Greater brain response of left-handers to drugs

Neuropsychobgia, Vol. 23, No. 1, pp. 6147, Printed in Great Britain

GREATER

1985.

0

BRAIN RESPONSE

OF LEFT-HANDERS

PETER Laboratory

0028-3932/85 $3.CO+O.o0 1985 Pergamon Press Ltd.

TO DRUGS

IRWIN*

for EEG and Psychopharmacology, Department of Psychiatry and Behavioral University of New York at Stony Brook, NY 11794, U.S.A. (Accepted

19 January

Science, State

1984)

Abstract-Among subjects participating in 14 placebo-controlled drug cross-over studies, lefthanders showed a greater drug-related change in their electroencephalograms (EEGs) than did righthanders. Response differences between left- and right-handers were not hemisphere-specific. Further. the magnitude of EEG changes correlated with handedness scores. A greater effect ofcentrally active substances in left-handers may, in part, explain the high incidence of left-handers among those with certain brain-related pathologies and the evolution of right-hander predominance in the general population.

INTRODUCTION LIMB BIAS has been shown in a number of mammal species. It is found symmetrically distributed in all except humans [2,4, lo]. Estimates of the proportion of left-handers in the human population have ranged between 6 and 16% [9] and, from a study of hand-use depictions in art forms, have remained within this range for at least 5000 yr [S]. This proportion may have been greater among early humans [17] and has been reported to be higher among those with certain brain-related pathologies--.the mentally retarded, epileptics and the learning-disabled [ 18, 201. Explanations for these observations remain controversial. The relative contributions of genetic and environmental factors are in dispute. Data on the handedness of relatives and studies in twins, which have been used to support genetic models for the development of handedness [3, 143, have been alternatively interpreted as supporting sociocultural theories of this development or theories that left-handedness may result from left hemisphere pathology in would-be right-handers [18]. Missing from the genetic models has been reference to some heritable characteristic associated with handedness that might explain the higher incidence of left-handers among certain populations and the anomalous handedness distribution among humans. The present report provides a possible link. In a study of hemispheric differences in drug response, IRWIN and FINK [12] incidentally observed that four left-handers had distinctly larger drug-induced changes in their electroencephalograms (EEGs) than non-left-handers. To further explore this finding, I examined our entire EEG data base of 19 placebo-controlled cross-over studies. Each study had been designed to identify psychoactive drugs and predict their therapeutic properties by comparison with other drugs and placebo, as described by FINK [6]. Fourteen of the studies included at least one left-hander.

*Present

address

and address

for reprints:

Sandoz

Inc., East Hannover, 61

NJ 07936, U.S.A

62

PETERIRWIN

METHODS Hand preference in these studies had been recorded to control for its influence on task performance. Handedness or left-handed’!” Answers were recorded as “left”. was defined by response to the question. “Are you right-handed “ambidextrous” or “right”. A more rigorous determination was subsequently made, as will be described. Subjects in these 14 studies were 104 male volunteers, primarily university students. They were between 19 and 29 yr of age and weighed between 50 and 90 kg. Each had a normal health history, was without evident pathology, and had a normal resting EEG record with well-defined occipital alpha activity. Sixteen professed to be left-handed. foulambidextrous and 84 right-handed. The proportion ofleft-handers in our total data base. I6 of I I2 subjects (14”,,J. is consistent with estimates among males in the general population [9]. A 15-min EEG had been recorded from the left and right occipital-to-vertex regions before and at multiple times after drug administration. All left and some right hemisphere signals were quantified in lo- or 20-set segments, using power spectra1 density analysis. Resulting spectra were averaged over all segments in each 15-min recording, and the intensity in each cycle-per-second (cps) band was expressed as a percentage of the mean Intensity in the entire spectrum. Further details of methodology are reported elsewhere [7]. The drugs in these studies differed in their pattern and time course ofeffects on the EEG. 1.0 get a single mcasurc of drug effect in each session that would be comparable across drugs, I first subtracted pre-drug values from post-dl-ug values in each cps band between 1 and 30 cps and averaged the unsigned differences. This measure is called a “spectral difference index” and has been shown to be sensitive to differing effects of drugs [I 11. I then used the maximum value of the spectral difference index among all sampling periods in a session (SDI,,,) as the single measure of EEG response to drug.

