Sensory-evoked potentials: measures of neurotoxicity.
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Animals↗
Biomedical subjects
W K Boyes
Publications and source records attributed to W K Boyes.
Alterations in rat flash and pattern reversal evoked potentials after acute or repeated administration of carbon disulfide (CS2).
Because solvents may selectively alter portions of visual evoked potentials, we examined the effects of carbon disulfide (CS2) on flash (FEPs) and pattern reversal (PREPs) evoked potentials. Long-Evans rats were administered ip carbon disulfide either acutely or for 30 days. FEPs or PREPs were recorded prior to and 1, 2, 4, 8, or 24 hr after a single dose of CS2 (0, 100, 200, 400, or 500 mg/kg). Flash evoked potentials were also recorded 1, 2, 6, and 24 hr after the last of 30 doses of 200 mg CS2/kg/day. Acute exposure to CS2 consistently decreased the amplitude of FEP peak N160 at 1 hr, depressed peak N30 amplitude over 2-4 hr, and increased the latency of peaks P21, N30, P46, N56, and N160 for up to 4 hr after treatment. Carbon disulfide decreased the amplitude of PREP peaks P65, N83, P88, and N122 4 hr after treatment. Colonic temperature was depressed up to 8 hr after treatment. Administration of 200 mg CS2/kg/day decreased the amplitude of FEP peak N30 and increased the latencies of peaks P21, N30, P46, N56, and N160 up to 24 hr after the last dose. The differential effects of CS2 on portions of FEPs indicate that FEP peaks can be independently modulated. Changes in PREPs were temporally correlated with alterations in early FEP peaks, but FEP peak N160 was depressed at an earlier time point. Repeated CS2 exposure affected FEPs at lower doses and for a longer time than an acute exposure, similar to the reported greater severity of neurological disturbances following repeated CS2 exposures in humans.
Animals↗
Rat flash-evoked potential peak N160 amplitude: modulation by relative flash intensity.
The flash-evoked potential (FEP) of rats has a large negative peak (N160) approximately 160 ms following stimulation. This peak has been reported to be modulated by the subject's state of behavioral arousal and influenced by several test parameters. These experiments examined the influences of repeated testing, the number of stimuli/session, interactions of ambient illumination and flash intensity, and the effect of pupillary dilation on the development and amplitude of peak N160. The amplitude of peak N160 increased with daily testing and reached an asymptotic amplitude by about day 10. This amplitude was affected by the intensity of the flash stimulus relative to the ambient illumination (RFI) and appeared to reach a "ceiling" amplitude at greater than 50 dB RFI. The number of stimuli/session and dilation of the subject's pupils did not have a large influence on the growth or asymptotic level of peak N160 amplitude. The data are consistent with the hypothesis that the growth of peak N160 may represent a sensitization-like phenomenon.
Animals↗
The effects of 2,4-dithiobiuret on sensory and motor function.
2,4-Dithiobiuret (DTB) exposure causes a delayed onset muscle weakness in rats that has been attributed to depressed neuromuscular transmission. The present study compares the effects of DTB on both sensory and motor function in rats. Adult male Long-Evans hooded rats were exposed to saline, 0.25, 0.5, or 1.0 mg/kg/day DTB, ip, for 5 consecutive days (Days 1-5). Body weights were monitored throughout the experiment. Motor activity was measured for 1 hr in figure-eight mazes on Days 0, 6, 13, and 27. Forelimb and hindlimb grip strength were assessed on Days 6, 13, and 27. Auditory thresholds were determined for 5- and 40-kHz tones using reflex modification of the startle response on Days 0, 7, 14, and 28. Visual function was examined on Day 6 in animals exposed at 0.5 mg/kg/day using flash- and pattern-elicited visual evoked potentials (FEPs and PEPs, respectively). Thermal sensitivity was measured using the hot plate procedure. All motor endpoints were decreased in a dosage- and time-dependent manner; the higher the dosage the longer the effects lasted. There were no effects on any measure of sensory function with the exception of peak N2 of the FEP. Both the amplitude and latency of FEP N2 were altered by DTB exposure. Decreases in body weight were maximal on Day 9 at 1.0 mg/kg/day (20% from control), but recovered by Day 22. Motor activity was suppressed on Day 6 only, whereas grip strength measures were decreased on both Days 6 and 13. Auditory thresholds were not significantly altered; however, baseline startle amplitude was decreased at the highest dosage on Days 7 and 14, but recovered by Day 28. Hot plate latencies were not altered by DTB treatment. These data demonstrate that DTB produces a reversible impairment of motor function, without altering auditory, thermal, or pattern visual function. FEP N2, which is thought to arise from activity generated in the superficial layers of visual cortex, was diminished by DTB treatment, indicating that DTB can alter the function of the CNS, although effects on the motor system are more pronounced.
