and man are indicated by providing a Roman numeral designation for the human component in parentheses following the feline notation, e.g., P4 (V). With bilateral SOC destruction, there was a significant and marked attenuation of waves P2 (III), P3 (IV), P4 (V), P5 (VI), and the sustained potential shift (SPS) amounting to as much as 80% of preoperative values. Following unilateral SOC destruction the attenuation of many of these same ABR components, in response to stimulation of either ear, was up to 50%. No component of the ABR was totally abolished even when the SOC was lesioned 100% bilaterally. In unilaterally lesioned cats with extensive neuronal loss (> 75%) the latencies of the components beginnign at P3 (IV) were delayed to stimulation of the ear ipsilateral to the injection site but not to stimulation of the ear contralateral to the injection. Binaural interaction components of the ABR were affected in proportion to the attenuation of the ABR. These results are compatible with multiple brain regions contributing to the generation of the components of the ABR beginning with P2 (III) and that components P3 (IV), P4 (V), and P5 (VI) and the sustained potential shift depend particularly on the integrity of the neurons of the SOC bilaterally. The neurons of the lateral subdivision (LSO) and the medial nucleus of the trapezoid body (MNTB) of the SOC have a major role in generating waves P3 (IV) and P4 (V).     

Gonadotropin-releasing hormone effects on placental hormones during gestation: II. Progesterone, estrone, estradiol and estriol

The release of progesterone (P), estrone (E1), estradiol (E2) and estriol (E3) from human placental tissue in vitro was found to be related to the gestational age of the placenta. The basal release of P, E1 and E2 on Day 1 of culture was highest from placentas of early gestation (9-13 wk). The release of P then declined, reaching a nadir by 15 wk, and continued at that level. The release of E1 and E2, reached a nadir at 17 weeks, and then again increased by term. In contrast, the basal release of E3 increased with increasing gestational age of the placenta. Thus, it appears that differing factors may influence placental P, E1, E2 and E3 production. In addition, the effect of synthetic gonadotropin-releasing hormone (GnRH) on these hormonal releases was studied. The stimulation of P by GnRH was greatest in placentas of 16 and 17 wk of gestation after extended culture when the basal release of P had declined. As much as a 240-fold increase was observed on the eighth day of culture. A large stimulation of P (32-fold) was also observed in the term placental cultures. A stimulation of E1 and E2 by GnRH was observed during the initial days of culture and in mid-gestational placental cultures (16-17 wk). A stimulation of E2 only was also observed at 13-15 wk and at term. A stimulation of E3 was observed in certain individual placentas. A correlation of the P and human chorionic gonadotropin (hCG) response to GnRH stimulation was noted, as well as an inverse relation of estrogens and hCG stimulation by GnRH. These data demonstrate that steroidogenic competence of the placenta differs with gestational age and that GnRH can influence steroid release. The degree and pattern of response to GnRH varied with the gestational age of the placenta and its endocrine milieu.     

Pulmonary rapidly adapting receptors reflexly increase airway secretion in dogs

We attempted to determine whether stimulation of pulmonary rapidly adapting receptors (RARs) increase tracheal submucosal gland secretion in anesthetized open-chest dogs. Electroneurographic studies of pulmonary afferents established that RARs but not lung C-fibers were stimulated by intermittent lung collapse during deflation, collapse being produced by removing positive end-expiratory pressure (PEEP, 4 cmH2O) or by applying negative end-expiratory pressure (NEEP, -4 cmH2O). We measured tracheal secretion by the "hillocks" method. Removing PEEP or applying NEEP for 1 min increased secretion from a base line of 6.0 +/- 1.1 to 11.8 +/- 1.7 and 22.0 +/- 2.8 hillocks.cm-2.min-1, respectively (P less than 0.005). After PEEP was restored, dynamic lung compliance (Cdyn) was 37% below control, and secretion remained elevated (P less than 0.05). A decrease in Cdyn stimulates RARs but not other pulmonary afferents. Hyperinflation, which restored Cdyn and RAR activity to control, returned secretion rate to base line. Secretory responses to lung collapse were abolished by vagal cooling (6 degrees C), by pulmonary vagal section, or by atropine. We conclude that RAR stimulation reflexly increases airway secretion. We cannot exclude the possibility that reduced input from slowly adapting stretch receptors contributed to the secretory response.     

