Viewpoint on the Brain Disorder in Autism

Viewpoint on the Brain Disorder in Autism

  (based on a review of research papers in the medical literature)

Viewpoint on the brain disorder(2003) (View in 2000)

The auditory system The inferior colliculus Hemoglobin & the brain

Concepts of autism Autism spectrum Social responsibility


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Conrad Simon Memorial Research Initiative
Posted:  December 14, 2003
© Copyright 2003
Eileen Nicole Simon
Introduction | I. Brain damage at birth | II. Auditory system | III. Language
IV.  Childhood handicaps | V. Brainstem Damage | VI.  References | Summaries
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Topics (section links):


1 - Asphyxia at Birth
2 - Hypoxic Birth
3 - Asphyxia Versus Hypoxia
4 - Human Conditions
5 - Stages of Asphyxia
6 - The Umbilical Cord Lifeline
7 - Developmental Delay
8 - Poor Manual Dexterity
9 - Progressive Degeneration
10 - Autism and Complications at Birth
11 - Mercury, and Other Toxic Factors

12 - Metabolic Rank Order
13 - The Auditory System
14 - Auditory Dysfunction

15 - Language by Ear
16 - Verbal Auditory Agnosia
17 - Echolalic Speech
18 - Echolalic Speech is Pragmatic

19 - Auditory and Motor Handicaps
20 - Increased Incidence of Autism
21 - Fetal to Postnatal Adaptation
22 - Forgotten History
23 - Worth Remembering
24 - Hemoglobin
25 - Infant Anemia
26 - Autism in Twins
27 - Male-Female Differences

28 - Variable Vulnerability
29 - Patterns of Damage
30 - Wernicke's Encephalopathy
31 - Suffocation at the Molecular Level
32 - Thiamine Deficiency
33 - Brain-Gut Relationship

VI. REFERENCES (for all sections)
34 - Bibliography (for section IV)
35 - Autism and Complications at Birth
36 - Umbilical Cord Clamping

Summaries (for all sections)
    Summaries (for section IV)

[Site Links]

Overview (Chilldhood Handicaps):

High blood flow in the inferior colliculus supports the highest rate of aerobic metabolism in the brain. Protective mechanisms go into action under adverse conditions that preserve function in the inferior colliculus. Hemoglobin delivers oxygen in exchange for carbon dioxide, and may provide the quickest response to carbon dioxide produced by high metabolic activity in the inferior colliculus during a hypoxic episode. Hemoglobin becomes depleted of oxygen under hypoxic conditions, but the inferior colliculus can obtain enough to remain undamaged leaving nothing for other areas of the brain.

Myers (1972) demonstrated that the inferior colliculus is selectively and predictably damaged by a few minutes of total oxygen deprivation at birth; but prolonged partial hypoxia late in gestation damages the cortex and other less metabolically active areas of the brain, without involvement of the inferior colliculus. The spectrum of childhood disorders from cerebral palsy to autism may represent damage of motor cortex at one extreme, and autism at the other.

. . . .



19 - Auditory and Motor Handicaps
The syndrome of autism described by Kanner (1943) did not include indications of neurological problems [123]. Children with the "core syndrome" of Kanner autism develop motor milestones on time, are toilet trained on time, and even appear to begin speaking on time. By the age of three or four however, speech development is clearly aberrant.

Delayed motor development and residual physical awkwardness are however indications of neurological impairment in many children with autism, and especially in those with a diagnosis of Asperger's syndrome. Few children fit the narrow description of Kanner autism; Kanner even commented on the individual differences he observed. To explain the autism spectrum: Impairment of function in the inferior colliculi (by asphyxia at birth) might be at one end of the spectrum and involvement of motor systems (by hypoxic birth) at the other. Most children with autism show signs of both auditory dysfunction and some delay of motor development.

Asperger's syndrome is a far more hopeful diagnosis than autism. Children with Asperger's syndrome may be late learning to speak and their speech is full of pedantic sound-bytes with often peculiar and pun-like connections to conversational context. But command of language is the tool by which children with Asperger's syndrome can learn and grow. Language disorder is the most serious impediment to human development.

Lack of manual dexterity was noted as the most common residual deficit in monkeys asphyxiated at birth. The normal climbing ability of monkeys was also never achieved. Control of wrist, ankles, and digits remained inadequate. A reduced level of spontaneous activity was observed. The asphyxiated monkeys were described as hypoactive, docile, unemotional, and not easily disturbed.