Animals↗
The comparability of rat and human visual-evoked potentials.
A series of experiments addressed the issue of comparability among neurological processes in pigmented rat and human visual systems. In the first set of experiments, transient visual-evoked potentials (VEPs) were elicited by the onset of sine-wave gratings of various spatial frequencies. The spatial frequency-response profiles of the first positive and immediately succeeding negative components differed from one another, but were similar in the two species. In addition, amplitude of the negative, but not the positive, component was strongly attenuated in both species following stationary pattern adaptation. In the second set of experiments, steady-state VEPs were elicited by the onset and offset of the gratings. The spatial frequency profiles of the 1F (response amplitude at the frequency of stimulus onset-offset) and 2F response components differed from one another, but were similar in both species. The final set of experiments indicated that diazepam, a GABA agonist, reduced amplitude of 2F, but not 1F, in both species. These results suggested that at least some functional subsystems mediating spatial vision in humans may have qualitatively similar counterparts in rats.
Adaptation, Ocular↗
Quantitative methods for cross-species mapping (CSM).
Cross-species extrapolation will be defined as prediction from one species to another without empirical vetification. Cross-species mapping (CSM) is the same except empirical vetification is performed. CSM may be viewed as validation of methods for extrapolation. Algorithms for CSM may originate from theory, from empirical observations or a combination of the two. Regardless of their origins, CSM algorithms must be explicated and confidence intervals given around their predictions. This paper offers a quantitative method for constructing CSM equations which is useful in evaluation of the CSM and as an aid in the design of new experiments in CSM and extrapolation. The method requires fitting mathematical models for the physiological or behavioral phenomena to be mapped across species. A CSM equation can then be derived from the models in each species and approximate confidence limits may be obtained for predictions from the equation. The method is useful even when the models in the two species differ in form, implying differences in physiology or behavioral principles between species. The method proposed has a number of remaining uncertainties and possible problems.
Animals↗
An alpha 2-adrenergic mode of action of chlordimeform on rat visual function.
The hypothesis that chlordimeform increased the amplitude of components N1P1 and P1N3 in rat pattern-reversal visual evoked potentials through actions on alpha 2-adrenergic receptors was tested with two sets of experiments. First, rats received single injections of either vehicle, an alpha 2-adrenergic antagonist yohimbine (0.1, 0.5, or 2.0 mg/kg), or an alpha 2-adrenergic agonist clonidine (0.05, 0.1, or 0.5 mg/kg). Yohimbine alone had no effect on pattern-reversal evoked potential amplitude. Clonidine treatment produced a dosage related increase in amplitude of both components similar to that produced by chlordimeform (W.K. Boyes and R.S. Dyer, 1984, Brain Res. Bull., 10, 817-823). Second, rats were given double injections of either vehicle or yohimbine (0.05, 0.5, 2.0, or 5.0 mg/kg) followed by either vehicle, clonidine (0.1 or 0.2 mg/kg) or chlordimeform (10, 20, or 40 mg/kg). Yohimbine pretreatment attenuated the effects of subsequent treatment with either clonidine or chlordimeform. These results support the hypothesis that chlordimeform alters rat pattern-reversal evoked potentials through actions as a central nervous system alpha 2-adrenergic agonist.