Mechanisms of subcellular cytosolic Ca2+ signaling evoked by stimulation of the vasopressin V1a receptor.

Receptor activation may result in distinct subcellular patterns of Ca2+ release. To define the subcellular distribution of Ca2+i signals induced by stimulation of the vasopressin V1a receptor, we expressed the cloned receptor in Xenopus oocytes. Oocytes were then loaded with fluo-3 and observed using confocal microscopy. Vasopressin induced a single concentric wave of increased Ca2+ that radiated inward from the plasma membrane. With submaximal stimulation, however, regions of the Ca2+ wave spontaneously reorganized into repetitive (oscillatory) waves. Focal stimulation of a small part of the plasma membrane resulted in a Ca2+ wave which began at the point of stimulation, radiated toward the center of the cell, then reorganized into multiple foci of repetitive, colliding waves and spirals of increased Ca2+i. The pattern of Ca2+ signaling induced by focal or global stimulation was not altered in Ca(2+)-free medium, although signals did not propagate as fast. Finally, subcellular Ca2+ signaling patterns induced by vasopressin were inhibited by caffeine, while neither vasopressin nor microinjection of inositol trisphosphate blocked caffeine-induced increases in cytosolic Ca2+. Thus, stimulation of the V1a receptor in this cell system induces a complex pattern of Ca2+ signaling which is influenced by (1) the magnitude of the stimulus, (2) the distribution of the surface receptors that are stimulated, and (3) mobilization of Ca2+ from the extracellular space as well as from two distinct endogenous Ca2+ pools. The manner in which a single type of receptor is activated may represent an important potential mechanism for subcellular Ca2+i signaling.     

Pretecto-tectal influences

(1)From the dorsal surface of the toad (Bufo b. spinosus, B. marinus) optic tectum (OT), field potentials (FP) were recorded at 9 reference sites in response to electrical stimulation of the optic nerve (ON). The FP showed 4 main components, besides an initial deflection attributed to axonal potentials: two negative waves N1, N2 (attributed to postsynaptic excitatory processes) and two positive waves P2, P3 (attributed to postsynaptic inhibitory processes). The responses across the reference sites were rather similar in different individuals. (2) Electrical stimulation of an area in the ipsilateral pretectal lateral posterodorsal and posterior (Lpd/P) thalamic region evoked tectal FPs showing mainly a negative and a positive wave. Regarding wave amplitudes, the FPs displayed disproportionalities across the reference sites. (3) Electrical stimulation of the contralateral Lpd/P evoked mainly a positive wave in the tectal FP whose disproportionality corresponded roughly to the one obtained to ipsilateral Lpd/P stimulation. (4) The inital negative wave of the tectal FP in response to ON stimulation was nearly abolished, if Lpd/P stimulation preceded ON stimulation at a delay of 17–25 ms. (5) Since FPs showed adaptation to repetitive stimulation, various experiments were carried out to distinguish adaptation phenomena from effects of neuronal interactions between Lpd/P and OT. (6) The results provide evidence that ON- and Lpd/P-mediated inputs interact in superficial tectal layers, whereby pretectotectal input suppresses retinotectal excitatory information transfer. Input of Lpd/P to the contralateral superficial OT suggests postsynaptic inhibition. This study provides no information about pretectal inputs to deeper tectal layers, which anatomically are known to exist.Abbreviations A-I recording sites from the dorsal tectal surface - D _t delay between Lpd/P and ON stimulation - EPSP IPSP excitatory and inhibitory postsynaptic potentials, respectively - FP field potential - L latency of FP waves - ON optic nerve - OT optic tectum - Lpd/P lateral posterodorsal and posterior pretectal thalamic region - Lpv lateral posteroventral pretectal thalamic nucleus - N, P negative and positive waves of FPs, respectively - PRE presynaptic axonal input - TH pretectal thalamic neurons     

Neural generators of the somatosensory evoked potentials: Recording from the cuneate nucleus in man and monkeys