RESULTS Drugs eliciting greater EEG effects than placebo were identified by means of a pairedvalues (PcO.05 criterion). Of 26 drug doses examined in these samples r-test of SDI,,, studies, 15 had an effect on the EEG that was discriminable by this criterion. These will subsequently be referred to as “active” drugs. They included diphenhydramine, 50 rng----an antihistaminic; brotizolam, 0.3 mg, and flurazepam, 10 mg--~sedative/hypnotics; mlanserin, 6 and 10 mg--an antidepressant; flutroline, 30 rng-~-an antipyschotic; clonidine, 0.075 mg an antihypertensive; aspirin, 1950 mg-an analgesic/antipyretic: and five investigational compounds*--0RG 2566, 10 and 20 mg, ORG 2305, 40 mg, 6-azamianserin, 2 mg (two studies), GC-46, 15 mg. and ORG 2408. 20 mg. The distribution of drug-minus-placebo SDI,,, differences was examined for each of the 15 active drug doses (Fig. 1). Although only 13 (15%) of the 88 subjects who received these active substances were left-handed, a lefthander had the highest response to two-thirds of them Among the 11 drug doses not demonstrably active by the SDI,,, (Fig. 2), fibe of the drugs were shown to be active in the brain at higher doses or by other criteria. These included brotizolam, 0.1 mg, and aspirin, 650 mg, which were found above to be active at higher doses; phenytoin, 1000 rng--an anticonvulsant: imipramine, 30 mg-~~-~an antidepressant; and haloperidol, 4 rng- -an antipsychotic. After these five drugs, left-hander responses were more frequently above than below a median. The remaining six drug doses were found not to affect the EEG and included terfenadine, 60 mg--an antihistaminic; ACTH,_,, 60 rng--a segment of adrenocorticotrophic hormone; des-tyr-IN-endorphin, 2,4.5 and 9 mg---an investigationai substance; and pirenzepine, 150 mg-an anti-ulcer drug. After these EEG-inactive drug

*Chemical structures of the mvestigatlonal compounds are as follows: ORG 1566, Irans-2-dimethylamlno1,2,3,4,10,14b-hexahydro-dibenzo[c,flpyrido[1.-2-a]azepine monohydrochloride; ORG 2305. 1,2,3,4.4a.9hexahydro-2-methyldibenzo [c,fl pyrimidino(l,6-a)azepine(E)-2-betenedioate: 6-azamianserin (ORG 3770), 1,2,3,4,10,14B-hexahydro-2-methylpyrazino(2,l-a)pyr~do(2,30c)(2)benzazepine: GC-46,2[N]-methy!-1,3,4.14bzr31,2,3,4,10.14b-hexahydro-2.7-dimethyltetrahydro-2H-pyrazino[l,2-d]dibenzo[b.f[1,4]oxazepine: ORG 2408, dibenzo[c,qpyrazine[l,2a-azepine](z)-2-butendioate. Further information about these and the other substances may be obtained from references [6] and [l l] and from the International Association for Psychiatric Rcsearih, Inc. P.O. BOX 457, St. James, New York.

tiREATER

BRAIN

RESPONSE

OF LEFT-HANDERS

TO DRUGS

63

Distributions of EEG Responses to Active Drugs Drug-Placebo SDI,,, (% powericps)

Dlphenhydramlne

50

ORG 2566

10

ORG 2566

20

ORG 2305

40

6.Azamlanserln

2 2 03 10 6 10 15 30 0 075 1950 20

FIG. 1. Locations of left-handers (letters) are shown withm the distributions of FEG responses to active drugs. The SD],,,,, after each of these drugs is greater than after placebo (P~0.05). .Although less than one in five subjects receiving any single dose is left-handed, a left-hander is the highest responder to ten of the 15 treatments. A left-hander response is below a median in cnlp four of 23 instances, and in no case is in the bottom quartile. All drugs were administered orally.