Amidines↗
Temperature-dependent changes in visual evoked potentials of rats.
The effects of alterations in body temperature on flash and pattern reversal evoked potentials (FEPs and PREPs) were examined in hooded rats whose thermoregulatory capacity was compromised with lesions of the preoptic/anterior hypothalamic area and/or cold restraint. Body temperature, measured with a rectal thermometer, was manipulated via exposure to different ambient temperatures. To describe the data, a model was used in which both linear and quadratic relationships could be estimated. PREP amplitudes were not significantly influenced by body temperature over the range of 27-42 degrees C, although in one experiment FEP amplitudes did show a linear decline as temperatures fell below approximately 30 degrees C. Both FEP and PREP latencies were strongly influenced by temperature and became progressively longer as body temperature was lowered. The non-linear component affecting latencies became more prominent as body temperature decreased. These data demonstrate the temperature dependence of FEP and PREP latencies independent of anesthetic or other drugs.
Animals↗
Morphometric and electrophysiological evidence for a diameter-based rate of degeneration in the optic nerve of the rat.
The diameter-based rate of degeneration in the rat's optic nerve was examined using coordinated morphological and electrophysiological techniques. Long-Evans, male rats were implanted with indwelling stimulating electrodes in the optic chiasm and recording electrodes in the stratum opticum of the superior colliculus. After 1 week, unilateral enucleation was performed with the unoperated side serving as the control. Electrically evoked recordings, obtained on the day of enucleation (D0), displayed three distinct peaks, Pre, N1 and P3, with peak latencies of 1.22, 2.22, and 4.04 ms, respectively. In a parallel set of rats, morphological analysis of the optic nerve over D1-7 was performed. Electron micrographs were taken of cross sections of the entire optic nerve from both the enucleated and unoperated (i.e., control) side. Computer-linked morphometric analysis of the ultrastructurally normal axons from each nerve was assembled in three-dimensional, diameter-based histograms at each time point. The control population consisted of axons with diameters ranging from less than 0.5-5.0 microns with a modal peak of 1.5 micron and a well developed tail in the 3.5-5.0 microns range. By D1,2, a selective loss of large diameter (greater than 3.5 microns) axons occurred in the optic nerve, with medium diameter (2.0-3.5 microns) axons degenerating at D4 and smaller diameter populations (less than 2.0 microns) persisting until later time points (D5-7). A linear regression analysis showed an exponential rate of degeneration which was a direct function of axonal diameter. In summary, this study demonstrates that the fiber population of the optic nerve is separable electrophysiologically and by its rate of degeneration, with larger diameter fibers degenerating faster in response to transection.
Analysis of Variance↗
Electrophysiological and morphological evidence for a diameter-based innervation pattern of the superior colliculus.
Neurophysiological and morphological techniques were used to describe changes in the optic tract and superior colliculus (SC) in response to unilateral enucleation. Long-Evans, male (greater than 250 g) rats were implanted with chronic bipolar stimulating electrodes located in the optic chiasm and a recording electrode located below the stratum griseum superficiale (SGS) and referenced to a skull screw electrode. In rats with satisfactory electrode placements (n = 15), peaks corresponding to rapidly conducting presynaptic activity (Pre), rapidly conducting postsynaptic activity (N1), and slowly conducting postsynaptic activity (P3) were identified according to peak latency, polarity, stimulation threshold, and resistance to 100-Hz stimulation. These peaks diminished differentially over a 7 day (D1-7) postenucleation period. Those peaks reflecting rapidly conducting axons (i.e., Pre, N1) decayed by D2, whereas those reflecting slowly conducting axons (i.e., P3) persisted until D4 and decayed completely by D7. In a separate set of enucleated rats (n = 25), the progression of degeneration in the SC was outlined morphologically from D1-7 using both light and electron microscopy. Light microscopy of semithin epoxy sections indicated that degenerative changes, consisting largely of swollen axons and myelin debris, appeared first in the upper stratum opticum (SO) and lower SGS on D1,2, progressed upward throughout the middle SGS by D4, and finally involved the entire SGS and lower stratum zonale (SZ) by D5-7. Electron microscopy, however, indicated that although degenerated terminals were seen in the lower SGS, at (D1,2), the majority of degenerated synapses were restricted to the upper SGS at the later time points. Coupled with the electrophysiological data, these observations indicate that within the SGS, early degenerating, large diameter optic nerve fibers terminate below slower degenerating, smaller diameter fibers.
