Auditory Detection and Perception in Normal Man

and in Patients with Adrenal Cortical

Insufficiency: Effect of Adrenal Cortical Steroids

ROBERTI. HENKIN and ROBERTL. DALY

From the Clinical Endocrinology Branch, National Heart Institute,Bethesda, Maryland 20014 and Gallaudet College,Washington, D. C. 20002

A B S T R A C T Auditory detection thresholds forsinusoidal tones and various tests of auditory per-ception were determined in 12 patients with ad-renal cortical insufficiency (seven with Addison'sdisease and five with panhypopituitarism) andcompared to those in normal volunteers. In adrenalcortical insufficiency auditory detection sensitivitywas significantly more acute than normal, andjudgments of loudness and of the contralateralthreshold shift were made at levels more than 20db below those of normal subjects. Thus both thelower and the upper limits of the dynamic auditoryrange are significantly decreased in these patients.Speech discrimination ability of the patients wassignificantly impaired as was their difference lim-ens, their alternate binaural loudness balances,and their ability to localize tones in space.

Treatment of the patients with deoxycorti-costerone acetate decreased serum potassium con-centration, raised serum sodium concentration, andproduced gains in body weight but did not alterauditory detection or perception.

Treatment with prednisolone or with mainte-nance doses of carbohydrate-active steroids re-turned auditory detection and perception to normalin every patient tested.

Dr. Henkin is a member of the Clinical EndocrinologyBranch, National Heart Institute.

Mr. Daly is a faculty member of Gallaudet College,Washington, D. C. His present address is Department ofAudiology and Spee-h, Johns Hopkins Hospital, Balti-more, Md. 21205.

Received for publication 31 Julyw 1967 and in revisedform 8 Febritarip 1968.

The inability of the untreated patients to per-form the various auditory perception tasks indi-cates that they have a defect in their ability tointegrate incoming sensory stimuli. This defectmay be related to the alteration in the timing oftransmission of neural impulses along axons andacross synapses which occurs in these patientswhen their carbohydrate-active steroid is removed.This decreased integrative capacity occurs at thesame time that they are able to detect many typesof sensory stimuli significantly better than normalsubjects. This interrelationship between increaseddetection sensitivity and decreased perceptualability is dependent upon the absence of carbohy-drate-active steroids, for when these steroids arereplaced both detection sensitivity and perceptualability revert to normal.

INTRODUCTION

It has been shown previously that patients withuntreated adrenal cortical insufficiency exhibitmarkedly increased detection sensitivity for taste,smell, and hearing. Treatment of these patientswith deoxycorticosterone acetate (DOCA) for2-9 days produced no alteration in taste, smell.or hearing thresholds, but treatment with carbo-hydrate-active steroids for 18-72 hr generallyreturned taste, smell, and hearing thresholds tonormal (1-3). These studies indicated furtherthat changes in extracellular fluid volume couldnot account for these effects (1-3).

Careful observation of the responses of the pa-

The Journal of Clinical Investigation Volume 47 1968 1269

tients with untreated adrenal cortical insufficiency(luring these experiments suggested that althoughdetection sensitivity for taste and smell was sig-nificantly increased in a number of sensory modali-ties, perceptual ability was decreased. Initialobservations suggested that these phenomena alsooccurred in hearing; e.g., when placed in the soundchamber before auditory testing and deprived ofvisual and gestural cues patients had difficulty incarrying out instructions given through the ear-phones.

Because of these observations, it became appar-ent that patients with untreated adrenal corticalinsufficiency experienced difficulty with perceptionor "integration" of sensory stimuli. The presentstudy was designed to evaluate the manner inwhich patients with adrenal cortical insufficiencyrespond to a battery of auditory perceptual tasksand to explore the effect of treatment with adrenalcortical hormones and adrenocorticotropin.

