Some speculations concerning a possible biochemical basis of minimal brain dysfunction

Life Sciences Vol. 14, pP . 1605-1621 Printed in II . S.l1.

Pergeaon Press

MIIAIRSVISSI

SOME SPECULATIONS CONCERNIIVG A POSSIBLE BIOCHEMICAL BASLS OF MIIVIMAL BRAIN DYSFUNCTION Paul H. Wander, M. D. University of Utah College of Medicine, Salt Lake City, Utah 84132 (itacaivad in final form 16 January 1974) Minimal brain dysfunction (MBD) is one of a number of designations for a common behavioral syndrome of childhood . Other terms which have been employed include :

The hyperactive child syndrome,

hyperactivity, hyper

kineeis, minimal brain damage, minimal cerebral dysfunction, etc.

The

boundaries of the syndrome are unclearly defined, but there is general consensus regarding the signs of typical MBD children .

These are: (1) behavioral ;

(2) perceptual and cognitive . Ae good a summary as any of the behavioral abnormalities Ls that of L.aufer and Denkoff is their description of the "kyperkinetic behavior syndrome" . Among the characteristic features are : kyperactivity -- "involuntary and constant over-activity that completely surpasses the normal. . . and may already be present during early infancy" ; a short attention span and poor powers of concentration, wick the children generally being unable to persist for Long in an activity whether at play or st school ; impulsivity and "inability to delay gratification" -- the child is described se "doing things oa the spur of tke moment, without thinking" ; aahedonia -- the child "despite the mother(e)' best efforts is tense, unhappy and demanding" . . . poor school work which "seems to be a compound of problems is the visual motor perception (mentioned below) and concentration areas" . A variety of forms of perceptual-cognitive dysfunction ezist. These Include impa[rments 1605

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in visual and auditory discrimination, visual and auditory memory, spatial relations, and abstraction.

In terms of concrete tasks, these are children

who will show difficulty in right-Left discrimination, separating their p'e and q's, spelling phonetically, and reading .

Two characteristics, one of which

has been mentioned, that I have found to be particularly prominent among MBD children and which may deserve special emphasis, are a diminished ability to ezperience pleasure and frequent refractoriness to disciplinary measures of any sort .

It ie important to emphasize that the two measured

categories of deficit (behavioral and perceptual-cognitive) though linked, may occur independently .

Some children manifest only the behavioral difficulties ;

others manifest only perceptual and cognitive problems ; and, finally, some children manifest dysfunction is both areas . The purpose of this brief review ie not to delineate all aspects of the syndrome but to provide the basic facts necessary for biochemical speculation . Still, a few words oa prevalence, prognosis, etiology and treatment are in order .

Prevalence :

Exact estimates are difficult to obtain since the bouad-

areas of the syndrome are unclear ; still, prevalence figures from a variety of areas come up with the same order of magnitude, five to ten percent . Etlobgy. In the peat the disorder had been thought to be due to brain damage (hence, one of its names) ; evidence suggesting other etiologies will be advanced presently . Prognosis :

In the past MBD had been thought to be a disorder which was out-

grown with age ; the definitive answer is missing but present evidence would suggest that is many children the disorder persists well into adolescence . Therapy : A number of pharmacological and social therapies have been employed .

The most dramatically effective, at least on a short term basis,

has been pharmacological .

MBD children often respond dramatically to treat-

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meat with stimulant medication . It ie this fact which has prompted eo much controversy over the disorder and its treatment . If MBD children had had the wisdom and foresight to respond to Lithium, their treatment would have avoided much moralistic lnvecttve from -- mirab[le dicta -- the far left and the far r ig ht . Having presented an over-abbreviated summary of MBD, I would Like to advance some straight forward hypotheses about MBD and briefly present evidence which 1e consistent with them . My major hypotheses are: (l) That MBD ie a family of disorders which is quite broad and whose boundaries are very unclear ; (2) that it is a genetic disorder of monoamine metabolism ; (3) a third assertion, which I wish to make, although I will not attempt to adduce evidence for it here, ie that MBD is, in many instances, a life-Long disorder . The extent of the minimal brain dysfunction syndrome The delimitation of MBD posse the same problems as does that of any other psychiatric disorder .

