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Early History of ADHD

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Early History of ADHD

  1. 1. Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=njhn20 Download by: [Syracuse University Library] Date: 21 October 2015, At: 10:47 Journal of the History of the Neurosciences Basic and Clinical Perspectives ISSN: 0964-704X (Print) 1744-5213 (Online) Journal homepage: http://www.tandfonline.com/loi/njhn20 The Early History of the Neuroscience of Attention- Deficit/Hyperactivity Disorder Alan A. Baumeister , Kristopher Henderson , Joni Lee Pow & Claire Advokat To cite this article: Alan A. Baumeister , Kristopher Henderson , Joni Lee Pow & Claire Advokat (2012) The Early History of the Neuroscience of Attention-Deficit/ Hyperactivity Disorder, Journal of the History of the Neurosciences, 21:3, 263-279, DOI: 10.1080/0964704X.2011.595649 To link to this article: http://dx.doi.org/10.1080/0964704X.2011.595649 Published online: 22 Jun 2012. Submit your article to this journal Article views: 643 View related articles
  2. 2. Journal of the History of the Neurosciences, 21:263–279, 2012 Copyright © Taylor & Francis Group, LLC ISSN: 0964-704X print / 1744-5213 online DOI: 10.1080/0964704X.2011.595649 The Early History of the Neuroscience of Attention-Deficit/Hyperactivity Disorder ALAN A. BAUMEISTER, KRISTOPHER HENDERSON, JONI LEE POW, AND CLAIRE ADVOKAT Department of Psychology, Louisiana State University, Baton Rouge, LA, USA Research on the neurobiology and pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD) has grown exponentially since 1980. A reasonable question is whether this research has improved our understanding and treatment of ADHD. This article describes relevant developments that took place roughly between 1900 and 1970. During this time, the efficacy of stimulant therapy for the disorder was established and the symptoms of ADHD were linked to many possible nervous system disorders including in the brain-stem, reticular formation, diencephalon, basal ganglia, frontal lobes, and cortex. In 1970, the catecholamine hypothesis of ADHD was proposed. It is concluded that early theories about the neurobiologic basis of ADHD anticipated core ideas of modern theory. Keywords attention-deficit/hyperactivity disorder, hyperkinetic reaction of childhood, organic driveness, encephalitis lethargic, Charles Bradley, Alexander Crichton, George Still, Conan Kornetsky, methylphenidate, amphetamine Introduction Attention-deficit/hyperactivity disorder (ADHD) has three core symptoms: attention deficits, hyperactivity, and impulsivity (American Psychiatric Association, 1994). Three subtypes of ADHD are recognized: (a) ADHD Predominantly Inattentive Type, (b) ADHD Predominantly Hyperactive-Impulsive Type, and (c) ADHD Combined Type. The literature on ADHD has grown exponentially since 1980 (L´opez-Muñoz et al., 2008). During this time over five thousand original articles have appeared worldwide. Seventy percent deal with pharmacotherapy, with methylphenidate (Ritalin) being the most studied drug. However, a recent trend and stimulus for research is the introduction of new formulations of other drugs, such as amphetamine salts (e.g., Adderall). Psychiatry depart- ments produced most studies on ADHD. Neurobiological and genetic aspects of ADHD are other areas of research emphasis in the modern literature (L´opez-Muñoz et al., 2008). A reasonable question is whether knowledge about the neurobiologic aspects and medical treatment has grown at the same pace as the literature. To assess this we have undertaken an analysis of the history of neuroscience of ADHD roughly between the years 1900 and 1970. This period witnessed several major developments including (a) the estab- lishment of the concept of “organic behavior,” (b) the introduction of stimulant therapy for childhood behavior disorders, and (c) the development of neurobiologic theories of ADHD. Address correspondence to Alan A. Baumeister, Department of Psychology, 236 Audubon Hall, Louisiana State University, Baton Rouge, LA 70803, USA. E-mail: abaumei@lsu.edu 263 Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  3. 3. 264 Alan A. Baumeister et al. Table 1 Chronology of Important Events in the Early Neuroscience of ADHD 1798 Crichton provides the first clinical description of attention disorder linking it to disturbances of the nerves. 1902 Still proposes disorders of brain cell metabolism as the cause of attention disorders. 1920s Encephalitis pandemics and their association with ADHD confirm organicity. 1926 Bond and Partridge describe post-encephalitic hyperkinetic syndrome linking ADHD to the basal ganglia. 1929 Hans Berger introduces the electroencephalography. 1931 Von Economo reports the brain stem is damaged in encephalitis patients. 1934 Kahn and Cohen propose concept of “Organic Drivenness” and link it to a lesion of the brain stem. 1937 Bradley observes EEG abnormalities in behavior-disordered children. 1937 Bradley reports the therapeutic effect of stimulants and proposes that they activate inhibitory cortical systems. 1939 Cutts and Jasper report amphetamine reduces behavior problems without reducing EEG abnormality. 1954 Methylphenidate is discovered. 1957 Lauffer, Denhoff, and Solomon propose a dysfunction of the diencephalon based on photo-metrazol EEG studies. 1957 Sigg and Schneider report that methylphenidate and reticular formation stimulation suppresses reserpine-induced rhinenchephalitic seizures in cats. 1958 Zimmerman and Burgemeister use methylphenidate in behaviorally disordered children. 1958 Bradley and Key report that amphetamine and methylphenidate act on the reticular activating system. 1959 Knobel et al. propose a “syndromic” approach using neuropsychological tests to establish organicity. 1960s Various researchers, based on neuropsychological tests, propose that ADHD is caused by deficient cortical inhibition of subcortical structures. 1970 Kornetsky proposes the “Catecholamine Hypothesis” of ADHD. These early neurobiologic theories anticipated some core concepts of modern theory. Table 1 contains a chronology of major developments in the early history of ADHD. ADHD was first formally recognized by psychiatry when it appeared in the second edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-II) published by the American Psychiatric Association in 1968. The DSM-II referred to the condition as “Hyperkinetic reaction of childhood.” It lists attention disorder and hyperactivity but not impulsivity as characteristics of hyperkinetic reaction. The name of the syndrome was changed to “Attention Deficit Disorder” in 1980 with the publication of the DSM-III. This revision did not consider hyperactivity to be an essential aspect of the disorder. Thus, the criteria that define the syndrome have changed with time. Mainly, this article deals with the period before the syndrome was formally recognized in its present form. Because the definition of ADHD has changed with time, to avoid confusion, much of the following discussion refers to specific signs and symptoms associated with ADHD rather than ADHD per se. Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  4. 