The neural generators of the somatosensory evoked potentials (SEPs) elicited by electrical stimulation of the median nerve were studied in man and in rhesus monkeys. Recordings from the cuneate nucleus were compared to the far-field potentials recorded from electrodes placed on the scalp. It was found that the shape of the response from the surface of the human cuneate nucleus to stimulation of the median nerve is similar to that of the response recorded more caudally in the dorsal column, i.e., an initially small positivity followed by a negative wave that is in turn followed by a slow positive wave. The beginning of the negative wave coincides in time with the N14 peak in the SEP recorded from the scalp, and its latency is 13 msec. The response from the cuneate nucleus in the rhesus monkey has a similar shape and its negative peak appears with the same latency as the positive peak in the vertex response that has a latency of 4.5 msec; the peak negativity has a latency of about 6 msec and thus coincides with P6.2 in the vertex recording. Depth recordings from the cuneate nucleus and antidromic stimulation of the dorsal column fibers in the monkey provide evidence that the early components of the response from the surface of the cuneate nucleus are generated by the dorsal column fibers that terminate in the nucleus.The results support the hypothesis that the P14 peak in the human SEP is generated by the termination of the dorsal column fibers and that the cuneate nucleus itself contributes little to the far-field potentials.     

Spatial distribution of hippocampal response to tooth pulp stimulation and acoustic stimulation

Evoked potentials (EP) and neuronal responses produced by tooth pulp stimulation and a clicking sound were recorded at different hippocampal sites using microelectrodes in unrestrained rats. Spatial distribution of EP was found to be the same for both types of stimulation. Averaged EP consisted of a high amplitude negative preceded by a low-amplitude positive component (N₁ and P₁, respectively). Latency of the N₁ wave reached its minimum (of 27 msec) at the middle third of the molecular layer of the dentate gyrus and the outer portion of the CA₃ apical dendrites. Latency of N₁ was considerably longer in the stratum radiatum layer of the CA₁. Laminar profiles of the amplitude of the N₁ componenent of EP produced in the dentate gyrus and the CA₃ by tooth pulp stimulation resemble those observed during perforant path stimulation; in the CA₁ they are similar to those evoked by stimulating the Schaffer collaterals. Maximum amplitude of the P₁ component was observed above the pyramidal layer of the CA₁ and the hilus. Neuronal discharge pattern changed in all hippocampal regions under the effects of both tooth pulp stimulation and the clicking sound. It is deduced that information can reach the hippocampus by two routes: via a "fast" (inhibitory) pathway through the fimbria and the fornix and a slower (excitatory) path through the entorhinal cortex.P. Flexig Institute for Brain Research, Karl Marx University, Leipzig, DR. Institute of Physiology, Pecs University Medical School, Pecs, Hungary. Translated from Neirofiziologiya, Vol. 19, No. 1, pp. 36–46, January–February, 1987.     

Cervical and scalp recorded short latency somatosensory evoked potentials in response to epidural spinal cord stimulation in patients with peripheral vascular disease

Somatosensory evoked potential (SEP) studies were performed in 14 patients with peripheral vascular disease who received epidural spinal cord stimulation (SCS) for chronic pain relief of the lower limbs. Signals were amplified and filtered between 20–2000 Hz and 200–2000 Hz to better identify activities in the high frequency range. In 7 patients bit-colour maps were also computed. In all the patients a homogeneous short-latency scalp evoked potential with a prevalent diphasic shape (P1-N1) was recorded. In all our scalp records, even with the wide bandpass, small short-latency positive deflections were observed on the descending front of the first major positive wave and they were better defined as a series of up to 6 wavelets, preceding the major negative scalp wave in the tracings filtered through the narrow bandpass. They appeared in an interval ranging from 5.5 to 15.6 msec. Bit-colour maps showed consistent positive fields, with a maximum at the vertex, starting mainly at about 5.5 msec; in 3 patients, a prominent positivity between 8.5 and 10.5 msec was recorded followed by smaller components preceding the major positive-negative (Pl-Nl) complex. More synchronous volleys during direct SCS produced clear short-latency SEPs. Although they were of larger amplitude, we regarded them as corresponding to those described by previous authors obtained by stimulation of nerves of the lower limbs, and probably arising from subcortical structures.     