"Classical" MBD ie defined by the presence of

the behavioral and perceptual-cognitive signs already mentioned . UafortunaEely, in practice one fads individual children who run the gamut from possessing all of the signs mentioned to possessing a few or only one. Given the fact that MBD is a disorder with varying manifestations, how are we to eetabl[eh Lts bouadariee7 Compare what has been done in the definition of rheumatic fever, a disorder which may present with varying combinations of neurological, cardiac and jotnt signs. Unlike MBD, rheumatic fever is a disorder with a fairly well accepted pathogenesis and a reasonably well documented micro scopic and gross pathology. One can predict the existence of the underlying tissue pathology fairly well by the utili$ation of certain clinical predictors (decision rules) . It has been found empirically that individuals who have at

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Least two "major" or one mayor and two "minor" eigna (symptoms) have a high probability of possessing the underlying tissue pathology characteristic of rheumatic fever . How are we to establish some "major" and "minor" criteria for MBD since we can not proceed to discuss the phenomenological In terms of known underlying pathology?

The answer is that we can not (although opera-

tional criteria are often established by fiat for research purposes which require the defining of populations) . The eetabllshmeat of the boundaries of MBD suffers from the same epistomological frailties ae does that of any other psychiatric disorder . The problem with MBD ie extremely similar to that which exists in the case of schizophrenia . It is a problem, I suspect, which will yield to the same research strategies . There are a number of phenomenological states which bear varying degrees of resemblance to one another, all of which have been designated by the term "achlzophrenia", despite their eymtomatic diversity. Compare the acute, the borderline and the process schizophrenic . Among the process schizophrenics, compare the dissociated hebephrenic and the litiginoue bcally deluded paranoid .

Lastly, consider

Kallman's "echizoidia", a term applied

to very faint manifestations of schizophrenia . What evidence is there suggesting any relationship between these seemingly heterogeneous disorders?

The

answer is a very simple one. The. relationship between these disorders was suggested not only by overlapping aspects of observed behavior but also by classical genetic pedigree etudes . Esrly twentieth century psychiatrists, who investigated the relatives of typical schizophrenics, felt that these relatives manifested as increased prevalence of various schizophrenic-like behaviors. These findings were not universally accepted beeauee these early studies were

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subject to criticisms with regard to methodology and with regard to their premature conclusion that the increased prevalence of such dieordere among the relatives of true schizophrenics was aecesearily genetic .

I am alluding, of

course, to the familiar point that familial association of behavioral attributes can be the result of both genetic and social transmission.

Until recently, the

truth of the echizoidia concept or schizophrenic spectrum concept could not be ascertained. A way out of the dilemma, which has shown a biological relatednose of these various dieordere and confirmed the observations of the early workers, ie the use of the strategy

of adoption to separate nature

and nurture. This is a technique which has been put to use by my collaborators, David Rosenthal and Seymour Katy and myself in the study of schizo phrenia.

The moat interesting finding of these schizophrenia studies to me

was not the fact that schizophrenia was indeed a genetic disorder but the fact which we are wrestling with at present, that schizophrenia is a disorder which does occur along a phenomenological spectrum .

It ie like intelligence, height

or weight, and ie not an all or nom phenomenon. Despite our diïficulty In uaderetanding it, there ie something very much is common between the charming, promiscuous borderline, the smearing hebephrenic, and the dry schizoid social isolate. What is particularly interesting -- and I will discuss this is terms of MBD -- is that it is hard, if not impossible, to pick one, much lees several, basic attributes that all of these Individuals have in common .

Ia the

case of the various schizophreaiae, two states may show no qualities in common; yet each shares qualities wlth a third.

This type of "family related-

neee" is one I am hypothesizing also takes place with regard to MBD . Schematically, it may be illustrated ae follaave : Syndrome A has characteristics lthrough 3, syndrome B has characteristics 2 through 4, C has 3 through

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5, D has 4 through 6.

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le D related to A 7 No general abstract answer can be

provided ; if one found more D's among the adopted-away offspring of A'e than ezpectable by chance, one would assume that D's are "genetically related to" A's despite the fact that D's share a relatedness only through "intermediaries'. In the case of MBD, A might be a clumsy, overactive child without any perceptual and cognitive problems, and D might be a normally active, well coordinated child with a "specific learning disorder" . Neither shares any characteristic with the other, but both share characteristics with a third child with "full-blown" manifestations of MBD, that is, a hyperactive, clumsy child with perceptual and cognitive abnormalities . The only study is the literature which supports this assertion is that of Hallgren . I encounter this MBD spectrum phenomenon so repeatedly when obtaining family histories, that I take the phenomenon for granted. I know -- or at least would hope -- that the hackles of the reader would rise in response to the kind of logic just advanced . logically this approach is fallacious .