METHODSThe subjects of this study were 20 normal volunteers,aged 18-42, seven patients with adrenal cortical insuffi-ciency, aged 19-57; and five patients with anterior pitui-tary insufficiency, aged 14-54. All patients with adrenalcortical insufficiency had clinical features of this disease,urinary 17-hydroxycorticosteroid excretion below 2 mg/24 hr, which did not increase with 40 U of adrenocortico-tropin (ACTH) given intravenously over 8 hr each dayfor 4 days (except for V. M. and C. M. whose urinary17-hydroxycorticosteroids rose to 5.0 and 11.6 mg/24 hr,respectively, on the 4th day of ACTH). All patients withanterior pituitary insufficiency had hypothyroidism, hypo-gonadism, and adrenal cortical insufficiency, with urinary17-hydroxycorticosteroids below 2.2 mg/24 hr, risingabove 10 mg/24 hr after infusion of 40 U of ACTHgiven intravenously over 8 hr each day for 2 or moredays. Taste, smell, and (or) hearing thresholds havebeen previously reported for 8 of these 12 patients (1-3).All patients remained on an air-conditioned metabolicward and ate a regular diet, which was well toleratedeven when they were not receiving treatment. Sodium in-take was 100-200 mEq/day. Body weight, determinedwith metabolic scales daily on arising, was used to pro-vide a gross estimate of changes in the volume of bodyfluids. None of the subjects or patients gave a historyof hearing loss or of ear disease. Otolaryngeal examina-tion revealed no gross abnormality in any of the normalsubjects or patients with adrenal cortical insufficiency.The patients were studied under five conditions: (a) un-treated for 4 or more days, (b) treated with DOCA, 20mg/day for 3-9 days, (c) treated with prednisolone, 20mg/day for 2-7 days, (d) treated with 40 U of ACTHintravenously over 8 hr for 5 days, and (e) treated with

maintenance dosages of 9 alpha-fluorohydrocortisone(0.05-0.10 mg/day) and prednisolone (5.0-7.5 mg/day),dexamethasone (0.5 mg/day), or cortisone acetate (37.5mg/day).

Auditory measurements were obtained by the two ex-

perimenters of the study, on seperate occasions, in the af-ternoon hours. One of the experimenters (R.L.D.) par-ticipated in the' study on a double-blind basis. If, for a

given treatment condition, the independent measurementsdetermined by the two experimenters differed by more

than 5 db, the data were discarded, and the experimentwas repeated.

All auditory measurements were made with the sub-jects and patients seated alone, comfortably, in an arm

chair, in an Industrial Acoustic Corporation 1204 soundchamber. Acoustic signals were provided by a BeltoneModel 15C clinical audiometer with a fixed 20 db at-

tenuator in line with the output from the audiometer.The signal was presented separately to the left and rightears of each subj ect or patient through TelephonicsTDH-39 earphones with MX-41/AR, cushions. Noisemeasurements were obtained with the internal sawtoothnoise generator of the Beltone audiometer. Speech sig-nals were provided by standard recorded lists of pho-netically balanced words (PB) and standard recordedlists of low-pass filtered speech (LPFS) ; i.e., words fromwhich frequencies above 500 cps had been filtered at a

rate of 17 db/octave (4). These recorded lists were playedthrough the audiometer circuit by an Ampex 300 seriestape recorder. The speech signals were calibrated withreference to a 1000 cps tone set at 0 intensity on the Vol-ume Unit (VU) meter of the Beltone audiometer. Theoutput of the audiometer was calibrated relative to theInternational Standards Organization (ISO) standardfor hearing thresholds (5).

Auditory detection thresholds for sinusoidal tones over

the frequency range of 125-8000 cps were obtained in a

standard manner previously described for audiometricthresholds (6). These were obtained by an ascendingtechnic with 5 db intensity increments and a 100% re-

sponse criterion. Presentation of tones was varied to

eliminate order and practice effects. Audiometric thresh-olds differ in a number of respects from the type ofthresholds we reported previously for some of these pa-tients (3). Audiometric thresholds, although not quiteas precisely located as the previously reported thresholds,are the most common measurements used for the clini-cal description of detection sensitivity. The two types ofthresholds may be made roughly comparable by appropri-ate conversion formulas (5). Measurements are ex-

pressed in decibel hearing level from the ISO 1964 Stand-ard for hearing thresholds (5); i.e., the attenuator was

calibrated such that 0 hearing level corresponded to thestandard value for normal hearing, positive values,poorer than normal hearing, and negative values, betterthan normal hearing. The data presented here are themean thresholds for the second or better ear tested.Threshold values for normal subjects obtained by thistechnic are directly comparable to, and in good agree-ment with, those reported by other investigators (5, 6).