Animals↗
Focal lesions of visual cortex--effects on visual evoked potentials in rats.
Focal lesions were placed in the visual cortex of Long-Evans hooded rats, immediately below skull screw recording electrodes. Lesions were produced by heat, and extended an average depth of about 0.9 mm below the cortical surface. Evoked potentials recorded from the electrode overlying the cortical lesion were compared with simultaneously recorded potentials from a contralateral homotopic site. The effects of the lesion were selective. Flash-evoked potential peaks P1, P2, and N2 were depressed by the lesion, and peaks N1 and P3 were augmented; peak N3 was unaffected. Pattern reversal evoked potential peak N3 was depressed by the lesion, and peaks N1 and P2 were made more distinct. The results emphasized that different peaks have different generators, and suggest in particular that flash-evoked potential peaks P1 and N2, and peak N3 of the pattern reversal-evoked potential require the superficial layers of the cortex.
Animals↗
Investigations of amitraz neurotoxicity in rats. I. Effects on operant performance.
Amitraz (AMZ) is a formamidine pesticide which is often compared to chlordimeform (CDM). The effects of AMZ (6.25-75 mg/kg) and CDM (5-20 mg/kg) on the schedule-controlled performance of rats were examined using a multiple fixed-ratio (FR) 10 fixed-interval (FI) 300-sec schedule of milk reinforcement. Following dose-effect determinations, rats received three daily doses of AMZ (50 mg/kg). Low to intermediate doses of AMZ (6.25-25 mg/kg), administered 20 min presession, significantly decreased FI responding but not FR responding. In contrast, CDM appeared to decrease responding similarly under both components. Both compounds disrupted the temporal pattern of responding within the interval; AMZ had only a moderate influence at all effective doses but CDM produced a marked dose-dependent disruption of temporal response patterning. The effects of the high doses of AMZ (50-75 mg/kg) were more pronounced 24 hr after dosing, whereas the rats had recovered from lower doses at this time. Performance was progressively disrupted and the rats' health rapidly deteriorated during the course of three daily injections of AMZ (50 mg/kg). Operant performance recovered more quickly than did the general health of the rats. Thus AMZ produced effects of multiple-schedule performance that were distinct from the effects of CDM. Moreover, the signs of intoxication and the effects on schedule-controlled behavior following a high dose (50 mg/kg) were augmented and persistent with short-term repeated administration.
Animals↗
Investigations of amitraz neurotoxicity in rats. II. Effects on visual evoked potentials.
