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The subjects were six adult males, in- cluding the three authors and three laboratory personnel. All had a history of so- Table 1. Latencies of auditory brainstem potential peaks before and after alcohol consumption. The statistical significance of the change in each peak latency is given; N.S., not significant.
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-Latency of peak (milliseconds after stimulus onset) ject I II III IV V VI VII Before alcohol 1 1.68 2.97 3.85 5.10 5.80 7.58 9.18 2 1.50 2.83 3.81 5.18 5.88 7.35 9.05 3 1.49 2.82 3.60 4.84 5.38 6.93 8.37 4 1.81 2.70 3.68 4.90 5.40 7.05 8.57 5 1.77 2.82 3.78 5.04 5.90 7.20 8.54 6 1.40 2.73 3.83 5.11 5.71 7.54 9.14 Mean 1.61 2.83 3.78 5.05 5.70 7.29 8.83 After alcohol 1 1.65 2.97 3.82 5.13 5.90 7.68 9.25 2 1.47 2.78 3.95 5.40 6.05 7.60 9.25 3 1.53 2.92 3.80 5.13 5.64 7.21 8.88 4 1.82 3.03 3.87 5.14 5.58 7.21 8.86 5 1.80 2.87 3.88 5.16 6.05 7.28 9.06 6 1.44 2.82 3.94 5.31 5.87 7.77 9.33 Mean 1.62 2.90 3.88 5.21 5.85 7.46 9.10 Change 0.01 0.07 0.10 0.16 0.15 0.17 0.27 P N.S. N.S. <.05 <.01 <.001 <.01 <.01 0036-807578/0714-0174$00.50/0 Copynght 1978 AAAS
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cial drinking but not of alcohol abuse. They were neurologically intact and had normal hearing. Testing was conducted in the afternoon after the subjects had fasted since breakfast. Alcohol dosages were selected for each subject according to his capacity for alcohol as judged from the frequency and amount of alcohol normally used. The aim was to achieve a uniform stage of clinical intoxication for all subjects. The resulting dosages of al- cohol ranged from 0.55 to 1.65 ml per kilogram of body weight, and were given in the form of commercially available vodka mixed with orange juice to a concentration of 20 percent (by volume).
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The subjects consumed the drinks at their own rate within a maximum time limit of 30 minutes. During testing the subjects reclined on a bed situated in a sound-attentuating chamber. Monaural auditory stimuli consisting of 0.5-msec clicks were presented through earphones at a rate of 10 per second. Each ear was tested. Two stimulus intensities were used, 75 and 55 dB above the threshold for normal hearing. Electrodes were at- tached at the vertex and mastoids, with the ipsilateral mastoid serving as the reference electrode and the contralateral mastoid the ground. The brain electrical activity was amplified by a factor of 105 with a bandpass of 100 to 3 kHz. Aver- aged potentials were summed over 2048 click presentations for 10.48 msec fol- lowing click onset. When midlatency potentials were recorded the averaging epoch was extended to 51.2 msec, with an amplification bandpass of 7 to 500 Hz. Replicated waveforms were collected in all conditions. Before administration of alcohol, recordings were taken for 1 hour in a normal condition. After the alcohol was consumed, recordings were taken at regular intervals for up to 2 hours. Blood samples were taken from each subject 1 hour after alcohol ingestion and after the completion of testing.
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All subjects reached a level of moder- ate intoxication as indicated by slight slurring of speech, dizziness, slight ataxia, and joviality. Analysis of blood samples indicated alcohol levels of 44 to 147 mg/100 ml (10), although the clinical effect of the alcohol was similar across the subjects.