1270 R. 1. Henkin and R. L. Daliy

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TABLE I IAuditory Detection and Perception Thresholds in Adrenal

Loudness judgments

UpperMean limit Discom- Discom-

Serum Serum comfort comfort fort level fort levelPatients Sex Age Weight Na K level level (speech) (noise)

yr kg mEq/liter db*Addison's disease

A. B. F 54 56.31 146 3.6 45 55 60 47.5J. A. E. F 33 52.15 137 3.9 52.5 62 67.5 48V. McC. M 52 62.99 136 5.0 50 60 70 52Clar. M. M 60 74.04 125 4.5 55 60 65 39P. K. F 24 51.63 141 2.5 42.5 60 65 45R. P. F 54 62.97 137 2.8 27.5 51 62.5 60R. E. M 19 50.67 137 4.1 10 30 35 30

Mean :IsEM 40±6.1: 5444.4t 61 44.4t 46±3.61

PB, phonetically balanced; LPFS, low-pass filtered speech.* db hearing level from International Standards Organization (ISO) 1964 Standard.1 P <0.01 with respect to results of normal volunteers or to results after treatment with carbohydrate-active steroids.§ P <0.01 with respect to results of normal volunteers; P <0.05 with respect to results after treatment with carbohy-drate-active steroids.

Only values for 500 and 1000 cps will be presented sincethese were the frequencies to which the perceptual mea-surements were referenced.

Loudness judgments were obtained by determiningvarious comfort and discomfort levels for speech andnoise by standard techniques previously described (6, 7).The mean comfort level for speech (MCLS) is definedas the mean loudness level of conversational speech thatthe subject appreciates as comfortable. This was deter-mined as follows. The speech circuit of the Beltone audi-ometer was calibrated to 0 on the VU meter with respectto the conversational live speech level of the investigator.Using this speech, the investigator instructed the sub-ject to signal when the words heard through the ear-phones were comfortably loud. Speech was presented inascending intensity from barely detectable to uncom-fortable levels at 5-db intervals. If there was a range ofloudness within which different intensities seemed equallypreferable, the mean of the range was taken as the com-fort level. The upper limit of the comfort level for speech(ULCLS) was defined as that sound level at which thesubject reported the speech of the investigator to beloud, but not uncomfortable. The discomfort level forspeech (DLS) was defined as the sound level at whichthe subject first reported discomfort with the speech ofthe investigator. The discomfort level for noise (DLN)was defined as the sound level at which the subject firstreported discomfort to the sawtooth noise stimulus fromthe Beltone audiometer. Each of these four measurementswas repeated three times for each subject and for eachear tested. The mean of these three determinations for thesecond or better ear is reported. Each subject was brieflytrained before the testing in order to acquaint him withthe test procedure. A range of intensities was explored,

and the subject was questioned as to the loudness char-acteristics of the sound stimuli.

Speech discrimination measurements were obtained athearing levels 40 and 60 db above each subject's auditorydetection threshold at 1000 cps. Standard phoneticallybalanced lists of 50 words each (filtered and nonfiltered)were presented to each subject in a standard manner(4, 6). The subject was required to repeat the stimulusword, and his response was recorded. Results are reportedin per cent of correct responses at 40 and 60 db above1000 cps threshold (PB 40 and PB 60, respectively forthe nonfiltered words; LPFS 40 and LPFS 60 for thefiltered words). Before the presentation of the filteredwords a 50 word practice list was presented to each sub-ject 40 and 60 db above threshold in order to familiarizehim with the nature of the test stimuli.

A difference limen -for intensity (8, 9) was obtainedwith a 500 cps amplitude modulated (warbling) tone, pre-sented at a level 20 db above each subject's auditory de-tection threshold at that frequency. The test tone wascalibrated on an oscilloscope in decibels of modulation.Modulation was determined from the formula log1o AI/I,in which AI represents a change in intensity, and I is thereference intensity. For the test, the tone was varied be-tween 0 and 5 db modulation. The subject was requiredto signal when he first perceived a transition from a

steady to a warbling or from a warbling to a steady tone.

Each transition was measured three times in each direc-tion for each ear, and the mean of the three measurementsfor the second ear tested was taken as the differencelimen. The data are reported in decibels of modulation.

The contralateral threshold shift (CTS) was deter-mined by a variation of a technic used in a number of

1272 R. 1. Henkin and R. L. Daly

Cortical Insufficiency Treated with Deoxycorticosterone Acetate

Speech discriminationContra- Auditory detection

PB LPFS lateral thresholdDifference threshold

40 60 40 60 limen shift 500 cps 1000 cps

%correct db modu- db* db*lation

72 86 6 22 >5.0 45 -5 -1072 88 8 16 2.3 50 -10 -1080 94 18 38 0.8 55 -15 --1552 92 4 24 >5.0 40 +10 +1080 - 84 4 34 0.8 40 -10 -1542 88 0 -12 2.4 50 -12 -1852 88 12 16 1.0 50 -25 -20