4. The Early History of the Neuroscience of ADHD 265 Evolution of the Concept of Organic Behavior Many authorities today consider ADHD to be a neurobiological disorder. This is not a new idea. A book by Scottish physician Sir Alexander Crichton, titled An Inquiry into the Nature and Origins of Mental Derangement (Crichton, 1798/1976), contains the earliest known clinical description of attention disorders. In this book, Crichton devotes an entire chapter to “Attention, and its Diseases” (p. 254). He notes that these diseases make people “incapable of attending with constancy to any one object of education” (p. 271), that they cause “mental restlessness,” “walking up and down,” and the “fidgets” (p. 272). Crichton mentions all of the core features of ADHD except impulsivity. Palmer and Finger (2001) have argued that the disorder described by Crichton (1798) is the inattentive subtype of ADHD. Crichton recognized that attention disorders can have multiple etiologies including “debility, arising from neglecting to exercise the faculty [attention] sufficiently” (p. 275), but he emphasized neurobiologic causes: The incapacity of attending with a necessary degree of constancy to any one object, almost always arises from an unnatural or morbid sensibility of the nerves. . . . It may be either born with a person, or it may be the effect of accidental diseases. (p. 271) Although Crichton clearly described attention disorders, George Still, a British pediatri- cian, is often credited with being the first person to describe ADHD (Schachar, 1986; Walters & Barrett, 1993). In 1902, Still gave a series of lectures on Some Abnormal Psychical Conditions in Children (Still, 1902a, 1902b, 1902c). He focused his discussion on defective moral control in children. By moral control, Still meant “the control of action in conformity with the idea of the good of all” (Still, 1902a, p. 1008). Still’s case materials, upon which the lectures were based, came from his many years of pediatric practice. The children described in the three lectures were extremely diverse. They included mentally retarded children, children who had suffered brain damage from various insults (e.g., tumors, encephalitis), as well as a small subset of children with normal intelligence and with no clear physical defects. Many of Still’s subjects, especially those with normal intelligence, would be considered to have conduct disorder today. The idea that Still described ADHD comes from passing statements about children with normal intelligence, such as “lack of attention which is very noticeable in many of these cases . . . no doubt accounts to a considerable extent for backwardness in school acquirements” (Still, 1902b, p. 1081), and “a notable feature in many of these cases of moral defect without general impairment of intellect is a quite abnormal incapacity for sus- tained attention” (Still, 1902c, p. 1166). Still is describing a group of children that would probably be labeled ADHD today. However, the subtype of ADHD that Still describes is unclear. He mentions children with attention disorders but does not describe this sub- set as hyperactive or impulsive. On the other hand, Still emphasizes the importance of impaired “inhibitory volition” in these children, which implies impulsivity. Thus, he may be describing either the inattentive or mixed subtypes. Although Still recognized the importance of the social environment in establishing inhibitory volition, he clearly placed emphasis on biological determinants of defective moral control and attention: “there is not only a perversion of function in the higher ner- vous centres but an actual physical abnormality underlying the moral defect,” and “the fact that a similar moral change occurs after more general diseases, particularly the specific fevers, and is followed sometimes by complete recovery, suggests that cell-modification Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  5. 5. 266 Alan A. Baumeister et al. dependent upon interference with cell-nutrition, may be the physical basis for the moral defect” (Still, 1902c, p. 1166). This is one of earliest suggestions that childhood behavior disorders can have a biochemical basis. The occurrence of encephalitis pandemics between 1917 and 1926 firmly established the association of behavioral disorders characteristic of ADHD with infectious disease. Encephalitis lethargica (or von Economo’s encephalitis), as the disease was called, was a sequelae of the Spanish flu (Ravenholt, 1993), which began during World War I and killed some 40 million people worldwide (Kolata, 2001). Encephalitis lethargica often occurred months after acute influenza and was characterized by lethargy, fever, and oculo- gryic crisis. The disease was fatal in about one third of cases. Among the survivors, fully 80% developed Parkinson’s disease (Post-encephalic Parkinsonism) during the ensuing decades. The encephalitis epidemics led to the recognition that behavioral sequelae could be a manifestation of brain damage in children who otherwise appear normal. The medical lit- erature of the 1920s is replete with descriptions of behavior disorders among children who survived acute encephalitis (e.g., Happ & Blackfan, 1920; Happ & Mason, 1921; Hohman, 1921, 1922; Leahy & Sands, 1921; Auden, 1922; Ebaugh, 1923; Strecker & Ebaugh, 1924; Bond & Partridge, 1926). The characteristics of these children and the range of behav- ior problems attributed to encephalitis were as varied as those described by Still (1902a, 1902b, 1902c). But it was documented and became accepted that “The behavior changes in children . . . are mainly associated with some degree of hyperkinesis” (Bond & Partridge, 1926, p. 34). This post-encephalitic hyperkinetic syndrome included all the cardinal fea- tures associated with ADHD, including overactivity, attention deficits, impulsivity, conduct disorders, and poor school performance. Thus, with the encephalitis epidemic we have the first clear descriptions of the combined form of ADHD. The motor disturbances (akinetic, dystonic, and hyperkinetic) seen in post-encephalitic children suggested a disorder of extrapyramidal function. In the early 1900s, experimental studies in animals showed that lesions of the basal ganglia produce motor disturbances, suggesting a motor function for these structures (Percheron et al., 1994). Thus, Bond and Partridge (1926), in a review of the literature on the sequelae of encephalitis, concluded that “The most purely neurological theory of the behavior reactions would account for these changes as due not to some general effect upon personality, but to definite physical changes, localized most probably in the basal ganglia” (p. 40). This is among the earliest statements linking ADHD signs and symptoms to a disorder in a particular brain region. The next step in the evolution of the concept of ADHD as a neurobiologic disorder occurred in 1934 with the proposed existence of a syndrome called “Organic Drivenness” by Kahn and Cohen (1934). A “surplus of inner impulsion” characterized the disorder. This was manifest in “general hyperkinesis,” “inability in maintaining quiet attitudes,” “explosive motor release of all voluntarily inhibited activity” (p. 750), as well as “extreme fluctuation of attention or lack of continued concentration” (p. 752). Kahn and Cohen pro- posed that Organic Drivenness resulted from a lesion of the brain stem, based on the findings of von Economo (1931) that “it is the brain-stem above all which encephalitis lethargica selects as a favorite target” (von Economo, 1931, p. 87). They also argued that any insult that damages the brain stem, including encephalitis, can produce Organic Drivenness. Thus, significantly, the authors proposed that Organic Drivenness was not solely the result of a single disease (e.g., encephalitis), but, rather, it had a multitude of potential etiologies. The work of Kahn and Cohen is important in that it extended organic behavior beyond encephalitis and subsumed all of the core features of ADHD under a single term. Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  6. 