Short-term memory also appeared deficient in asphyxiated monkeys. But tests of learning involved repeated trials, and the asphyxiated monkeys were described as difficult to coax as if they gave up shortly after beginning training trials. The behaviors were compared to the condition known then as "minimal cerebral dysfunction" (MCD) in children. Clinical signs listed for MCD included problems with attention, impulse control, interpersonal relations, and hyper- or hypo-reactivity, along with lack of coordination and learning disabilities. Some children with MCD might now be viewed as having Asperger's syndrome or attention-deficit hyperactivity disorder (ADHD).

20 - Increased Incidence of Autism
As long ago as 1975 I proposed that echolalic speech of children with autism might be the result of damage to the inferior colliculi, and that asphyxia at birth is an example of how such damage could take place [152]. But now immediate clamping of the umbilical cord has become a standard obstetric practice, whether or not the infant has begun to breathe. Unless breathing is established within seconds after cutting off umbilical circulation, asphyxia will occur and brainstem nuclei like the inferior colliculus will be damaged or impaired.

Four minutes is generally recognized as the time beyond which resuscitation becomes less likely following accidents such as drowning or cardiac arrest. It is a common belief that infant humans and animals can withstand oxygen deprivation longer than mature beings. But Myers (1972) described changes in neurons (seen only under the microscope) in the inferior colliculus of monkeys subjected to asphyxia of duration too short to cause visible damage [2]. Asphyxia had to be of seven to eight minutes duration before visible damage was seen, and Faro and Windle (1969) found progressive neuropathologic changes in monkeys kept alive for months or years following asphyxia at birth, even in monkeys without the characteristic lesions of the inferior colliculi [30].

It would seem dangerous to assume that a newborn child is more resistant to anoxia and can withstand a few minutes of asphyxia until breathing is initiated by artificial ventilation. Myers found that it is the infant heart that withstands asphyxia better than that of the adult (not the brain). Failure of attempts for prompt resuscitation after cutting the cord will result in at least some impairment of the brain.

Who has the evidence that minimal brainstem damage is not important? Research data clearly implies that damage confined to the brainstem results in developmental deficits. That early brain damage heals because of "plasticity" was disproved when Faro and Windle discovered that with time early brainstem damage leads to progressive widespread changes throughout the brain.

Delayed onset of breathing after the cord has been cut deserves consideration as a contributing factor to increased numbers of children with developmental disorders, and the increased incidence (or prevalence) of autism. A low Apgar score five minutes after birth is considered ominous, and has been correlated with later developing autism [56, 57]. Increases in autism have been noted during the same period that immediate cord clamping has become routine.

In addition to complications at birth, autism is associated with many medical conditions, which include prenatal exposure to alcohol and drugs, pre- and postnatal infections, lead poisoning, gastrointestinal disorders, neurologic (seizure) disorders, and diverse genetic predispositions [57, 83-95,153-179, 180-210]. All of these conditions are likely to have a catastrophic effect on metabolism similar to that caused by asphyxia at birth. Prenatal exposure to alcohol, drugs, and medications might be linked to the increased prevalence of autism. But genetic mutations are unlikely to be increasing at such a high rate.

21 - Fetal to Postnatal Adaptation
Mercer and Skovgaard (2002) noted that early clamping of the umbilical cord may have been put into practice without adequate evidence of its safety [211]. They further described how clamping of the cord obstructs normal completion of transition from pre- to postnatal life. Most dangerous is the potential reduction of neonatal blood volume from 25 to 40 percent.

Ventilation alone is not sufficient to expand the lungs. Mercer and Skovgaard call attention to the need for adequate blood volume to stimulate erection of capillaries in the alveoli of the lungs, and thus to initiate oxygen transfer to the red blood cells. They point out also that activity of other organs, like the gut, is low during gestation, and capillary erection may also be involved in stimulating function of all body organs.

In the fetal state 40 percent of the cardiac output is to the placenta to obtain oxygen from the mother. Transition to postnatal life depends upon utilization of blood from the placental circuit to activate all organs for extra-uterine survival. In the fetal state the lungs secrete amniotic fluid, and according to Mercer and Skovgaard, "capillary erection may be the natural stimulus for the lung to change both structure and function immediately at birth from an organ of fluid secretion to an organ of gas exchange."