doses, left-hander responses were equally distributed about the medians. A left-hander had the lowest response to only one of all 26 drug doses. To facilitate statistical comparisons, 1 ranked the responses to each substance in each study separately and expressed the ranks as percentiles. Left-handers did not differ from other subjects in their ranked responses to placebo. Of the 13 left-handers, 11 had a greater mean rank-percentile after active substances than after other substances, including placebo (Pt0.001, Wilcoxon matched-pairs signed-ranks test). Left-handers were not, therefore, more sensitive to the entire experimental situation, but were specifically more sensitive to the active drugs. These findings were based on data from the left occipital-to-vertex region. Since the left hemisphere controls motor function in the right side of the body, I investigated whether the observations were hemisphere-specific by examining all of our available data from the right occipital-to-vertex region. Data from five studies had been quantified previous to this investigation and were found to be representative of the entire data set. Results from these two derivations were almost identical, suggesting that the greater drug rospcnses of the lefthanders were not hemisphere-specific (Table 1).

PETERIRWIN

64

Distributions of EEG Responses to Drugs Not Demonstrably Active by SDI,,.

Drug~Placebo SDI,.. (“b powerlcps, -2 L

Dose(mg)

Drug

_~~

-1 1~

o

2

3

I

J

n

EEG-lnaclm Tmfenadlne

60

18

ACTH, I,

60

12

Des~tyr-y-endorphln

2

6

Ues-tyr-y-endorph,n

45

12

Des~tyr-y-endorphln

9

12

150

10

Plrenreplne

M&an

Phenytol”

1000

12

A, E.....P

= LEFT-HANDERS

FIG. 2. Locations of left-handers (letters) are shown wlthin Ihc distrlbutlons of EEC; responses to drugs which did not ditkr from placebo in their effects on the SDI,,,. With six drug doses which were “EEG-inactive”, the distribution of left-hander responses IS indistmguishable from that of the other hubjects. With five substances demonstrably active m the brain by other EEG criteria or at a higher dose, five left-hander responses are above and only one below a median. and left-handers hale the highest response to two of the drugs. Des-ryr-;,-endorphin has administered Intramuscularly, the other drugs orally. Phenqtoin and halopcridol wcrc admmistered in divided doses. u ith an Interdosc inter\24 of 1X and 80 min respectively.

1 next asked how direct the drug-response/handedness relationship was. The initial classification of handedness had been crude. A number of authors have claimed that handedness is a continuum and that self-classified left-banders use their right hands for up tc: 90:?({of queried activities [l, 13, 16. 191. To examine the relationship between degree of lefthandedness and drug response, I mailed a 17-item hand-use questionnaire to each subject. The questionnaire items and scoring followed those of J~INS~ONE rr cr!. [13], who had adapted the earlier questionnaires of OI.DFIEI_I~1161 and of ANYFIT Cl]. The) reported high correlations between scores on their version and both unimanual task performance and EEG asymmetry. I added a question about overall hand preference. Seventy subjects (62.5%) replied to the mailing. Of these, 56 were among the 88 subjects who had received at least one active drug. Scores ranged from - t 2, all tasks done with the left hand, to + 12, all tasks done with the right hand. With the exception of one left-hander. who reclassified himself as a right-hander, no setf-classed left-hander had a handedness score

GREATER

Table

1. Hemispheric

BRAIN

RESPONSE

comparison

OF LEFT-HANDERS

of the EEG response

65

TO DRUGS

of left-handers

to drugs

Percentile rank of SDI,,, (mean & S.D.) Sessions

Left hemisphere (%)