I am fully aware that

In fact, it is the Barbara fallacy which

von Domarus has judged to be pathognomonic of schizophrenia . It ie the logical equivalent of saying A is a B, C ie a B, therefore A ie a C, or "the mother of God's name was Mary", "My name ie Mary", therefore, "I am the Mother of God" .

It may reassure the reader that although employing schizo-

phrenic logic, I still retain insight. I am belaboring this state of affairs because, since it occurs is schizophrenic, a disorder in which we have shown the genetic characteristics play a large role, the same state of affairs may hold true with regard to MBD, which

I

likewise regard as

a

disorder which ie genetic in origin,

Studies of psychiatric illness among the parents of MBD children have been

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performed, and reveal as increase of some forms of psychiatric illness ; the parents also show a greater than chance expectancy of having been hyperactive is childhood .

Likewise, there is data showing the familial clustering of

"dyslexia" (a term used to describe reading impairment which is often associ aced with the perceptuai-cognitive problems mentioned) .

To be precise, family

studies can not prove that a disorder is transmitted genetically . What is needed are adoption studies which separate nature and nurture ; two studies have been performed and are consistent only with genetic transmission . If one takes careful histories of families of MBD children, and by careful I mean leisurely accounts where one explores the personality of parents,

grand-

parents, uncles and aunts, siblings, etc ., one is impressed with the fact that MBD does not "breed true" . But -- and this to me is very important -- there seems to be an increased, difficult to characterize, prevalence of what I would refer to se "MBD non-specifitie" among such relatives . Oae relative is clumsy, another is impulsive, another has a hot temper, another has a read :g disability .

Or, starting with a child with a reading disability, one finds a

sibling who is hyperactive but has no perceptual or cognitive problems .

This

state of affairs bothers aoeological hardheade . It would have bothered me had I not had ten years of experience with the adoption studies of schizophrenia. I now accept the spectrum model as typical for genetic mental illness and would be disappointed not to find it present among MBD. There ie another parallel between MBD sad the schizophreatas .

Some

types of the schizophreniae respond well to treatment with the phenothiazinee while others respond partially, and still others respond not at all. Ia general, the acute schizophrenic might recover, the excited chronic schizophrenic calm down with anti-psychotic drugs, while the borderline shows no appredabb

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response . Though these various conditions do not share similarity of drug responsiveness, they do possess genetic relatedness.

I hypothesise that a

eimllar state of affairs eziste with regard to MBD. I am not alarmed by the fact that the hyperactive child without learning disability responds brilliantly to stimulant drugs while the child with learning disabilities without hyper activity does not .

By analogy with the echisophrenias, I am prepared to

expect this state of affairs and do not believe it to contradict the fact the two conditions may be genetically related. A Possible Biochemical Basis for MBD If MBD does occur on a genetic basis, what aspect of brain function is being genetically transmitted?

Using a computer analogy, the genetically

transmitted abnormality must be manifest either in the components (tubes, relays, transitors, or neurons), the wiring, or the programs . Gives our present neurological knowledge and techniques, one must hope that the genetic abnormality is in the elements . Furthermore, one must hope that the genes) is question are controlling ensymes rather than protein structure . In short, one hopes that the defects will be in ensymatic function in certain portions of the nervous system. There are two pieces of naturalistic data that suggest the possibility of such a biochemical, ensymat[c, deficit. The first is a relationship of MBD to von Economo's encephalitis . The World War I pandemic of laflueasa sometfrrns produced a post-encephalitic Parkinsoniaa syndrome in adults and a poetencephalitic behavior disorder in children . The now 50 year old descriptions of the post-encephalitic behavior disorder Bound very much like typical MBD . Since Parkinson's syndrome apparently is associated with the destruction of certain dopaaminergic neurone, one inference that might be drawn from these