64±5.2$ 89±1.3§ 7h2.2t 2343.6t 2.540.1I 4741.1T -1044.01 -11 43.5t

laboratories (10, 11). It is a phenomenon produced bythe bilateral reflex contraction of the intra-aural muscleswhen either ear is stimulated by high-intensity sound(10), and it bears a reasonably constant relationship tothe upper limits of hearing. Direct investigation of theupper limits of hearing entails the risk of producingpermanent damage to the hearing mechanism. Thus theCTS which may be evoked by sound intensities whichdo not cause damage to the ear was chosen to estimate theupper limits of hearing. The sawtooth noise of the audi-ometer was introduced into the contralateral ear at alevel 5 db below the detection threshold previously de-termined. The 500 cps probe tone was increased in in-tensity until a threshold response to the tone was ob-tained. If this postnoise stimulation threshold was thesame as determined before noise stimulation, the noisestimulus was increased by 5 or 10 db and the procedurerepeated. When the new threshold obtained exceeded thepreviously determined threshold by at least 5 db for twosuccessive increments of noise, the noise level producingthe contralateral threshold shift was recorded in decibels.

RESULTS

Auditory detection and perception in normalsubjects. The auditory detection thresholds forfrequencies 500 and 1000 cps in 20 normal subjectsare presented in Table I. Since the data presentedin this paper are related to changes in hearinglevel for each subject or patient, only changes rela-tive to each subject's detection level need be con-sidered. For the purposes of this study, data for

the normal subjects and for the patients aregrouped together irrespective of age.

Values for thresholds and for the loudnessjudgments (MCLS, ULCLS, DLS, and DLN)are essentially the same as those obtained by otherinvestigators (5, 7, 12). The values for speechdiscrimination (PB and LPFS, 40 and 60) arealso in good agreement with values obtained byother investigators (6, 13). The values obtainedfor the difference limen and for the CTS areessentially the same as those obtained by otherinvestigators using techniques similar to the onesemployed here (8-1 1).

Auditory detection and perception in patientswith adrenal cortical insufficiency receiving nosteroid. The auditory detection thresholds forfrequencies 500 and 1000 cps in each of the 12patients with untreated adrenal cortical insuffi-ciency are presented in Table I. Mean detectionthresholds for these two frequencies are signifi-cantly lower than those for normal subjects, irre-spective of age, as shown previously by anothertechnique (3).

The loudness judgments (MCLS, ULCLS,DLS, and DLN) were below those obtained innormal subjects by more than 20 db and werestatistically significantly different (Table I).Judgments of DLS, a reliable correlate of the

Auditory Perception in Adrenal Insufficiency 1273

upper limit of audition, were approximately 30 dbbelow those of normal subjects. The ULCLS innormal subjects is usually 5-10 db below the DLS(7); in these untreated patients the ULCLS wassignificantly below normal but maintained therelationship of being 5-10 db below the DLS.

Speech discrimination of these patients was sig-nificantly impaired. At 40 and 60 db above thresh-old mean intelligibility scores were more than20 and 9% below those of normal subjects, re-spectively. Only two of the subjects attained scoresof 100% at 60 db above threshold, whereas thisscore is common among normal subjects. Althoughthe intensity level at which these words werepresented was increased to 70 and 80 db abovethreshold in the other 10 patients, intelligibilitylevels did not increase above 94%. Speech dis-crimination for filtered words was impaired evenmore. At 40 and 60 db above threshold thesepatients achieved a mean score of only 6.5 and23%o, respectively. Both scores were significantlybelow the mean scores of the normal subjects. At40 db above threshold, 3 of the 12 subjects wereunable to recognize even one of the 50 wordscorrectly. This inability to recognize filtered speechdid not appear to be primarily intensity dependent,for even though the words were presentetd atlevels up to 90 db above threshold, none of thepatients correctly perceived more than 50% ofthe words.

The ability of patients with untreated adrenalcortical insufficiency to differentiate a steady froma warbling tone was significantly impaired. Fourof the patients required about 1.1 db to recognizethe tonal change, which is normal for our equip-ment. Five could not recognize the change even atthe 5 db maximum modulation. The average dif-ference limen for untreated patients was 3.3 dbor approximately two and one-half times the soundenergy required for normal subjects.

The CTS in these subjects is below that for thenormal subjects by approximately 30 db, a statis-tically significant difference (Table I). In normalsubjects, the CTS is elicited between 75-90 db.This difference indicates that, "off treatment," thereflex threshold, and hence the upper limit of theauditory range in these patients, is markedlyreduced.