6. The Early History of the Neuroscience of ADHD 267 The Origin of Stimulant Therapy for Childhood Behavior Disorders The discovery that stimulant medications are useful in treating behavior disorders in chil- dren was critical to further development of neurobiological theories of ADHD, because early and modern theories are based, in part, on the mechanism of action of stimulants (see below). The practice of treating behavior-disordered children with stimulants began at the Bradley Hospital in Rhode Island in the 1930s (Bradley, 1936). Charles Bradley, the Medical Director of the Bradley Hospital, was the first to report that stimulants have useful therapeutic effects in behavior-disordered children. The ubiquitous modern use of stimulants for this purpose is directly traceable to experiments conducted by Charles Bradley in the 1930s (Figure 1). There are two different accounts about the impetus for Bradley’s original trial of amphetamine. According to one, the discovery was purely serendipitous (Baumeister, Hawkins, & L´opez-Muñoz, 2010). The account comes from a friend and colleague of Bradley’s, Dr. Maurice Laufer, who verbally passed it along to Dr. Mortimer Gross (1995). According to Gross, children at the Bradley home were given routine spinal taps in preparation for pneumoenchephalography. The loss of spinal fluid gave the chil- dren severe headaches. According to Laufer (as recounted by Gross), Bradley gave the children amphetamine with the hope that it would stimulate spinal fluid production and reduce the headaches. To Bradley’s surprise, teachers at the school reported that the drug seemed to improve behavior and academic performance. In the second account, given by Bradley in the seminal report on the subject, amphetamine was given to children because of reports “describing its effect upon the mood and other psychological reactions of adults” (Bradley, 1937, p. 577). Among these effects were a decrease in fatigue, increase in mood, Figure 1. Charles Bradley. The first medical director of the Bradley Hospital and discoverer of stimulant treatment of behavior disorders in children. Used by permission of the Bradley Hospital. Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  7. 7. 268 Alan A. Baumeister et al. alleviation of depression, neuroses, and catatonic stupor, increased capacity for work, and increased intelligence test scores in adults and children (Davidoff, 1936; Myerson, 1936; Sargant, 1936; Carlisle, 1937; Molitch & Sullivan, 1937; Nathanson, 1937; Wilbur, 1937). Bradley’s account diminishes the role of serendipity. The original clinical trial of amphetamine was conducted on 30 children (21 boys and 9 girls) ranging in age from 5 to 14 years. The children had diverse behavior problems and medical conditions. They included children with school-related behavior problems and specific learning disabilities, a withdrawn “schizoid” child, and an “aggressive, egocentric epileptic.” All children had intelligence in the normal range. The study had a pretest- posttest design. Teachers and nurses observed the children’s behavior one week prior to medication, one week on medication, and one week off medication. “The most striking change in behavior during the week on Benzedrine [amphetamine] therapy occurred in the school activities. . . . Fourteen children responded in spectacular fashion” (Bradley, 1937, p. 578). Increased interest in school work, increased drive to work, and increased speed of comprehension and accuracy, particularly in math, were among the reported school- related benefits. School staff started referring to amphetamine as math pills (Gross, 1995; Brown, 1998). Fifteen children responded with “subdued” emotional responses includ- ing decreased mood swings, decreased motor activity, and decreased “noisy, aggressive, domineering behavior” (Bradley, 1937, p. 579). Published reports on the new therapy came primarily from the Bradley Hospital dur- ing the 15 years after its introduction. During this time Bradley and colleagues continued to add subjects and to refine their analysis. They reported, for example, that, although amphetamine improved scholastic performance, it did not increase IQ, as measured by the Stanford-Binet test (Bradley & Green, 1940), and that amphetamine and Dexedrine (the d isomer of amphetamine) were equal in efficacy (Bradley, 1950). However, nothing fun- damentally new regarding the therapeutic use of amphetamine was reported during this period despite numerous publications on this subject (Cutts & Jasper, 1939; Bradley & Bowen, 1940, 1941; Bradley & Green, 1940; Bradley, 1942, 1950). Only a few studies before circa 1950 not originating in the Bradley Hospital were found. One was by Bender and Cottington (1942). These authors reported that amphetamine was “a useful adjunct to the treatment of the neurotic child, in that it gives him a feeling of well-being, and temporarily allows him to feel secure and loved” (p. 120). They also reported that it decreased aggression in psychopathic children but did not decrease the overactivity of two boys with evidence of brain anomalies. Bakwin (1948), using wording similar to Bender and Cottington (1942) but based on independent studies, reported that amphetamine “gives the neurotic child a feeling of well-being and temporarily allows him to feel secure” (p. 216). Pasamanick (1951) reported that anticonvulsant and sedative drugs were “uniformly disappointing” in treating behavior disorders in children. In contrast, of 10 children treated with amphetamine, 4 showed marked or obvious improvement. The discovery of methylphenidate in 1954 by Ciba laboratories in Switzerland (Meier, Gross, & Tripod, 1954) advanced significantly stimulant therapy for ADHD. Methylphenidate is a structural analogue of amphetamine (Figure 2). The chief advantage of methylphenidate is that it is a milder stimulant. It has a shorter half-life (about 2 hours) than amphetamine (7 to 30 hours) and is less likely to produce psychosis and other side effects. However, the clinical effects of methylphenidate and amphetamine are qualita- tively similar. Both drugs are thought to stimulate the release of catecholamines and block catecholamine reuptake. But, methylphenidate is thought to enhance vesicular exocytosis, whereas amphetamine stimulates the release of newly synthesized catecholamines from a nonvesicular site by causing catecholamine transporters in the presynaptic membrane to Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  8. 8. The Early History of the Neuroscience of ADHD 269 Figure 2. The structures of amphetamine (Top) and methylphenidate (Ritalin; Bottom). Retrieved from http://en.wikipedia.org. pump catecholamines out of the cell rather than in, a phenomenon known as exchange diffusion (García-García et al., 2009). Although methylphenidate was introduced to the United States in 1955, the first men- tion of its use to treat childhood behavior disorders was found in a paper by Laufer and Denhoff published in 1957. The focus of this paper is on the treatment of behavior disor- ders with amphetamine. However, in a brief section on “Other Medications” the authors write: “A variety of other medications have been advocated, such as Benadryl, Phenergan, Ritalin, desoxyn, Miltown, Meratran, Dramamine and Bonamine, and Atarax” (p. 473). The earliest published empirical clinical study of methylphenidate found was by Zimmerman and Burgemeister (1958). These investigators were prompted to try methylphenidate in children because they were looking for a stimulant that had fewer side effects than amphetamine: The rather excessive and well-known side reaction of Benzedrine . . . appeared . . . in such a high percentage of cases that it was necessary to search for a drug . . . on a physiological scale halfway between caffeine . . . and Benzedrine. Methyl-phenidylacetate hydrochloride (Ritalin) appears to be that drug. (p. 323) The subjects in this study were 108 children and adults with “emotional problems” includ- ing hyperactivity. Half