Non-painful and painful stimulation of human skin and muscle: analysis of cerebral evoked potentials

The present study compared the cerebral processing of non-painful and painful cutaneous CO₂ laser stimulation and intramuscular electrical stimulation in 11 normal subjects. The overall wave form morphology of the long-latency evoked potentials (EPs) at the central vertex (Cz) was identical and surface topographic mappings of the 21-channel recordings showed similar distributions, suggesting involvement of common neural generators. However, the EPs caused by intramuscular stimulation differed from cutaneous stimulation in several distinct ways. First, the latency of the major positive and negative components were significantly shorter with intramuscular stimulation (N 128–145 ms; P 274–298 ms) compared to cutaneous stimulation (N 235–286 ms; P 371–383 ms) (P<0.001). Second, the peak-to-peak amplitude and root-mean-square values of intramuscular EPs recorded at Cz showed a ceiling effect in the painful range, whereas the laser EPs continued to increase in this range. Third, painful intramuscular, but not non-painful, stimulation caused a frontal activity which not was observed with cutaneous laser stimulation at any intensity. Conduction velocity measurements indicated activation of nociceptive A-delta afferents with cutaneous laser stimulation (10.2±0.2 m/s) and activation of a mixed nerve fiber population with intramuscular electrical stimulation (65.8±25.8 m/s). Differences between laser and intramuscular EPs may be due to different types and origins of activated afferent fibers. Laser EPs can be used specifically to assess cutaneous A-delta fiber function, whereas intramuscular EPs reflect the cerebral processing of a mixed afferent input from muscle tissue.     

Specific immunotherapy with vaccinia oncolysates

Summary Short- and long-term effects of IV administration of human fibroblast interferon (HFIF) on natural cytotoxicity was studied in patients with HBsAg-positive chronic active hepatitis. Short-term kinetics demonstrated a transient decrease of natural cytotoxicity, when measured 2 or 4 h after IV administration of HFIF (1–10×10⁶ U/injection). Twenty-four hours after the initial injection of HFIF natural cytotoxicity was increased to 196%–282% of pretreatment values. The kinetics of NK activity during chronic stimulation with HFIF revealed the following features: (a) The highest relative increase was seen during the initial phase of HFIF application; (b) enhanced NK activity could be maintained for 2–4 weeks of therapy; (c) at a plateau of high activity short-term increases were much less pronounced; (d) in all patients monitored so far over a period of several weeks a gradual decrease of augmented NK activity has been observed despite continued administration of high doses of HFIF.These findings indicate that in vivo administration of HFIF results in an augmentation of NK activity in man. Prolonged treatment with HFIF seems to exhaust the NK cell system. Monitoring of natural cytotoxicity may be of critical importance for the determination of an administration schedule of interferon for future therapy.     

Expression pattern of glypican-3 (GPC3) during human embryonic and fetal development

Glypicans represent a family of cell surface proteoglycans. Loss-of-function mutations in the human glypican-3 (GPC3) gene results in the Simpson-Golabi-Behmel syndrome, characterized by severe malformations and pre- and postnatal overgrowth. Because the expression of GPC3 during human embryonic and fetal periods remains largely unknown, we investigated by immunohistochemistry its pattern of expression during four periods of human development covering the embryonic period (P1) from 5 to 8 weeks of development, and the fetal periods (P2, P3 and P4) from 9 to 28 weeks of development. Hepatocytes were homogeneously positive for GPC3 during the four periods while pancreatic acini and ducts showed a rather high staining only during P1. GPC3 was also detected in several kidney structures and in the genital system where the sex cords were weakly positive in P1 and P2. In later developmental stages the male's genital system expressed GPC3 while the female's did not. While the mesenchyme in the limbs showed positive staining in P1, GPC3 was not detected during the following stages. The mesenchymal tissue localized between the most caudal vertebrae was also positive in P1. A strong GPC3 signal was observed in neurons of the spinal cord and dorsal root ganglia in P2 and P3, while the brain was negative. In sum our studies revealed that GPC3 expression is highly tissue- and stage-specific during human development. The expression pattern of GPC3 is consistent with the abnormalities seen in the Simpson-Golabi-Behmel syndrome.