The patients had great difficulty in performingother auditory perceptual tasks during the time

they were untreated. Localization of conversa-tional speech more than 300 away from eitherside of a midline presentation was in error by15-45'; however, they were able to localize soundsaccurately when presented in or very close to themidline. The direction of the error was not con-sistent. Results of alternate binaural loudness bal-ance tests (ABLB), when performed in thestandard manner (14, 15), were within normallimits; i.e., patients could match the loudness oftones presented alternately to the two ears within+ 20 db. However, when presented with a seriesof "soft" or "loud" comparison tones the patientsmatched as equally loud tones which differed byas much as 40 db. This phenomenon appeared tobe partially dependent upon the duration of thecomparison tone, and has been commonly called"anchoring" or stimulus dependence, because thepatients tend to make judgments predicated uponprior stimuli more readily than normal subjects.The magnitude of these errors in some patientswas such that they were matching as equal tonesthat were four times as loud or as soft as thestandard tone.

The data indicate that, considered as separategroups, patients with either Addison's disease orpanhypopituitarism, off treatment, detect and inte-grate auditory stimuli in a significantly differentmanner than do normal subjects. The responses ofthese two groups of patients are statistically thesame and can thus be considered as being thesame (Tables I and III).

During the time which these auditory percep-tion tasks were performed the patients exhibitedboth hyponatremia and hyperkalemia (Table I).

Auditory detection and perception in patientswith adrenal cortical insufficiency treated withDOCA. The results of the auditory detection andperception tasks performed by the patients withadrenal cortical insufficiency treated with DOCAalone are presented in Table II. The values forthe auditory thresholds at 500 and 1000 cps, forthe loudness judgments (MCLS, ULCLS, DLS,and DLN), speech discrimination (both filteredand nonfiltered speech), the difference limen, theCTS, the sound localization, and for the ABLBare virtually the same as those observed in patientsoff treatment (Table I) and are significantly belowthose obtained in normal subjects despite decreases

1274 R. I. Henkin and R. L. Daly

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Auditory detection and perception in patientswith adrenal cortical insufficiency treated withprednisolone. The results of the auditory detec-tion and perception tests performed in each patientwith adrenal cortical insufficiency treated only withprednisolone, 20 mg/day, for 2-4 days, are pre-sented in Table III. In all patients, either withAddison's disease or with panhypopituitarism, theauditory detection thresholds for 500 and 1000 cpsincreased significantly as has been previouslyshown (3). Loudness judgments changed signifi-cantly and fell within the normal range for eachmeasurement made; the MCLSincreased approxi-mately 20 db over the untreated state, as did theULCLS, the DLS, and the DLN. Speech discrimi-nation improved significantly for both filtered andnonfiltered words and returned to scores similar tothose obtained for normal subjects by ourselvesand by other investigators (13). The differencelimen for intensity decreased significantly by morethan 2 db and returned to the values obtained innormal subjects as did the values for the contra-lateral threshold shift.

This increase in ability to perform auditoryperceptual tasks associated with a decrease in audi-tory detection sensitivity occurred after treatmentwith maintenance doses of carbohydrate-activesteroid alone or together with maintenance dosesof sodium-potassium-active steroid added; thisoccurred both in patients with Addison's diseaseand with panhypopituitarism. Similarly, in thosepatients with adrenal cortical insufficiency withsome remaining cortical function or with pan-hypopituitarism, treatment with ACTHfor 4 dayssignificantly increased the patient's ability to per-form these varied auditory perceptual tasks aseffectively as treatment with carbohydrate-activesteroids (Table III).

DISCUSSION

The meaning of the loudness judgments and of theCTS may be evaluated more clearly by comparingthe response levels of normal subjects with thoseof patients with untreated adrenal cortical insuffi-ciency (Fig. 1). The auditory detection thresholdsof the patients. are significantly below those of thenormal subjects, as previously described (3). Thisillustrates, once again, their extreme sensitivityat the lower end of the dynamic range of hearing.