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data is that the voa Economo's virus had a predilection for neurons containing catcholamines . Oae may then speculate that when the infection occurred is as adult, Parkinson's disease was the result, and when the same or other neurone containing catcholamiaes were effected in children, MBD was the result . The implication is that a deficiency of catacholaminergic function can produce MBD symptomatology . Presumably, this deficiency might be the result of aaatomical Lnsult or functional underactivity. More direct evidence indicting dopaminergic neurons to particular will be dtecuseed later . The second datum suggesting a biochemical deficit to certain MBD children ie the response of such children to drugs . I have used this argument many times is the peat and I am aware of its pitfalls . Response of arthritis to cortisone does not imply a lack of adequate adrenal function in arthritis and response of pneumococcal pneumonia to penicillin does not imply a defect Ln the enzymes of the penicillinsynthesizing gland . Nonetheless, the response of some MBD children to stimulant, and more rarely to antidepressant medication, does suggest that is these children s specific deficit is being reversed . All who have treated MBD children with these medications are aware that in an appreciable fraction of instances they produce very specific effects . By this I mean that such drugs produce changes in behavior at levels far more complez and important than simple motor activity .

The effect of stimulant drugs and antidepressant drugs

in some MBD children is remarkable . For the duration of their action, these drugs can produce immediate psychological growth . At such times the children mny display moss mature cognitive, social and interpersonal behavior thaw they have ever shown. Such responsiveness suAgeste an intervention close to the origin of the causal chain. What then becomes intriguing ie that, knowing something about the mechanism of action of these agents, we may make some inferences

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as to what kinds of deficits are being corrected .

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The stimulant and aati-

depressant drugs act variously to increase the functional activity of those areas of the CNS in which noreplnephrlae, dopamine, neuro-transmitters .

and serotoaia are the

By direct and unoriginal analogy with the "monoamine

hypothesis of depression" one may infer that at least one sub-group of MBD children has a functional underactivity of one or more of the monoamiaergic systems . Given the hypothesis that some MBD children have a functional monoaminergic deficiency, one may proceed ae follows :

first, one may attempt to

specify certain primary (in the Bleulerian sense) characteristics of MBD chüdrea .

Nest, one may inspect what ie known about pharmacology and be-

havior to see if monoaminergic activity is related to these characteristics . This is the tack I chose is previous speculations .

I proposed that many child-

ren said to have MBD are characterized by two major abnormalities :

(L) an

apparent increase in arousal, accompanied by an increased activity level and a decreased ability to concentrate, focus attention and inhibit response to the irrelevant ; (2) a diminished capacity for positive and negative affect, the apparent subjective effect of which was a

diminished ability to experience

pleasure and pain and the behavioral aspect of which was a diminished seneitivity to positive and negative reinforcement .

I then proceeded to outline

mechanisms by which these primary deficits might result in the observed behavioral abnormalities .

For example, the attentional deficit would account

in part for the . reported disobedience since what ie not heard is not acted upon . "Forgetting" parental and teacher requests will produce a picture of social non-compliance .

Obviously, failure to attend to classroom material, despite

its excessive redondance, will result in decreased performance .

The second

deficit would be expected to impair social learning through positive and

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negative reinforcement. As a result, "shoulde" and "should note" would be less effective.

Children would fail to heed cautions, requests and demands .

By extrapolation, if internal controls developed In parallel or analogously to external controls, such children would be expected to have less "self control and be more "impulsive".

Such a model does not account for many other

behavioral characteristics frequently seen in MBD children such as clumsiness, perceptual and cognitive difficulties, etc.

The failure to accommodate all the

data is unfortunate but not, I feel, devastating.

Compare the currently popular

dopaminergic theory of schizophrenia. Evidence supporting this theory comes from the fact that large doses of amphetamines can induce a state similar, if not indistinguishable, from as acute paranoid schizophrenic reaction, that anti-psychotic agents which reverse amphetamine toxicity and decrease schizophrenic eymptomatology have structures similar to dopamine, and that antipsychotic agents seem to Mock dopaminergic receptor sites . The theory does not explain why borderline schizophrenics, who are genetically related to process schizophrenia do not benefit from anti-psychotic medication or why in chronic schizophrenia only certain schizophrenic symptoms respond to antipsychotic medication . Facetiously, this theory of MBD is just as bad -therefore just as good -- as the incomplete schizophrenia theory . To recap my previous speculations, I examined the available data regarding the role of monoamines in arousal and reinforcement and clinical or laboratory data relating to arousal and retaforceability in MBD children . MBD children appear to be hyper-aroused.