As a part of a series of studies investigating the possible neurotoxicity of amitraz (AMZ), a formamidine pesticide, visual evoked potentials were recorded from Long-Evans rats following acute and short-term repeated exposures to AMZ. The first of three experiments examined the relationship between a single ip injection of AMZ (0, 50, and 100 mg/kg) and the latency and peak-to-peak amplitude of pattern-reversal (PREP) and flash-evoked potentials (FEP). The effects of another formamidine, chlordimeform (CDM; 40 mg/kg), were also studied for comparison purposes. Two hours after treatment, AMZ exposure produced large, dose-related increases in PREP amplitudes. Exposure to CDM produced similar changes. Neither compound changed FEP amplitudes. Body temperatures were reduced and evoked potential peak latencies were increased by both compounds. The latency increases were probably a secondary consequence of hypothermia. In the second experiment, PREPs were recorded before and 2, 24, 48, and 72 hr after treatment with AMZ (100 mg/kg). The time course of changes was biphasic in nature, with increases in amplitudes (N1P1, P1N2, and N2P3) 2 hr after treatment followed by subsequent depression in amplitude (P2N3) at 48 hr. Recovery occurred by 72 hr after treatment. The third experiment examined the effects of three daily treatments with either vehicle or 50 or 100 mg/kg AMZ. Body weights and body temperatures showed dose-related reductions which progressed with each additional treatment and recovered partially by 6 days after cessation of treatment. The PREPs of AMZ-treated rats agains showed biphasic changes, with N1P1 and P1N2 amplitudes significantly increased on each day of treatment and 1-2 days following the third treatment. Amplitude P2N3 showed an initial increase on the first 2 days of treatment, followed by subsequent, progressive amplitude reductions. In summary, AMZ produced two phases of change in visual evoked potentials. The first phase was characterized by large increases in PREP amplitudes without increasing FEP amplitudes in the same rats. The second phase was characterized by suppression of PREP P2N3 amplitude. Short-term repeated exposure produced signs of accumulating intoxication including progressive loss of body weight, lowered body temperature, and prolonged duration of evoked potential changes.
Animals↗
Surface distribution of flash-evoked and pattern reversal-evoked potentials in hooded rats.
Simultaneous recording from 21 electrode sites in a 4 X 4 mm area over the posterior cortex was used to determine the surface distribution of all major peaks which constitute flash-evoked potentials (FEPs) and pattern reversal evoked-potentials (PREPs) in hooded rats. Topographical maps were constructed with respect to Bregma and midline reference points. The data indicate that not all of the peaks which constitute either evoked potential have their greatest amplitude within the classically defined primary visual cortex. Further, since the FEPs were produced by uniform stimulation, the data suggest that surface regions of the rat visual cortex differ in ways other than simply the portion of the visual field from which information is received.
Animals↗
Chlordimeform produces contrast-dependent changes in visual evoked potentials of hooded rats.
Previous experiments found that acute exposure to the insecticide/acaricide, chlordimeform (CDM), produced large increases in the amplitude of pattern reversal evoked potentials (PREPs) without changing the amplitude of flash evoked potentials (FEPs) in the same rats (W. K. Boyes and R. S. Dyer, Exp. Neurol. 86: 434-447, 1984). Current work investigated the influence of physical characteristics of the evoking stimuli on the action of CDM. Adult male Long-Evans rats with epidural visual cortex electrodes were used. In experiment 1, PREPs were elicited with alternating gratings having equal contrast (99%) and a square wave spatial luminance profile at several spatial frequencies. Rats treated 1 h previously with 40 mg/kg CDM had increased PREP amplitudes at 0.1, 0.2, and 0.4 cycles per degree (cpd), but not at 0.8 cpd. No changes were found after 5 mg/kg CDM. In experiment 2, PREPs were elicited with gratings oriented at 0 degrees (horizontal), 45 degrees, 90 degrees, or 135 degrees. Treatment with 40 mg/kg CDM increased PREP amplitudes and latencies regardless of orientation. In experiment 3, FEPs elicited with strobe flashes spanning four log units of intensity showed a small but significant CDM dose X intensity interaction on P2N2 peak-to-peak amplitude. In experiment 4, PREPs were elicited with alternating gratings having a sinusoidal spatial luminance profile, spatial frequency of 0.2 or 0.8 cpd, and contrast ranging from noise levels to 65%. Rats treated with 40 mg/kg CDM showed increased peak-to-peak amplitudes only at 0.2 cpd and only at contrast values above 10%. The failure of CDM to alter PREPs at 0.8 cpd was attributed to low contrast sensitivity at that spatial frequency. The results demonstrated that the action of CDM on visual evoked potentials was dependent on the amount of contrast in the stimulus pattern, and suggested that CDM alters the encoding of visual contrast.