However, the normal ear can accommodate tochanges in sound power over a range of approxi-mately 1014 power units between detection of anauditory signal to painful stimulation or maxi-mum-tolerated sound (6). Judgments of discom-forting loudness (DLS, DLN) and the CTS arerelated to the upper limits of auditory capacity,being elicited at about 80 db (108 power units)above detection threshold (16). Our data showthat the DLS and the CTS are evoked at a meanlevel of 83 db above normal hearing threshold(Table I). By contrast, patients with untreatedadrenal cortical insufficiency demonstrate meanCTS levels that are shifted downward even moremarkedly than their tonal detection thresholds;e.g., the CTS at 500 cps is evoked at 63 db abovethe mean 500 cps detection threshold of -12 db(Fig. 1). This corresponds to a reduction of thedynamic range of auditory capacity by a factor of102 power units; thus, the maximum tolerableloudness for patients with untreated adrenal corti-cal insufficiency is approximately 1/100th of thatfor normal subjects. Moreover, judgments of themid-range of loudness (MCLS, ULCLS) indicatethat in patients with untreated adrenal corticalinsufficiency compression takes place nonlinearly,occurring most markedly in the upper portion ofauditory range. This is an unusual finding for, inmost cochlear disorders, there is compression onlyat the lower end of the dynamic range (a sensi-tivity loss), whereas the upper limits remainvirtually intact (16). These findings correlate wellwith subjective reports of the patients, who statethat "off treatment," stimuli which normally donot annoy them produce discomfort to such degreethat these are the major complaints of many ofthem. We would also infer from these data thatpatients with untreated adrenal cortical insuffi-ciency are more sensitive to painful auditorystimuli as they are to painful stimuli of othermodalities (17). When the patients are treatedwith carbohydrate-active steroid all loudness judg-ments (MCLS, ULCLS, DLS, DLN) and theCTS return to levels observed in normal subjects.

Results of the difference limen indicate that pa-tients with untreated adrenal cortical insufficiencyexperience difficulty in perceiving small incrementsin sound intensity when untreated or treated withDOCA. When treated with carbohydrate-activesteroid their responses were not significantly dif-ferent from normal. Although this measurement

1276 R. 1. Henkin and R. L. Daly

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FIGURE 1 Comparison of audiometric thresholds and contralateral thresholdshifts (CTS) in normal subjects with those in patients with adrenal corticalinsufficiency, off treatment. A, The open circles at the top of the figure repre-sent the mean CTS determined in 44 normal subjects, aged 15-34, by Jepson(16); the upper and lower limits of the upper gray area represent the rangeof these responses (16). The closed circle within the upper gray area repre-sents the mean CTS determined in the 20 normal subjects of this study. Thelines above and below this closed circle represents + 1 SEM. Data for theCTS at 500 cps in the subjects of this study are similar to that obtained byJepson. B, The closed diamonds directly below the upper gray area representthe mean CTS obtained in this study of 12 patients with adrenal cortical in-sufficiency, off treatment, aged 19-57; the lines above and below these rec-tangles represents ± 1 SEM. C, The open circles at the bottom of the figurerepresent the mean audiometric thresholds in normal subjects obtained byJepson (16), the lower gray area, the range of these thresholds. The closedcircles within the lower gray area represent the audiometric thresholds ob-tained in the normal subjects of this study. The lines above and below thecircles represent ± 1 SEM. The closed diamonds below the lower gray arearepresent the audiometric thresholds obtained in patients with adrenal corti-cal insufficiency, off treatment. The lines above and below the rectanglesrepresent ± 1 SEM. At each frequency both mean audiometric threshold andCTS for the patients with adrenal cortical insufficiency were significantlybelow those of either group of normal subjects.

has been criticized as unreliable because of thedifficulty of the judgments involved (8, 18) themagnitude of the changes indicates that the differ-ences are indeed meaningful. This test indicatescochlear disease when the difference limen is small(8, 9). The present results indicate that either "offtreatment" or "on DOCA" the patients demon-strate normal cochlear function.

The speech discrimination tests were designedto examine another parameter of perceptual or

"integrative" capacity. Patients with untreatedadrenal cortical insufficiency exhibited grossly im-paired ability to "integrate" speech stimuli intomeaningful patterns. Similar results were shownby the failure of the untreated or DOCA-treatedpatients to perform sound localization tasks orABLB, whereas after treatment with carbohy-drate-active steroid they performed these tasksnormally. The anatomical localization of this per-ceptual defect is not clear. Patients with cortical