of the subjects were given methylphenidate and the other half, matched for numerous variables (e.g., age, sex, and diagnosis), were given reserpine1 as a control. The average age of the methylphenidate groups was 15 years. Eighty percent of the methylphenidate subjects had no discernible neurological abnormalities. Various outcome measures were taken before and after drug treatment. With respect to hyperactivity specif- ically, 50% and 66% improved on methylphenidate and reserpine, respectively. Although reserpine appeared to be superior in reducing activity, methylphenidate had less pro- nounced side effects. The efficacy of methylphenidate in treating behavior disorders in children was subsequently confirmed (Knobel, Wolman, & Mason, 1959; Lytton & Knobel, 1959). In 1961, it was approved by the FDA for the treatment of childhood behavior disorders (Mayes, Bagwell, & Erkulwater, 2008). It quickly supplanted amphetamine as the first-line medication for ADHD. 1 Reserpine is an antipsychotic and antihypertensive agent. It blocks the transport of newly syn- thesized monoamines into synaptic vesicles. This makes the monoamines accessible to monoamine oxidase for catabolism. Sufficient doses cause depletion of monoamine stores throughout the body (Baumeister, Hawkins, & Uzelac, 2003). Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  9. 9. 270 Alan A. Baumeister et al. Electroencephalography and Childhood Behavior Disorders Research on the neuropathology of ADHD took a new tack in the 1930s. Hans Berger, a German psychiatrist, introduced the electroencephalographic (EEG) method into clinical medicine in 1929 (Swartz & Goldensohn, 1998; Niedermeyer, 2005). Charles Bradley was the first to employ the new technology in behavior-disordered children. The EEGs of 11 of Bradley’s original subjects showed a “spike and slow wave” form that was characteristic of petit mal seizures. He proposed that this EEG abnormality was indicative of impaired cortical function. He also reported that in 10 subjects, amphetamine reduced the “seizure waves.” Bradley noted that subdued behavior in hyperactive children seemed like a “para- doxical” effect of a stimulant. Significantly (see below), he suggested that this could be explained by stimulant-induced activation of inhibitory cortical systems (Bradley, 1937, p. 583). Jasper, Solomon, and Bradley (1938) conducted a more thorough analysis of EEG abnormalities in 71 diverse behavior-disordered children. They reported that 74% of patients with histories suggestive of central nervous system (CNS) disorder have abnormal EEGs. However, approximately 50% of behavior-disordered children with hyperactivity have no history suggestive of insult to the nervous system (Childers, 1935; Levin, 1938). Bradley reported that 38% of such children had abnormal EEGs. He concluded that “The electroencephalogram has succeeded in revealing a definite abnormality of brain function in over one half of a group of child behavior disorders which had been previously considered as largely psychogenic” (Jasper, Solomon, & Bradley, 1938, p. 655). A follow-up study conducted at the Bradley Hospital by Cutts and Jasper (1939) examined the relationship between EEG abnormalities, behavior disorders, and response to stimulant treatment. All the 12 children in this study exhibited erratic and asocial behav- ior. All were characterized as “epileptoid” based on EEG and clinical findings. Seven of the subjects had favorable behavioral responses to amphetamine, becoming less active, less impulsive, and more cooperative. All subjects who had a positive behavioral response exhibited the EEG abnormality. However, in contrast to Bradley’s original report (Bradley, 1937; see above), amphetamine had no effect on EEG abnormalities, even in children with behavioral improvements. The authors concluded that “The changes in personality with Benzedrine are probably due to an alteration in the patient’s emotional reactions to the type of brain disorder revealed in the electroencephalogram without any fundamental change in the disorder itself” (Cutts & Jasper, 1939, p. 1145). In numerous later stud- ies, Bradley and colleagues confirmed that about 50% of behavior-disordered children have abnormal EEGs that are unaffected by stimulants (Bradley & Bowen, 1940, 1941; Bradley & Green, 1940; Bradley, 1942, 1950; Lindsley & Henry, 1942; Laufer & Denhoff, 1957). Nevertheless, Bradley proposed that EEG abnormalities in a child characterized as “irritable, hyperactive, and aggressive, who has a short attention span” were sufficient to classify the child as having an organic behavior problem and “indicate a need for definite pharmacologic treatment” (Bradley, 1942, p. 774). At about this time other researchers reported that amphetamine controls petit mal seizures (Lennox, 1945; Livingston, Kajdi, & Bridge, 1948). But in contrast to stimu- lants, standard anticonvulsant drugs (e.g., diphenylhydantoin and phenobarbital) either had no effect or worsened behavior disorders in children (Pasamanick, 1951). The failure of amphetamine to eliminate EEG abnormalities and the exacerbation of behavior disorders by sedative anticonvulsants suggested the behavioral therapeutic effect of amphetamine was unrelated to its anticonvulsant action. This led Pasamanick to proposed the stimulant Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  10. 10. The Early History of the Neuroscience of ADHD 271 effect on behavior was caused by “inhibition of some of the random, circular and poorly integrated stimuli tracks, secondary to minor or major lesions” (p. 765). As the neuroscience of EEG evolved, techniques were developed to assess the func- tion of subcortical brain regions. One such technique was the photo-metrazol activation test developed by Gastaut (1950). This technique involves determination of the threshold doses of pentylenetetrazol (Metrazol) needed to obtain a particular EEG and myoclonic response in subjects exposed to a stroboscopic light. Abnormality (i.e., a lowered thresh- old) was thought to be associated with thalamic function (Gastaut & Hunter, 1950). Laufer, Denhoff, and Solomons (1957) used the photo-metrazol technique to evaluate brain function in behavior-disordered children. They reported lower thresholds in hyperactive children than in normal children. Also, thresholds were lower in both hyperactive children with a history of brain disease and those with no such history. Moreover, administration of amphetamine raised the threshold in hyperactive children. Based on the photo-metrazol findings, the authors postulated that in hyperactive children “dysfunction of diencephalon would alter resistance at synapses. This would allow incoming impulses to spread out of usual pathways and irradiate large cortical areas” (p. 45). Other studies suggested that the effects of stimulants on behavior disorders were medi- ated through an action on the reticular formation. Sigg and Schneider (1957) showed that reserpine produced rhinencephalic seizures in cats with “encephale isole” preparations. This effect was suppressed by electrical stimulation of the brainstem reticular forma- tion and by administration of methylphenidate. Bradley and Key (1958) showed that amphetamine lowered thresholds for cortical activation by electrical stimulation of the reticular formation. They concluded that amphetamine and methylphenidate have a direct action on the reticular activating system. A Neuropsychological Approach to Defining Organicity In about 1950, efforts to link the signs and symptoms of ADHD to neurobiologic lesions began to take more of a neuropsychological approach. That is, in addition to EEG and other neurologic indicators, investigators began using psychological tests that presumably evaluate