If an infant cries immediately at birth this transition has at least for the most part occurred. But it appears that the child who does not cry right away is the first to have the umbilical cord cut and be taken away for ventilation and other desperate efforts (including artificial blood volume expanders) to initiate breathing! These are the infants who could most benefit from allowing placental circulation to continue.

Mercer and Skovgaard note that, "Since the beginning of mammalian life, young have been born attached to a life-line that supports their transition to extrauterine life." They call attention to two exceptions: (1) human birth in recent times, and (2) attended births of some thoroughbred foals, which included rapid clamping of the umbilical cord, and in which a "convulsive syndrome" often occurred. Normally a mare and foal rest for about half an hour after birth, and the cord is broken only when either the mare or the foal rises.

Pathology found in foals that died of the convulsive syndrome included an absence of aeration of the alveoli. [Top]

22 - Forgotten History
Adequate blood volume is required at birth to stimulate opening of the capillaries within the lungs, gut, and other body organs that are dormant during gestation. But depriving an infant of placental blood at birth also leaves the child anemic. Wilson, Windle, and Alt (1941) investigated clamping of the umbilical cord as the cause of iron deficiency anemia in infancy [212]; they noted that the diet of an infant up to the end of the first year cannot make up for this deficiency. Infant anemia has since been found correlated with early childhood learning disorders [213-214].

It appears that during the 1930s use of anesthesia in childbirth and sluggish respiratory efforts of the newborn led to development of protocols for resuscitation, which included early clamping of the cord. The children described by Kanner in 1943 were all born during the 1930s, and at least two by cesarean. Anesthesia was first used in 1846, but obstetric textbooks through the 1930s still encouraged allowing the umbilical cord to cease pulsation before cutting it [58-65]. The teaching of older texts should be heeded, at least that the umbilical cord be left intact until the newborn infant is breathing on its own. How shocking that what was so clearly understood in the past has been disregarded and totally forgotten.

William Windle
Figure 15: William Windle (1898-1985)

The research of Windle and Myers is also already part of forgotten history. Subjecting monkeys to experimental asphyxia may never again be possible. Animal activists would object, insisting the results should be obvious. But the obvious did not happen: Damage of the cerebral cortex and ensuing cerebral palsy were not produced by asphyxia at birth, and damage in the inferior colliculi was almost overlooked.

To neglect the finding of auditory system damage caused by total asphyxia (or cortical damage caused by partial oxygen insufficiency) is to overlook the obvious. Maybe professional experts should heed what animal activists claim is already known. Genetics, toxic environment, maternal stress during pregnancy, and more are all under consideration as causes of autism. At the same time complications at birth are dismissed as mild rather than severe [88] or nonspecific [86], and without any unifying feature [91].


But the unifying feature of mild and nonspecific complications is the likelihood of lapses in oxygen delivery during the transition from placental to pulmonary respiration. In the hierarchy of human needs nothing is more essential and of immediate urgency [215].

Interference with respiration at birth should be thoroughly re-investigated and "ruled out" before any more esoteric causes of autism are entertained. The research of Windle and Myers still provides evidence that complications at birth can have serious consequences, and their findings merit continuing consideration in the search for understanding and preventing developmental disabilities.

23 - Worth Remembering
The following quotes from Windle (1969) are points worth remembering:

  • "In any delivery it is important to keep the umbilical cord intact until the placenta has been delivered.

    To clamp the cord immediately is equivalent to subjecting the infant to a massive hemorrhage, because almost a fourth of the fetal blood is in the placental circuit at birth."

  • "Spontaneous neurological deficits are practically unknown among rhesus monkeys born in their natural habitat…

    The female squats and drops the infant on the ground. During delivery most of the blood in the placenta passes to the infant."

  • "It is no longer acceptable to assume that the human fetus or newborn infant is so resistant to oxygen deficiency that it will escape harm from a short exposure to asphyxia neonatorum.

    If the infant's brain can be compared to the monkey's, asphyxia of such duration that resuscitation was required will certainly have damaged it."

  • "The briefly asphyxiated infant monkeys with minimal brain damage lost their signs of neurological deficit… The extent of this 'recovery' was surprising.

    The residual deficits of the surviving animals are now inadequate manual dexterity…"

  • "It is commonly recognized that improvement can be expected after a distressful birth…

    We know that the brain of a 'recovered' monkey is structurally damaged, whereas we only assume on clinical grounds that the brain of a 'recovered' human infant is normal."