Auditory Perception in Adrenal Insufficiency 1277

auditory impairment, e.g. after temporal lobectomyor with temporal lobe tumors, generally displaynormal or slightly depressed discrimination scoresfor unfiltered words. Since there is bilateral repre-sentation in the cortex, and since tumors arerarely bilateral, this result might be expected.Patients with eighth nerve defects or mild cochlearimpairments exhibit impaired speech discrimina-tion scores (19, 20). However, discrimination forfiltered speech is relatively unaffected by lesionsbelow the brain stem but markedly impaired withcortical involvement (20). The striking inability ofthese patients to perform the ABLB, a task whichnormal subjects perform with precision (14), hasbeen observed previously, with a similar degreeof impairment, in patients with lesions in auditorypathways between cochlea and brain stem (19,20). Thus, untreated or DOCA-treated patientspresent a pattern of altered perception consistentwith a cortical abnormality, but their multipleauditory abnormalities suggest a very complexphenomenon unrelated to any specific anatomicallesion. Rather, the results are more suggestive ofa diffuse metabolic abnormality. This inferenceseems supported by the fact that increased detec-tion sensitivity occurs in virtually all sensorymodalities in patients with untreated adrenal cor-tical insufficiency (1-3, 21) .1

One explanation for the "integrative defect"which occurs after removal of carbohydrate-activesteroid is that timing of transmission of neuralimpulses in both the central and peripheralnervous systems is significantly altered. Subjectiveresponses of these patients support this hypothesis.For example, sound localization, when the soundsource is in the midline, is essentially normal,whereas localization is markedly in error when thesource is more than about 300 from the midline.These results suggest that it is the temporal factorin sound localization that is critical for thesepatients. If the signal arrived at the two ears atthe same time, i.e. if the sound source was in themidline, the patients were able to make an appro-priate judgment of sound azimuth. However, whenthe time of arrival of the signal at the two ears

became disparate beyond a few milliseconds, i.e.when the azimuth increased to 300 or greater,they were unable to make a correct judgment.

1 Daly, R. L., and R. I. Henkin. Auditory function inadrenal insufficiency. Data in preparation.

Similarly, the increase in harshness or the "rasp-ing" quality of the experimenter's voice which theuntreated or DOCA-treated patients reportedwhile in the sound chamber (3) is interesting inthis respect, for these patients did not perceive thisquality when they were treated with carbohydrate-active steroid. This effect can be produced inspeech by altering frequency and intensity rela-tionships, or by altering temporal relations, e.g.,by rapid switching or "flickering" of the signal.No defect existed in our electronic equipmentwhich could adequately account for this phenome-non in terms of frequency or intensity distortion.We therefore suggest that the effect may be theresult of a distortion in the patient's appreciationof temporal relationships.

Abnormalities in both peripheral nerve conduc-tion velocity and visual cortical-evoked potentialsamong patients with adrenal cortical insufficiencysupport this hypothesis. Previous studies from thislaboratory have demonstrated that ulnar nerveconduction velocity in untreated or DOCA-treatedpatients with adrenal cortical insufficiency wasincreased above normal, due to a small decreaseof 0.5-1 msec in the time over which the nerveimpulse traversed the nerve from elbow to wrist(21). After treatment with carbohydrate-activesteroid this axonal conduction velocity returnedto normal, the conduction time increasing to nor-mal (22). These same studies have also indicatedthat the time of conduction of the nerve impulseacross the myoneural junction studied was sig-nificantly increased above normal by 1.5-3 msec.2Studies of visual and auditory cortical-evokedpotentials in these untreated or DOCA-treatedpatients have demonstrated a significant increasein latency of their responses when compared totheir latencies after treatment with carbohydrate-active steroids. These increases in latency were ofthe order of 5-30 msec and were presumably dueto the summation of synaptic delay as the impulsetraversed the multisynaptic visual and (or) audi-tory systems (23). The most marked increases inlatency, more than 15 msec, occurred in the later,nonspecific portions of the evoked response, i.e.,portions associated with reticular formation activ-ity (23). Less marked but still significant increasesin latency of 5-10 msec also occurred in the spe-cific, earlier portions of the evoked response (23).

2 Henkin, R. I. Unpublished observations.

1278 R. I. Henkin and R. L. Daly

When these patients were treated with carbo-hydrate-active steroid all latency changes revertedto normal (23). These results correlate well withsimilar results obtained in adrenalectomized ani-mals both by ourselves as well as by other investi-gators. These results suggest that increases inlatency of cortical-evoked potentials occur in re-sponse to stimuli such as electrical stimulation,touch, or pain (23-26); latencies also return tonormal after treatment with carbohydrate-activesteroids (23, 26). These increases in latency "offtreatment" were considered to be due to increasesin synaptic delay. Indeed, preliminary results fromthis laboratory suggest that adrenalectomy andsubsequent treatment with carbohydrate-activesteroid produces changes in synaptic delay asmeasured by microelectrode implantation acrossone synapse in the spinal cord of the cat.3