Amidines↗
Body temperature-dependent and independent actions of chlordimeform on visual evoked potentials and axonal transport in optic system of rat.
Pattern-reversal-evoked potentials (PREPs), flash-evoked potentials (FEPs), rapid axonal transport in the optic system and body temperature were measured in hooded rats, treated with either saline or the formamidine insecticide/acaricide, chlordimeform (CDM). Rats receiving chlordimeform had low body temperatures when housed at standard laboratory room temperature, 22 degrees C, but not at 30 degrees C. Peak latencies of flash-evoked potentials were prolonged by chlordimeform at 22 degrees C, but not at 30 degrees C. The rate of axonal transport was slowed in chlordimeform-treated hypothermic rats, but not in chlordimeform-treated warmed rats. These findings suggest that the flash-evoked potential and axonal transport changes produced by chlordimeform were an indirect consequence of hypothermia. In contrast, chlordimeform increased pattern-reversal evoked potential peak latencies and peak-to-peak amplitudes independent of body temperature. These findings confirm and extend previous reports of chlordimeform-induced hypothermia, emphasize the importance of changes in body temperature as a possible confounding factor in studies of neuroactive agents and demonstrate that chlordimeform has both body-temperature-dependent and independent actions in the visual system in the rat.
Amidines↗
Monoamine oxidase inhibition cannot account for changes in visual evoked potentials produced by chlordimeform.
Chlordimeform (CDM), a formamidine insecticide and monoamine oxidase (MAO) inhibitor, has recently been shown to produce large changes in visual evoked potentials of hooded rats (Boyes and Dyer, 1984a). Two experiments were performed to determine if the changes in evoked potentials were a result of the inhibition of MAO. In the first, the degree of inhibition of MAO in the brains of rats treated with chlordimeform (1.0-100 mg/kg, i.p.) was compared with that produced by pargyline (0.3-30 mg/kg, i.p.). Both compounds preferentially inhibited MAO-B, although MAO-A was substantially inhibited at larger doses. Pargyline was a relatively more potent inhibitor of MAO than chlordimeform, but not more efficacious. In the second experiment, pattern reversal evoked potentials (PREPs) and flash-evoked potentials (FEPs) were recorded from groups of rats after treatment with either saline, 0.4 mg/kg pargyline, 20 mg/kg pargyline or 40 mg/kg chlordimeform. The latter two groups were selected so as to have similar levels of inhibition of MAO, about 90% inhibition of MAO-B and 60% inhibition of MAO-A. The results showed a doubling of the amplitude of pattern reversal evoked potentials and increased latencies of the pattern reversal evoked potential and the flash-evoked-potentials in the chlordimeform-treated group, but no significant changes from saline control values in the pargyline-treated groups. These results confirm that chlordimeform is a MAO inhibitor at doses which produce behavioral and electrophysiological changes, but demonstrate further that the changes in visual evoked potentials produced by chlordimeform are not a direct result of the inhibition of MAO.
Amidines↗
Neurophysiological consequences of acute exposure to methylpyridines.
A series of neurophysiological tests was performed on Long-Evans hooded rats treated with either 2-, 3-, or 4-methylpyridine at dosages of 100 mg/kg, approximately one-half the ip LD50. The tests contained measures of sensory function (paired pulse flash evoked potentials, pattern reversal evoked potentials, and brainstem auditory evoked responses) and cerebral excitability (pentylenetetrazol seizures and hippocampal afterdischarges). In general, rats treated with 2- and 3-methylpyridine were more affected than those treated with 4-methylpyridine. The changes observed were in many ways similar to those seen following administration of depressant compounds: increased latency of evoked potentials and increased latency to PTZ seizures. Not all findings, however, were consistent with previously observed patterns of central nervous system depression.
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