The cognitive chsracteristica

of MBD children resemble those seen is ostensibly highly aroused adults . Such characteristics include decreased attentiveness, inability to focus oa the relevant, and increased difficulty is figure-ground discrimination ; they are

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similar to those seen in early schisophreaic excitement and mania. Another datum suggesting hyperarousal comes from the reported sleep characteristics of MBD children . I know of no controlled studies, but it appears that MBD children seem to have more than their share of sleep difficulties including early awakening and difficulties is falling and remaining asleep.

The deter-

urination of the arousal state of MBD children demands operational criteria of arousal. Stevens, et al, studied the EEG's of children with behavior dieorders and found a positive correlation between hyperactivity and inattentivenoes and occipital slowing. Wickler, et al, found ezceeaive non-age-depe~ent EEG slow activity is "hyperactive" children, i. e. , there was lean of a bendmcy for the percentage of time of slow wave activity to decrease with age . Insofar as slow activity is a measure of decreased activation, both these studies support the assertion that MBD children are hypo-aroused . Using the GSR as a measure of arousal, Satterfield and Dawson ezamtned "hyperkinetic" children and found a elgnificaat fraction of them to have higher skin resistance and fewer variations in resistance, both characteristics that are assumed to indi cats Low arousal.

In conflict with these laboratory data is the clinical observa-

tion that some young MBD children sleep better on amphetamines and two clinical experiences of mine with MBD children grown up who remained symptomatic and who described becoming more sleepy on etimulaatmedicatioa. Having unsuccessfully resolved the question of whether MBD children are hypo or hyper aroused, what are the animal data about the relationship between monoamines and arousal? Simply that the two seem intimately, related . The question is how?

There ie a rapidly growing mass of confusing data . The

confusion stems from the possibility that the same eubetancemry®rtoppoeite effects in different parts of the brain, that apeciea reapoasea may vary, that

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generalisation from pharmacological experiment to physiological function is unwarranted, and that arousal in man may have little to do with the excitement and hyperactivity we measure in animals . Illustrative of the difficulty is the fact thatnorepineprine injected iatraventricularly produces sedation while when injected infra-hypothalamically it produces ezcitation. A crude overview would suggest that serotonin appears to decrease motor activity whereas dopamine and particularly norepiaephrine appear to increase activity and decrease sedation . With regard to the neurochemical basis of reinforcement, the second postulated functional deficit, there ie a fair amount of animal data relating reinforceability and monoaminergic function.

The animal behaviors moat

frequently studied have been operant reinforcement by electrical stimulation of the brain and active and passive avoidance conditioning . Since the data are not all congruent, it becomes Important to determine which animal paradigm, if any, parallels the impulsivq socially refractory behavior of MBD children . The animal data suggests that the reinforcement produced by electrical etimulation ie potentiated by drugs such as amphetamines which facilitate the activity of monoaminergic systems and ie decreased by agents that decrease the activity of such systems. Depending where the stimulation ie given, dopamiaergic .or aoradrenergic activity seems to mediate reinforcement. With regard to two-way avoidance, the data seem to indicate that increased Levels of norepinephrine facilitate and that decreased levels inhibit such avoidance, that the role of dopamine ie ambiguous, and that serotoain is apparently unrelated to such behavior . A difficulty is eztrapolating from these ezperiments ie that electrical stimulation of the brain and the two-way avoidance task may not provide a good model for social compliance and non-impuleivtty. Two-way

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avoidance is employed more frequently because the technology is simpler . However, It entails an animal's returning to an area where he has been ehacla:d which may be a greater measure of disinhibition than "animal caution" .

One-

way avoidance -- which is technically more of a aulsance, is probably a better parad[gm.

In this instance, the animal must refrain from entering an area

where he once has previously been shocked .

I have not looked at this literature

recently, but as I recall amphetamine decreases performance, i . e, increases impale rutty. A second overlapping strategy for unravelling the MBD problem would be to manipulate monoamiaergic activity levels, determine the effects on behavior and attempt to extrapolate to children . data which I have already mentioned .

This approach is included in the animgl Yet another approach ie to produce an

animal analog of MBD and see what, if any, are the accompanying neurochemical changes .

Corson and colleagues have reported on a number of dogs

which are behaviorally eaciteable, difficult to condition is a Pavlovian paradigm, and which are sedated and rendered conditionable by treatment with amphetamines .

Two other animal models have recently been produced ; sectlon-

lag the corpus calloeum of new-born kittens or giving sublethal doses of lead to new-born rate both produce exciteable adults who are sedated by treatment with amphetamines .