specific brain functions. Lauretta Bender (1949), an American psychiatrist who is best known for the development of the Bender-Gestalt Visual Motor Test, advocated neuropsychological testing as a way to diagnose organic brain disorders. She reported that post-encephalitic children, whose motor disturbance “was mostly extrapyramidal,” are unable to “copy a diamond or even a square . . . [and have] poor memory for digits especially backwards, inability to reproduce designs from memory, and failure often to distinguish weights” (p. 409). Most significant, she wrote, was poor performance on the Goodenough Draw-A-Man test. This test was developed in the 1920s by American psy- chologist Florence Goodenough as a projective test of intellectual maturity. According to Bender, this test, in particular, showed that post-encephalitic children are unable to organize perceptions into meaningful wholes. “This, in turn, leads to an increase in drive to contact [the external world] and to experience contacts and in itself accounts for the hyperkinesis” (p. 409). Knobel, Wolman, and Mason (1959) used neuropsychological testing combined with EEG and neurological examination to identify organic behavior disorders. Psychiatric evaluation of 40 behavior-disordered children showed 23 were hyperactive, 8 had mixed symptomatology, and 9 were hypokinetic. All subjects were given EEGs, neurological evaluations, and a battery of psychological tests. None of the three measures reliably dif- ferentiated hyperactive and nonhyperactive children. However, all hyperactive children Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  11. 11. 272 Alan A. Baumeister et al. who had positive psychological findings also displayed either EEG abnormalities or neurological signs. The authors concluded that “Though EEG and psychological tests may yield false-positives when considered singly, if they are combined with positive neurological signs, one can expect some abnormal occurrence in the nervous system” (p. 314). In a review of his “syndromic” approach, Knobel (1959) clearly described all the core behavioral and psychological features of ADHD, including “impulsivity, aggressiv- ity, distorted perception and hyperactivity” (p. 85). He argued that a purely diencephalic dysfunction was unlikely to be the cause of the behavior disorder, because such dys- function would produce “a more complicated symptomatology and more expressive psycho-neurologic and endocrine-metabolic sequelae” (p. 81). Instead, he was “inclined to think that the disorder may be cortical or more probably in the cortical-subcortical path- ways” (p. 81). More specifically, he implicated cortical areas of the frontal and temporal lobes. He based this hypothesis on the evidence that the frontal lobes are a control area and that dysfunction is associated with inhibitory releases (Jacobsen, 1931; Bricker, 1936). The temporal lobes were implicated by behavioral disturbances associated with tempo- ral lobe epilepsy (Gibbs, Gibbs, & Fuster, 1948; Bailey & Gibbs, 1951). Interestingly, Knobel (1959) concluded that in calling “acting out” behavior organic this “doesn’t nec- essarily mean anatomical or structural lesions; it could refer to an encephalic dysfunction for reasons presently not known, or a dysfunction due to a change in the enzymatic par- ticipation in brain metabolism” (p. 81). This is one of the earliest statements of a possible neurochemical basis for hyperactivity. Conners, Eisenberg, and Sharpe (1964) supported the idea that ADHD children have deficient inhibitory mechanisms. These investigators used neuropsychological tests to eval- uate the effect of methylphenidate in “emotionally disturbed” children who were not psychotic, brain damaged, or mentally retarded. The main finding was the drug had min- imal effects on a paired-associate learning task but improved performance on the Porteus Maze Test, a nonverbal test of intelligence developed by the Australian psychologist Stanley Porteus. It consists of paper forms on which the subject is required to trace paths through a series of drawn mazes. No time limit is placed on the test. However, subjects are penalized if they back-track or trace down blind alleys. The test is thought to place a premium on planning and impulse inhibition. The researchers interpreted the results of the Porteus Maze Test as indicating that methylphenidate inhibits “impulsive discharge.” Based on the proposition that behaviorally disordered children “lacked central cortical inhibitory capacity over their internal drives and the external stimuli impinging upon them,” they attributed the improvement in impulsivity to “some form of heightened cortical activity” (p. 15). Another early study by Connors (1966) showed that d-amphetamine improved per- formance on a visual discrimination test in hyperactive children (who had no evidence of brain damage) and that this effect was greatest under conditions of stress. Connors sug- gested “the drug may produce more organized perceptual response under stress . . . with effects being more dramatically noticeable in children with diencephalic lesions or other forms of imbalance between cortical and sub-cortical mechanisms” (p. 432). During the ensuing decades, a huge number of studies were conducted using a vast array of neuropsychological tests to try to identify the underlying neuropathology, the spe- cific psychological defects, and the effects of stimulants in ADHD. Beyond the general conclusion that ADHD children differ from normal controls in their attention and inhibitory capacities and that stimulants improve these capacities, modern neuropsychological testing has not yielded much new knowledge about the neuropathology of ADHD. Indeed, after Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  12. 12. The Early History of the Neuroscience of ADHD 273 reviewing the literature on this subject, Rapport and Kelly (1993) concluded that “There appears to be an inverse relationship between the number of studies investigating MPH [Ritalin] effects on children’s cognitive performance and our understanding of these effects” (p. 116). Nevertheless, neuropsychological theories have achieved considerable prominence in recent years. These theories focus on deficits in executive functions (e.g., planning and working memory) and inhibition of ongoing activity (Barkley, 1997). The latter, of course, is an idea that goes back at least to George Still in 1902 and was sup- ported by neuropsychological research in the 1950s and 1960s. Current neuropsychological research supports deficits in both areas of function, particularly in the combined type of the disorder. However, children under the generic label of ADHD display considerable neuropsychological heterogeneity, suggesting the possible existence of distinct disorders with distinct etiologies (Baumgaertel, Blaskey, & Antia, 2008). The First Neurotransmitter Theory of ADHD Specific neurochemical postulates about the brain pathology in ADHD are a relatively recent development. Apparently, Kornetsky (1970) was the first person to offer such a theory. Kornetsky proposed the action of amphetamine was to inhibit norepinephrine synthesis, turnover, or release. As mentioned above, it is now known that stimulants actu- ally increase catecholamine release and block catecholamine reuptake. But, based on his assumption that these drugs have the opposite effect, Kornetsky proposed, “there would simply be an increase in norepinephrine turnover causing increased hyperkinetic activity” (p. 130). This idea was called the “Catecholamine Hypothesis” of ADHD (Zametkin & Rapoport, 1987). Kornetsky also proposed that Since many of the drugs that are useful in treating behavior problems in children have marked effects upon catecholamine levels in the