Perception and integration of sensory stimuliin the visual and auditory systems have beenrelated, by numerous investigators, to the timedarrival of sensory stimuli in the cortex (27, 28).The small increases in conduction velocity alongperipheral axons coupled with the large increasesin latency in multisynaptic sensory systems ob-served in these patients may well result in a mark-edly abnormal pattern of neural stimuli reachingthe cortex. This pattern (coding) presumablycould not be interpreted in a normal fashion, andthe result might be an impairment of perception,such as that which we observed. In addition, thesum total of conduction from the time of depolari-zation at the sensory end organ to final corticalperception is significantly delayed in these patientsdue to the large increase in synaptic delay. Thisalso might contribute to their perceptual impair-ment. Whatever the hypothesized mechanism, theinstitution of treatment with carbohydrate-activesteroid returns neural conduction and sensoryintegration to normal. Since we have observed nospecific change in either detection, perception, orneural transmission after treatment with DOCA,we suggest that changes in extracellular sodium,potassium, or fluid volume have little effect uponthis phenomenon.

The increased detection sensitivity observed inthese patients may not be primarily related toalterations in neural transmission. Alternatively,these changes may be due to an increase in excita-

3 Evans, E., and R. I. Henkin. Unpublished observations.

bility of the nervous system after removal ofcarbohydrate-active steroid; i.e., depolarization ofthe nerve membrane may occur-at a lower thresh-old than it would were carbohydrate-active steroidnormally present.

Other investigators have suggested this possi-bility after studying the in vitro electrical charac-teristics of sciatic nerves taken from adrenalec-tomized rats (29). We have obtained onlyfragmentary data in patients to support thishypothesis. In some patients maximum contractionof the abductor digiti quinti, the muscle used inthe measurement of ulnar nerve conduction veloc-ity, could be obtained with the imposition of asignificantly lower voltage than that needed in thepatients when they were treated with carbohy-drate-active steroid. Similarly, amplitude of re-sponse to light in the visual evoked corticalpotentials is markedly increased in some untreatedor DOCA-treated patients as compared to theresponses of these same patients treated withcarbohydrate-active steroid.2

The explanation of these phenomena is notknown. However, the consistency with which theincrease in detection sensitivity accompanies thedecrease in perception or integration in thesepatients is impressive. A reinterpretation of dataobtained from studies dealing with sensory depri-vation or various forms of "schizophrenia" sug-gest that a similar dissociation between detectionand perception may be inferred (30-32). Studiesof auditory detection and integrative functions inpatients under the influence of various drugs, in-cluding lysergic acid diethylamide, also suggest asimilar dissociation (21). Wecan hypothesize thata specific relationship exists at all times betweendetection and perception. If detection were nor-mally set at a "low gain" to allow maximal inte-gration of all incoming sensory stimuli, and ifcarbohydrate-active steroid were to play a role inthe control of the input of sensory stimuli througha negative feedback mechanism, then removal ofcarbohydrate-active steroid from the system wouldsignificantly alter the normal gain-control mecha-nism; the nervous system would be bombardedwith sensory stimuli which normally would berejected. Further, this would occur in the nervoussystem at the expense of stimulus integration.

The mechanisms underlying these phenomenaare complex, and these studies represent only a

Auditory Perception in Adrenal Insufficiency 1279

beginning in their elucidation. However, the rela-tionship between detection and integration andthe role which steroid hormones play in conductionof the neural impulse both along the axon andacross the synapse are important for understandingthe manner in which the endocrine and the nervoussystems interact.

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20. Jerger, J. 1960. Audiological manifestations of le-sions in the auditory nervous system. Laryngoscope.70: 417.

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22. Henkin, R. I., J. R. Gill, Jr., J. R. Warmolts, A. A.Carr, and F. C. Bartter. 1963. Steroid dependent in-crease of nerve conduction velocity in adrenal insuffi-ciency. J. Clin. Invest. 42: 941. (Abstr.)

23. Ojemann, G. A., and R. I. Henkin. 1967. Steroiddependent changes in human visual evoked potentials.Life Sci. 6: 327.

24. Feldman, S., J. C. Todt, and R. W. Porter. 1961.Effect of adrenocortical hormones on evoked poten-tials in the brain stem. Neurology. 11: 109.

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27. Gouras, P. 1967. The effects of light-adaptation onrod and cone receptive field organization of monkeyganglion cells. J. Physiol. 192: 747.

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1280 R. I. Henkin and R. L. Daly