14 studies 15 active drug doses 11 inactive drug doses Placebo

23 17 21

75.1 +23.9 50.6 k 29.4 52.0 + 37.0

Subset of 5 studies 5 active drug doses 3 inactive drug doses Placebo

10 5 10

74.8k25.4 58.6k31.3 51.2k26.4

Right hemisphere (9’) 0

14.5 f 22.7 60.0 * 33.3 48.8 +29.1

In five studies from which both left and right occipital-vertex data were available, the means of percentile rank responses in the two hemispheres are indistinguishable. This indicates that the greater responses to “active drug-doses” are not hemisphere-specific. Percentile rank= 100 x (rank -0,5)/(number of subjects receiving drug-dose).

above 0, and no self-classed right-hander had a score below 3 (Fig. 3). Handedness score and EEG response to drug were linearly correlated. Of 24 subjects who had a score of 10 or less, nine had a mean response rank above 85 %, while none had a mean response rank below 28 %. Those with the least brain response to these drugs were almost exclusively right-handed.

DISCUSSION In the present study left-handers were found to have a greater EEG response than non-lefthanders to a variety of drugs. The magnitude of drug response was correlated with hand usage, and individuals with the least EEG change after drugs were almost exclusively righthanded. The range of properties of these drugs and the range of metabolic pathways and sites of action they represent suggest a general hypothesis that non-dextrals are more sensitive to centrally active substances than dextrals. There is support for this hypothesis in a recent investigation of the incidence of lefthandedness among schizophrenics. MCCREADIE et al. [15] found that among Feighnerpositive schizophrenics, 13 (68%) of 19 non-dextrals developed tardive dyskinesia, as compared to only 19 (29%) of 66 dextrals. Tardive dyskinesia is a movement disorder which develops in some patients after long-term treatment with neuroleptic drugs. The higher incidence of this illness among non-dextrals is consistent with the hypothesis that they are more sensitive than dextrals to centrally active drugs. If extended to endogenous substances, this hypothesis could account for the higher proportion of left-handers among previously cited subpopulations-patients with mental retardation, learning disabilities, or epilepsy [ 18,20]- -assuming that neuroactive substance concentrations are critical to these conditions. Similarly, a greater brain sensitivity of lefthanders to neuroendocrines may explain recent findings of a higher frequency of immune diseases among left-handers [S]. Neuroendocrines have been postulated to influence immune responses through, among other processes, hypothalamic regulation of endocrines and neurotransmitters [21].

66 Association of Ranked EEG Change after Drugs and Handedness

EEG (SDI,, ,, %rank)

50-j

I

~

FIG. 3. The response rank for each subject is his me:+c “,,-rank SDI,,, after all RC~IVCdrug doses he received. A least squares regression iine has been fitted to the medmr: rc>ponses and median handedness scores among subjects in each hanJcdncss score slix ( i i. rmcdIScl pri;duct mcment correlation coefficient calculated for this fit. Handedmx score = (sum of tasks dvne wth right hand) minus (sum of tasks done with left hand) [13].

From the perspective of evolution, a greater resistance of right-handrrs to centrally active substances, when man was a forager and before he learned to identify non toxic edibles, would have favored right-bander survival. This might account for rhe skew in the present handedness distribution that is unique to humans. It remain; to discover the etiology of this finding--whether left-handers differ in their absorption or metabolism of drugs, membrane barrier characteristics, or response thresholds. Results of such an inquiry could resolve the controversy over the relative influence of genetic and environmental factors on the development of hand preference.

GREATER URAlN RESPCNSEor LEFT-HANUERSTo URL’GS Acknowfedgcments-This work was supported, in part, by the International Association for Psychiatric Inc., St. James, New York, and by Biomedical Research Support Grant RR-05836 from the State ofNew data base was developed it-, collaboration with Professor Max Fink, M.D., whose comments and general gratefully acknowledge. Emily Pall Spelke, Bonny Barron, Linda Marino, Robert Newbold and Pierre assisted in data collection and ana!ysis. Each subject gave his informed, written consent to participate studies. All procedures ac? drugs administered were approved in advance by the Committee for Research Subjects at the State University of New York at Stony Brook, New York.

67 Research, York. The

support 1 M. Hahn in these in Human

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

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