brain, studies comparing urine catecholamine levels in various types of behavior disor- dered children after the administration of sympathomimetic amines might give specific direction to further research. (1970, p. 105) Kornetsky’s conjecture stimulated a massive amount of research trying to document vari- ous indices of catecholamine disturbances in hyperkinetic children. About 15 years later, Zametkin and Rapoport (1987) summarized this research. Scores of biochemical stud- ies were conducted looking for indices of monoamine function that distinguish between ADHD children and normal controls. These indices included urine MHPG (the principal metabolite of norepinephrine), peripheral autonomic functions, platelet monoamine oxi- dase activity, and cerebrospinal fluid monoamine metabolites. They concluded that “no consistent differences in any peripheral measure of monoamine or metabolites has been found between hyperactive and control children” (p. 678). They found that drug-induced biochemical changes correlated with clinical improvement in some studies but not in oth- ers. Nevertheless, based on the fact that stimulants affect catecholamines, they concluded that these transmitters are probably involved in the pathogenesis of ADHD. This idea still holds sway. A recent review of the topic concludes: The dominant hypothesis for the pathophysiology of ADHD is that of prefrontal cortical dysfunction, which is mediated by abnormalities of Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  13. 13. 274 Alan A. Baumeister et al. catecholaminergic neurotransmission in the catecholamine-rich fronto-striatal- cerebellar networks. The hypothesis is supported by the treatment effectiveness of stimulants, which increase the availability of extracellular catecholamines. (Baumgaertel, Blaskey, & Antia, 2008, p. 311) With the exception of the reference to catecholamines, which were not known to be brain neurotransmitters until about 1950, this hypothesis is entirely consistent with ideas that were put forward by researchers as early as the 1930s. Discussion From the time that attention disorders and hyperactivity were fist recognized to be a dis- tinct syndrome, it was proposed that they have an organic basis. Crichton (1798/1976), the first person to describe attention disorders, argued that they were caused by disturbances of the nerves. Still (1902a, 1902b, 1902c) thought that disorders of attention were caused by disorders of brain cell metabolism. The association of attention and other behavior disor- ders (e.g., hyperactivity) with encephalitis in the 1920s confirmed organicity. The salience of motor problems in these children led to the suggestion that the basal ganglia are the seat of these disorders. Subsequently, based on histopathologic studies of encephalitic children, the brain stem was blamed. Between the 1930s and 1950s, many studies showed that about 50% of children with behavior disorders have EEG abnormalities. EEG studies were used to link these disorders to hypothesized disturbances in many brain regions including the diencephalon, the reticular formation, the frontal and temporal lobes, and the cortex. The frequent occurrence of hyperactivity among children with normal EEGs led to efforts to combine EEG, neurological examination, and neuropsychological tests as a means to dis- tinguish between organic and nonorganic hyperactivity. Studies using combined metrics led to the widely held belief that childhood behavior disorders are mainly organic in nature. The early neuroscience of childhood behavior disorders anticipated aspects of modern ADHD theory. Based on EEG findings and neuropsychological tests, early investigators proposed that inhibitory functions of the frontal lobes are impaired in ADHD. Prominent current theories of ADHD (e.g., Barkley, 1997) attribute the disorder to impaired “exec- utive functions,” which are thought to reside in the frontal lobes. Furthermore, these impaired executive functions are thought to lead to a deficit in behavioral inhibition. This idea that higher brain functions inhibit lower brain functions and that a decrease in such inhibition is responsible for signs and symptoms of ADHD dates back to the 1930s. The advent of the EEG in 1929 was significant in that it represented a noninvasive diagnostic tool for assessing brain function and identifying focal lesions. EEG studies dominated the early research on the neuroscience of ADHD. In recent years, the use of EEG, outside of diagnosis of epilepsy, has declined substantially (Benbadis & Rielo, 2010; Boro & Haut, 2010). Nevertheless, EEG studies of ADHD children continue to the present. More recent studies have contributed little new knowledge. They have confirmed the main findings of earlier studies that (a) approximately 50% of ADHD children have abnormal EEGs, (b) the principal abnormality is a nonspecific slowing of brain wave activity, and (c) there is a poor relationship between EEG abnormalities and response to stimulant med- ication (Melo & Niedermeyer, 2005; Small, 2005). The results of modern EEGs studies are interpreted as showing that ADHD children have decreased cortical inhibitory control over lower brain centers, as was suggested by Bradley in the 1930s. In recent years, the use of the EEG as a method to study brain disturbances in ADHD has been largely replaced Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  14. 14. The Early History of the Neuroscience of ADHD 275 by new sophisticated neuroimaging techniques. Ironically, use of the more sophisticated neuroimaging technology has failed to reveal reliable differences between ADHD and non-ADHD children (Baumeister & Hawkins, 2001). The first neurochemical theory of ADHD (the Catecholamine Hypothesis) was proposed in 1970. It is interesting that this proposal was somewhat belated. The “psy- chopharmacology revolution” in psychiatry had been underway since the middle of the 1950s. One result of this revolution was the rise of theories about the underlying neuro- chemical pathology of mental disorders based on drug mechanisms of actions. Thus, in 1958 Everett and Toman (1959) proposed a monoamine theory of depression based on the observations that monoamine oxidase inhibitors, which increase monoamine levels, and reserpine, which decreases monoamine levels, are antidepressant and depressogenic, respectively. In 1962, Van Rossum proposed the dopamine hypothesis of schizophrenia (Baumeister & Francis, 2002). Again, the hypothesis was based on drug mechanisms of action. Drugs that stimulate dopamine function (e.g., amphetamine) worsen schizophrenic symptoms, whereas drugs that block dopamine function are antipsychotic. Like other the- ories of mental disorders of the time, the first neurochemical theory of ADHD was based on drug mechanism of action. Stimulants such as amphetamine were suspected of alter- ing catecholamine function as early as the 1930s (Nathanson, 1937). Therefore, it was proposed that disordered catecholamine function is responsible for ADHD. Although it is rarely acknowledged, amphetamine was the first modern psychiatric medication used for any clinical disorder. This is not well known because later devel- opments overshadow the discovery of stimulant drugs to treat ADHD. The introduction of antipsychotics in the 1950s played a role in one of the most important develop- ments in modern psychiatry: deinstitutionalization of the mentally ill (Johnson, 1990). In addition, the antipsychotics were the impetus for the psychopharmacology revolution. Nevertheless, neurobiologic theories of ADHD and stimulant treatment of the disorder have had a profound social impact too. Between 2 and 3 million children in the United States alone take stimulants for ADHD (Mayes, Bagwell, & Erkulwater, 