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The brainstem potentials for one sub- ject for the 75-dB stimulus taken before and 95 minutes after the start of the alcohol consumption are shown in Fig. 1. The seven peaks (labeled I to VII) are clearly distinguishable, as they were for all subjects, and fall within the normal la- tency limits for the stimulus intensity (7,11). However, after alcohol ingestion the peaks were shifted to longer latencies SCIENCE, VOL. 201, 14 JULY 1978 Latency (msec) j Fig. 1 (left). Auditory brainstem potentials for one subject before and . .!..after consumption of an intoxicating dose of alcohol. Replicated VII) were identified; their latencies before alcohol consumption are indicated by dashed vertical lines. The acoustic stimulus was a 75-dB, 0.5-msec click presented at a rate of 10 per second. Recording was initiated at stimulus onset. Positive voltage at the vertex referred to the ipsilateral mastoid is plotted upward. Each waveform is the average of data for 2048 stimulus presentations.
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Fig. 2 (right). Schematic auditory brainstem potential waveforms showing the mean amplitudes and latencies across the six subjects for the 75-dB stimulus; dashed line, before alcohol; solid line, after alcohol. compared to those in the control condi- tion, particularly the later peaks. The cu- mulative increase in peak latencies was seen for every subject (Table 1).
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The mean amplitudes and latencies for the 75-dB waveform peaks and troughs are shown in schematic form in Fig. 2. Although the data for each ear in each subject were analyzed separately, no differences were seen; consequently the mean data for both ears are presented.
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Several conclusions are clear from Fig. 2. (i) Alcohol had no effect on the latency of peak I, and thus presumably had no effect on auditory nerve activity. (ii) There was a progressive increase in the latency of peaks II through VII as shown in Table 1. (iii) Alcohol had no significant effect on the amplitude of any of the potentials.
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Similar effects were found for the lower (55-dB) stimulus intensity. Only the latencies for peaks III and V could be reliably determined at that intensity, however. The latency shifts due to alco- hol for peaks III and V at 55 dB were 0.11 msec (P < .1) and 0.10 msec (P < .01), respectively. Again, there were no changes in peak amplitudes.
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Although the effect of alcohol ingestion on the brainstem potentials was highly reproducible in all six subjects, the absolute latencies of the peaks, even after alcohol, were within the range of normal variation (7,11). It remains to be seen whether at higher doses the effect would be proportionately greater. Thus, even though this procedure is sensitive to small changes in peak latency, it is es- 14 JULY 1978 sential that brainstem potentials be re- corded in a normal condition before con- clusions regarding the effect of alcohol can be made for an individual subject.
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The analysis of the midlatency poten- tials was confined to the negative (Na) and positive (Pa) peaks with mean la- tencies of 18.9 and 29.4 msec, respectively. The latency of Pa was increased by 1.3 msec after alcohol ingestion (P < .05), while no change was seen for the latency of Na. There was no significant change in the amplitude measured between Na and Pa.
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In order to ensure that these effects of alcohol on auditory brainstem potentials were due to the alcohol and not to the time spent by each subject in the testing sequence, two subjects were retested over a 2-hour period without ingesting al- cohol. No significant changes in peak la- tency were found.
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The results of this study demonstrate that alcohol has a depressive effect on neural transmission within the primary auditory pathway in humans. Previous studies have indicated that auditory brainstem potentials are highly resistant to alterations in the state of the organism including arousal, sleep, and even meta- bolic coma (7,12,13). Since the prolongation of peak latency was seen at an early stage of sensory transmission (peak III), the effect of alcohol presumably oc- curs as peripherally as the relay nuclei in the medulla, such as the cochlear nucle- us or superior olive. These results are consistent with those found in rats (9) and cats ( 14). It is not surprising that al- cohol affects brainstem structures, since signs of brainstem dysfunction such as dizziness, unsteady gait, and nystagmus are prominent in both acute and chronic alcohol intoxication.
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The latency increases found here fol- lowed closely the clinical signs of alcohol intoxication. For instance, the clinical state and magnitude of the latency shifts were consistent across the six subjects even though the blood alcohol levels re- quired for intoxication were different for each subject. The smallest effect, in fact, was found for a subject whose blood al- cohol level was 102 mg/100 ml, while one of the larger effects was found for a sub- ject with blood alcohol concentration of only 44 mg/100 ml (Fig. 1), which is well below the usual level for legal intoxica- tion. It is possible, therefore, that the changes in the brainstem potentials more accurately correlate with the effect of al- cohol on the nervous system than do blood alcohol levels.