Neuroanatomical and aeurochemlcal studies of these three

animal models may provide more specific hypotheses concerning the type and location of the biochemical Lesion is MBD children . Suggeetlng that MBD is a genetically produced disorder of monoamine metabolism obviously suggests assessment of such metabolism is children . Direct meaeuresof such metabolism are not available and only indirect teats can be employed .

This places the theory in the same category as the mono-

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amine hypothesis of depression . What are some possible tests?

One may

suppose that the abnormality ie confined to the brain or that it ie only one manifestation of a generalized systemic abnormality.

One may aeaume that

the functional under-activity is due to decreased synthesis, release, or receptor sensitivity . So, we may: (1) Measure urinary monoamine metabolites in MBD children . This experiment has already been performed with a fairly heterogeneous group and failed to show any difference between the MBD and control groups .

It is possible that one sub-sample of MBD children does

have a generalized abnormality is monoamine metabolism.

In the study per-

formed, the variances in the MBD group were larger, although not significantly eo, than those of the comparison group. With the exception of MHPG, moat of the urinary metabolites are derived from extra-cerebral sources . Examination of urinary MHPG in homogeneous groups of MBD children would still make sense. (2) Tests of cerebral spinal fluids (CSF levels of monoamine metabolites) : If an abnormality does exist but is confined to the brain, one might expect to find differences in the CSF which were not reflected is the urine. In a lithium study of Greenhill and myself at the NIH, we obtained permission to do lumbar punctures on children but only did a few since these non-illchtl~3rea found the procedure very upsetting . Difficulties with this technique stem from the concern that the metabolites assessed may come from the spinal cord not brain metabolism and the fact that the metabolites are removed from the CSF. Theoretically, one could give probenecid to block 5-HIAA removal and thus measure eerotonin metabolism .

(3) Teste of altered autonomic nervous

system reactivity . If MBD children do have a generalized abnormality of monoamine metabolism, it might be evidenced in abnormalit[es of autonomic nervous system reactivity . Two possibilities exist . If there were diminished

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production and/or release, per[pheral receptors might ezhlbit increased sensitivity to ezogeaous amines (analogous to super-sensitivity in denervated receptors) .

Presumably, from the urinary study reported, production and

release are normal so that this possibility is unlikely . However, MBD chü]ren might have adequate production and release of amines with decreased receptor sensitivity.

In that event one would anticipate less cardiovascular responsive-

ness to ezogeaously administered sympathomimetic drugs . Ia particular, one might inspect the rate of blood preeeure increase produced by norepiaephrine is MBD end normal children. The possibility that variations of monoamiaeigic function may be produced by receptor reactivity rather than pre~ynaptic synthesis, release and metabolism is an important one. Oae pilot study has shown decreased blood pressure reactivity to ezogenoue aorepinephriae in seriously depressed patients . (4) Administration of drugs with known specific actions . By this technique one can perform a chemical dissection of transmitter function . Arnold, McCloskey and I evaluated the efficacy of D- and Lamphetamine is the treatment of a small group of MBD chiWrea. Ostensibly, and the facts do change from moment to moment, D-amphetamine ie ten times ae potent as L- is effecting norepinephrine metabolism but only equallyef8dive in chsagtng dopamine metabolism.

The fact that some MBD children respond-

ed to L-amphetamine as well as they did D-amphetamine implies that their lesion was dopamlaergic . A similar chemical dissection might be produced by testing the effects of a tertiary and secondary amine tricyclic antidepressant in MBD children . The former inhibits reuptake of both noreptaephrine and eerotoaia while the latter affect reuptake only of norepinephrine . If the former were effective while the latter were not, this would imply that eerdonin activity was diminished In MBD children .

(5)

Finally, one may administer

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amine precursors and blockers of amine synthesis .

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This is a strategy employ

ed in the study of depression, and is subject to the same Limitations .

If oaa

found that the precursors were effective therapeutic agents, one would still be in the dark as to what the underlying biochemical lesion was .

This is due to

the fact that pharmacological doses of precursor amines are apt to lodge in foreign neurons and act as "false transmitters" . I am not entirely satisfied with this monoamine hypothesis of MBD, not for theoretical but for pragmatic reasons .

Like the monoamine theory of

depression, this theory generates no predictions, failure of conformation of which would disprove the hypothesis .

It is a little too close to speculations

about the status of the iceboz light when the iceboz door is closed for complete scientific comfort .