2008; Denchev et al., 2010). Another interesting point is that the clinical benefits of stimulants were discovered before the advent of the randomized double-blind experimental design, the gold standard of today’s clinical science. This is also true of other major discoveries in psychopharmacology, including the antipsychotics and antidepressants developed in the mid-1950s. In conclusion, neuroscientists before 1970 anticipated the basic tenets of our current theories of the neuroanatomical and neurochemical substrates of ADHD. This is not to say that there have been no advances in our understanding of ADHD since that time. Complex neurocognitive models have been proposed (e.g., Barkley, 1997; Bush, 2010), but they remain highly speculative. Probably the most reliable recent finding relating to the patho- genesis of ADHD is its high heritability (60% to 90%) (Curatolo, D’Agati, & Moavero, 2010). However, whole genome linkage studies have not provided compelling evidence for regions of the genome that contain ADHD-susceptibility genes. Several specific genes, particularly those involved in dopamine metabolism, have been associated with ADHD in some studies, but results across studies are highly variable (Stergiakouli & Thapar, 2010). It is generally accepted today, as it was in the 1930s, that ADHD is not a uni- tary disorder with a single etiologic pathway. Rather, it is current consensus that ADHD is polygenetic, that environmental factors contribute to the disorder, and that genes and environment interact in complex ways producing variable ADHD phenotypes (Curatolo, D’Agati, & Moavero, 2010). Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  15. 15. 276 Alan A. Baumeister et al. References American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders. Washington DC, American Psychiatric Association, 4th edition. Auden GA (1922): Behaviour changes supervening upon encephalitis in children. The Lancet 28: 901–904. Bailey P, Gibbs FA (1951): The surgical treatment of psychomotor epilepsy. Journal of the American Medical Association 145: 365–370. Barkley RA (1997): Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychological Bulletin 121: 65–94. Baumeister AA, Francis JL (2002): Historical development of the dopamine hypothesis of schizophrenia. Journal of the History of the Neurosciences 11: 265–277. Baumeister AA, Hawkins MF (2001): Incoherence of neuroimaging studies of attention deficit/hyperactivity disorder. Clinical Neuropharmacology 24: 2–10. Baumeister AA, Hawkins MF, L´opez-Muñoz F (2010): Toward standardized usage of the word serendipity in the historiography of psychopharmacology. Journal of the History of the Neurosciences 19: 253–270. Baumeister AA, Hawkins MF, Uzelac SM (2003): The myth of reserpine-induced depression: Role in the historical development of the monoamine hypothesis. Journal of the History of the Neurosciences 12: 207–220. Baumgaertel A, Blaskey L, Antia SX (2008): Disruptive behavior disorders. In: Fatemi SH, Clayton PJ, eds., The Medical Basis of Psychiatry. Riverview NJ: Humana Press, 3rd edition, pp. 301–333. Bakwin H (1948): Benzedrine in behavior disorders of children. Journal of Pediatrics 32: 215–216. Benbadis SR, Rielo D (2010, March 8): Focal (nonepileptic) abnormalities on EEG. eMedicine. Retrieved from http://www.scribd.com/doc/19262401/Eeg-Atlas-Emedicine#outer_page_26 Bender L (1949): Psychological problems of children with organic brain disease. American Journal of Orthopsychiatry 9: 404–415. Bender L, Cottington F (1942): The use of amphetamine sulfate (Benzedrine) in child psychiatry. American Journal of Psychiatry 99: 116–121. Bond ED, Partridge GE (1926): Post-encephalitic behavior disorders in boys and their management in a hospital. American Journal of Psychiatry 83: 25–103. Boro AD, Haut S (2010, May 27): Focal EEG waveform abnormalities. eMedicine. Retrieved from http://emedicine.medscape.com/article/1139025-overview Bradley C (1936): A children’s hospital for neurologic and behavior disorders. Journal of the American Medical Association 107: 650–653. Bradley C (1937): The behavior of children receiving Benzedrine. American Journal of Psychiatry 94: 577–585. Bradley C (1942): Problem children: Electroencephalographic diagnosis and pharmacologic treat- ment. Connecticut State Medical Journal 6: 773–777. Bradley C (1950): Benzedrine and Dexedrine in the treatment of children’s behavior disorders. Pediatrics 5: 24–37. Bradley C, Bowen M (1940): School performance of children receiving amphetamine (Benzedrine) sulfate. American Journal of Orthopsychiatry 10: 782–788. Bradley C, Bowen M (1941): Amphetamine (Benzedrine) therapy of children’s behavior disorders. American Journal of Orthopsychiatry 11: 92–103. Bradley C, Green E (1940): Psychometric performance of children receiving amphetamine (Benzedrine) sulfate. American Journal of Psychiatry 97: 388–394. Bradley PB, Key BJ (1958): The effect of drugs on arousal responses produced by electrical stimula- tion of the reticular formation of the brain. Electroencephalography and Clinical Neurophysiology 10: 97–110. Bricker RM (1936): The Intellectual Functions of the Frontal Lobes. New York, Macmillan. Brown WA (1998): Images in Psychiatry: Charles Bradley, M.D., 1902–1979. American Journal of Psychiatry 155: 968. Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  16. 16. The Early History of the Neuroscience of ADHD 277 Bush G (2010): Attention-deficit/hyperactivity disorder and attention networks. Neuropsycho- pharmacology 35: 278–300. Carlisle CL (1937): Use of Benzedrine sulfate in catatonic stupors: Case reports. Medical Bulletin of the Veteran’s Administration 13: 224–227. Childers AT (1935): Hyper-activity in children having behavior disorders. American Journal of Orthopsychiatry 5: 227–243. Conners CK (1966): The effect of Dexedrine on rapid discrimination and motor control of hyperkinetic children under mild stress. Journal of Nervous and Mental Disease 142: 429–433. Conners CK, Eisenberg L, Sharpe L (1964): Effects of methylphenidate (Ritalin) on paired-associate learning and Porteus Maze performance in emotionally disturbed children. Journal of Consulting Psychology 28: 14–22. Crichton A (1798/1976): An Inquiry into the Nature and Origin of Mental Derangement. New York, AMS Press. Curatolo P, D’Agati E, Moavero R (2010): The neurobiologic basis of ADHD. Italian Journal of Pediatrics 36: 79–85. Cutts KK, Jasper HH (1939): Effect of Benzedrine sulfate and Phenobarbital on behavior problem children with abnormal electroencephalograms. Archives of Neurology and Psychiatry 41: 1138– 1145. Davidoff E (1936): A clinical study of the effect of Benzedrine therapy on self-absorbed patients. Psychiatric Quarterly 10: 652–659. Denchev P, Kaltman JR, Schoenbaum M, Vitiello B (2010): Modeled economic evaluation of alternative strategies to reduce sudden cardiac death among children treated for attention deficit/hyperactivity disorder. Circulation 121: 1329–1337. Ebaugh FG (1923): Neuropsychiatric sequelae of acute epidemic encephalitis in children. American Journal of Diseases of Children 25: 89–97. Everett GM, Toman JEP (1959): Mode of action of Rauwolfia alkaloids and motor activity. In: Masserman JH, ed., Biological Psychiatry. Proceedings of the Society of Biological Psychiatry San Francisco, May 1958. New York, Grune & Stratton, pp. 75–81. García-García P, L´opez-Muñoz F, Molina JD, Fischer R, Alamo C (2009): Methylphenidate extended-release capsules: A new formulation for attention-deficit hyperactivity disorder. Frontiers in Drug Design & Discovery 4: 228–246. Gastaut H (1950): Combined photic and Metrazol activation of the brain. Electroencephalography and Clinical Neurophysiology 2: 249–261. Gastaut H, Hunter J (1950): An experimental study of the