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Also, the time course for development of the alcohol effect on auditory brain- stem potentials went pari passu with that of intoxication. Although the time course was not studied systematically, there was a progressive change in which later peaks (V to VII) were first affected by alcohol, usually within the first half-hour after onset of drinking, followed by changes in the earlier peaks (III and IV). This roughly paralleled the subjects' ver- bal reports of maximal intoxication, which usually occurred 45 to 60 minutes from the onset of drinking.
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The sites of action of alcohol are not clear from this study. Presumably all except the lowest levels of auditory trans- mission in the brainstem were affected because the increase in latency was seen for all peaks except I and II. However, most of the latency increase occurred be- tween peaks III and IV and between peaks VI and VII; this suggests that the intervening processes between those peaks were most susceptible to alcohol. Alcohol intoxication produces definite and consistent changes in the early audi- tory evoked potentials from the human brainstem. The value of this observation lies not only in the information it pro- vides concerning the neurological effects of alcohol, but also in the possibility for a functional dissection of brainstem con- nections in an intact subject. System- atic correlations of the effects of different drugs, with known effects on dif- ferent central pathways, on the brainstem potentials offers a means of iden- tifying specific transmission or conduc- tion dysfunction.
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KENNETH C. SQUIRES NAI-SHIN CHU ARNOLD STARR Department ofNeurology, University ofCalifornia Irvine Medical Center, Orange 92668
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The mammalian choroid plexus is a highly vascularized villous structure, covered with a single layer of cuboidal epithelial cells. It is present in all four ventricles of the brain and constitutes the major site for the bulk production of cerebrospinal fluid (CSF). The fluid is formed by an active secretory process at a rate that varies considerably from spe- cies to species, but that is rather con- stant when expressed as a fraction of to- tal CSF volume or on the basis of plexus weight-approximately 0.5 percent of total CSF volume is replaced by newly formed fluid every minute (1). Little is known about the various physiological factors controlling the rate of CSF for- mation from the choroid plexus; the pos- sibility of a nervous influence has been suggested on the basis of histological studies, dating back as far as those of mean increase in central conduction time between the initial negative brainstem potential (mean latency, 1.55 msec) to the prominent positive potential (mean latency 3.81 msec) was 0.13 msec for a blood alcohol level of about 200 mg/ 100 ml. 15. Supported by PHS grant NS1 1876 and The Dis- tilled Spirits Council.
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27 September 1977; revised 20 December 1977
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Benedikt in 1874, which showed the presence of nerves in the plexuses (2). In spite of this, the possibility that the pro- duction rate of CSF is influenced by autonomic nerves has not been seriously investigated, probably because of the lack of unequivocal ultrastructural evi- dence for an innervation of the plexus epithelial cells, apart from the presence of vasomotor nerves (3). The present study is part of a series of investigations on the innervation of the mammalian choroid plexus and the effect of auto- nomic nerves on bulk CSF production as measured quantitatively by the ventric- ulocisternal perfusion technique ac- cording to Pappenheimer and co-work- ers (4).
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We used albino and randomly pigmented rabbits (weight, 2 to 3 kg) of ei- ther sex that were maintained on stan- Fig. 1. Fluorescence photomicrograph of whole mount of the choroid plexus from the third ventricle of a rabbit; formaldehyde reaction. Numerous delicate adrenergic axon terminals form a network in the parenchyma among the epithelial cells. Autofluorescent cells and granules are also seen (x 65). 00368075178/0714-0176$00.50/0 Copyright © 1978 AAAS Sympathetic Nervous Control of Cerebrospinal Fluid Production from the Choroid Plexus Abstract. The rabbit choroid plexus, responsible for the bulk production of cerebrospinal fluid, is well supplied by sympathetic nerves emanating in the superior cervical ganglia. Electrical stimulation ofthese nerves markedly reduces production ofcerebrospinalfluid, measured by [14CJinulin dilution during ventricular perfusion, whereas sympathetic denervation enhances the rate offormation. 176 SCIENCE, VOL. 201, 14 JULY 1978