mechanism of photic activation in idiopathic epilepsy. Electroencephalography and Clinical Neurophysiology 2: 263–287. Gibbs EL, Gibbs FA, Fuster B (1948): Psychomotor epilepsy. Archives of Neurology and Psychiatry 60: 331–339. Gross MD (1995): Origin of stimulant use for treatment of attention deficit disorder. American Journal of Psychiatry 152: 298–299. Happ WM, Blackfan, KD (1920): Insomnia following acute epidemic (lethargic) encephalitis in children. Journal of the American Medical Association 75: 1337–1339. Happ WM, Mason VR (1921): Epidemic encephalitis: A clinical study. Bulletin of the Johns Hopkins Hospital 32: 137–159. Hohman LB (1921): Epidemic encephalitis (lethargic encephalitis). Archives of Neurology and Psychiatry 6: 295–333. Hohman LB (1922): Post-encephalitic behavior disorders in children. Bulletin of the Johns Hopkins Hospital 33: 372–375. Jacobsen CF (1931): A study of cerebral functions in learning: The frontal lobes. Journal of Comparative Neurology 52: 271–339. Jasper HH, Solomon P, Bradley C (1938): Electroencephalographic analysis of behavior problem children. American Journal of Psychiatry 95: 641–658. Johnson AB (1990): Out of Bedlam: The Truth about Deinstitutionalization. New York, Basic Books. Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  17. 17. 278 Alan A. Baumeister et al. Kahn E, Cohen LH (1934): Organic drivenness: A brain-stem syndrome and an experience. New England Journal of Medicine 210: 748–756. Knobel M (1959): A syndromic approach to “Acting-Out” children. Diseases of the Nervous System 20: 80–87. Knobel M, Wolman MB, Mason E (1959): Hyperkinesis and organicity in children. Archives of General Psychiatry 1: 310–321. Kolata G (2001): Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus that Caused It. New York, Touchstone. Kornetsky C (1970): Psychoactive drugs in the immature organism. Psychopharmacolgia 17: 105–136. Laufer MW, Denhoff E (1957): Hyperkinetic behavior syndrome in children. Journal of Pediatrics 50: 463–474. Laufer MW, Denhoff E, Solomons G (1957): Hyperkinetic impulse disorder in children’s behavior problems. Psychosomatic Medicine 19: 38–49. Leahy SR, Sands IJ (1921): Mental disorders in children following epidemic encephalitis. Journal of the American Medical Association 76: 373–377. Lennox WG (1945): The petit mal epilepsies: Their treatment with Tridione. Journal of the American Medical Association 129: 1069–1074. Levin PM (1938): Restlessness in children. Archives of Neurology and Psychiatry 39: 764–770. Lindsley DB, Henry CE (1942): The effect of drugs on behavior and the electroencephalograms of children with behavior disorders. Psychosomatic Medicine 140: 140–149. Livingston S, Kajdi L, Bridge EM (1948): The use of Benzedrine and Dexedrine sulfate in the treatment of epilepsy. Journal of Pediatrics 32: 490–494. L´opez-Muñoz F, Alamo C, Quintero-Gutiérrez FJ, García-García P (2008): A bibliometric study of international scientific productivity in attention-deficit hyperactivity disorder covering the period 1980–2005. European Child and Adolescent Psychiatry 17: 381–391. Lytton GJ, Knobel M (1959): Diagnosis and treatment of behavior disorders in children. Diseases of the Nervous System 20: 334–340. Mayes R, Bagwell C, Erkulwater J (2008): ADHD and the rise of stimulant use among children. Harvard Review of Psychiatry 16: 151–166. Meier R, Gross F, Tripod J (1954): Ritalin, eine neuartige synthetische verbindung mit spezifischer zentralerregender wirkungskomponente. Klinische Wochenschrift 32: 445–450. Melo AN, Niedermeyer E (2005): The EEG in infantile brain damage, cerebral palsy, and minor cerebral dysfunctions of childhood. In: Niedermeyer E & Silva FL, eds., Electroencephalography. Basic Principles, Clinical Applications, and Related Fields. New York, Lippincott Williams & Wilkins, pp. 403–413. Molitch M, Sullivan JP (1937): The effect of Benzedrine sulfate on children taking the new Stanford Achievement Test. American Journal of Orthopsychiatry 7: 519–522. Myerson A (1936): Effect of Benzedrine Sulfate on mood and fatigue in normal and in neurotic persons. Archives of Neurology and Psychiatry 36: 816–822. Nathanson MH (1937): The central action of beta-aminopropylbenzene (Benzedrine). Journal of the American Medical Association 108: 528–531. Niedermeyer E (2005): Historical aspects. In: Niedermeyer E, Silva FL, eds., Electroence- phalography: Basic Principles, Clinical Applications, and Related Fields. New York, Lippincott Williams & Wilkins, pp. 1–15. Palmer ED, Finger S (2001): An early description of ADHD (inattentive subtype): Dr. Alexander Crichton and “Mental Restlessness” (1798). Child Psychology and Psychiatry Review 6: 66–73. Pasamanick B (1951): Anticonvulsant drug therapy of behavior problem children with abnormal electroencephalograms. Archives of Neurology and Psychiatry 65: 752–766. Percheron G, Fénelon G, Leroux-Hugon A, Féve A (1994): History of the basal ganglia: Slow development of a major cerebral system. Review of Neurology 150: 543–554. Rapport MD, Kelly KL (1993): Psychostimulant effects on learning and cognitive function. In: JL Matson, ed., Handbook of Hyperactivity in Children. Boston, Allyn and Bacon, pp. 97–136. Downloadedby[SyracuseUniversityLibrary]at10:4721October2015
  18. 18. The Early History of the Neuroscience of ADHD 279 Ravenholt RT (1993): Encephalitis lethargica. In: Kiple KF, ed., The Cambridge World History of Human Disease. New York: Cambridge University Press, pp. 708–712. Sargant W (1936): The effect of Benzedrine on intelligence scores. The Lancet 228: 1385–1387. Schachar RJ (1986): Hyperkinetic syndrome: Historical development of the concept. Clinics in Developmental Medicine 97: 19–40. Sigg EB, Schneider JA (1957): Mechanisms involved in the interaction of various central stimulants and reserpine. Electroencephalography and Clinical Neurophysiology 9: 419–426. Small JG (2005): Psychiatric disorders and EEG. In: Niedermeyer E, Silva FL. eds., Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. New York, Lippincott Williams & Wilkins, pp. 639–659. Stergiakouli E, Thapar A (2010): Fitting the pieces together: Current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatry Disease an Treatment 6: 551–560. Still GF (1902a, April 12): Some abnormal psychical conditions in children: Lecture I. The Lancet: 1008–1012. Still GF (1902b, April 19): Some abnormal psychical conditions in children: Lecture II. The Lancet: 1077–1082. Still GF (1902c, April 26): Some abnormal psychical conditions in children: Lecture III. The Lancet: 1163–1168. Strecker EA, Ebaugh FG (1924): Neuropsychiatric sequelae of cerebral trauma in children. Archives of Neurology and Psychiatry 12: 443–453. Swartz BE, Goldensohn ES (1998): Timeline of the history of EEG and associated fields. Electroencephalography and Clinical Neurophysiology 106: 173–176. von Economo C (1931): Encephalitis Lethargica: Its Sequelae and Treatment. Translated and adapted by Newman KO. London, Oxford University Press. Walters AS, Barrett RP (1993): The history of hyperactivity. In: Matson JL, ed., Handbook of Hyperactivity in Children. Boston, Allyn and Bacon, pp. 1–10. Wilbur DL (1937): Clinical observations on the effect of Benzedrine Sulfate. Proceedings of the Mayo Clinic 12: 97–112. Zametkin AJ, Rapoport JL (1987): Neurobiology of attention deficit disorder with hyperactivity: Where have we come in 50 years? Journal of the American Academy of Child and Adolescent Psychiatry 26: 676–686. Zimmerman FT, Burgemeister BB (1958): Action of methyl-phenidylacetate (Ritalin) and reserpine in behavior disorders in children and adults. American Journal of Psychiatry 115: 323–328. Downloadedby[SyracuseUniversityLibrary]at10:4721October2015

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