24 – Hemoglobin
Respiratory gas exchange is a biochemical process mediated by the hemoglobin molecule within red blood cells. The binding and release of oxygen from hemoglobin provides an explanation for why hypoxia is so different from the effect of asphyxia. The quickest adjustment to an environment of oxygen insufficiency is that provided by the action of hemoglobin in delivering oxygen first to tissues producing the most carbon dioxide.

Myers (1972) demonstrated that while the inferior colliculi are predictably and selectively damaged by a few minutes of total oxygen deprivation at birth, they are spared during a period of prolonged partial oxygen insufficiency. It takes a catastrophic and complete obstruction of aerobic metabolism for involvement of the inferior colliculus to take place. But this can happen to an infant born not breathing if the umbilical cord is cut before respiration can be established.

Some textbooks of biochemistry attach a name to the mechanism of oxygen in exchange for carbon dioxide, the "Bohr effect" [216-217]. Binding of oxygen at different pressures of carbon dioxide was determined in experiments done by Christian Bohr and co-workers a hundred years ago [31].

Christian Bohr was the father of the Nobel Prize winning physicist, Nils Bohr; but his derivation of the mechanism of oxygen binding by hemoglobin remains as important as the contribution by his famous son to the understanding of atomic structure. The paper by Schaffarzik and Spies (1996) pays tribute to Christian Bohr as a forgotten trailblazer of respiratory physiology [35].

Even Myers (1972) spoke of "oxygen dissolved in blood," (p 250), but only cells of primitive organisms can make use of oxygen by simple absorption from environmental fluids.

Christian Bohr
Figure 16: Christian Bohr (1855-1911)

Survival of multi-cellular organisms depended upon evolution of a more efficient means for exchange of respiratory gases. As White et al (1969) commented, the active metabolism of mammalian tissues remote from the atmosphere is possible only because, "Through the action of hemoglobin, oxygen is abstracted from the air, carried within a few seconds to the most distant parts of the body, and delivered to the tissues at a pressure only slightly less than that at which it existed in the atmosphere" [216].


25 – Infant Anemia
Windle warned that clamping the umbilical cord immediately after birth is equivalent to subjecting an infant to a massive hemorrhage. In 1941 a group of researchers including Windle reported iron deficiency anemia (low hemoglobin levels) in infants at 8 to 10 months of age whose umbilical cords had been clamped immediately at birth [212]. Hemoglobin is the iron-containing molecule of red blood cells; a deficiency of iron implies a deficiency of hemoglobin upon which oxygen delivery depends.

Deficient hemoglobin is equivalent to a hypoxic environment; less oxygen will be available for growth and development of the brain and other organs. Anemia in infancy is a state of chronic partial hypoxia, the effects of which can be compared to those produced by Myers (1972) on partial obstruction of umbilical blood flow.

Perhaps some of the on-going degeneration within the brains of monkeys asphyxiated at birth was due to anemia resulting from the way asphyxia was imposed – by clamping the umbilical cord. The residual inadequate manual dexterity of monkeys asphyxiated by umbilical cord clamping at birth could as well be the result of involvement of motor areas of the brain from postnatal anemia as from brainstem damage.

The paper by Saigal and Usher (1977) appears to have initiated the fear that delayed clamping of the umbilical cord could result in polycythemia (too many red blood cells) and jaundice [47]. But polycythemia is a physiological response to abnormalities like methemoglobinemia, which results from a genetic or drug-induced abnormality of the hemoglobin molecule [217, 218-220]. It may be time to question the opinions of modern authorities and look back again at some forgotten history.

Jellett (1910) in his Manual of Midwifery discussed the issue of polycythemia after stating, "The old dispute as to when the cord should be tied possesses now little more than an academic interest, as it is conclusively settled that this should not be done until all pulsations in the cord have ceased" [221].

Jellett cited research known at that time (but long since forgotten). White (1785) had written about the absurdity of supposing that it was possible for the change from placental to pulmonary circulation, with all that this implies, to take place in a moment, "that this wonderful alteration in the human machine should be brought about in one instant of time, and at the will of a bystander?" [222].

Jellett further cited research by Schmidt (1894) in which he found that 72 percent of children in whom immediate ligation of the cord was done were jaundiced, while only 42 percent were jaundiced when the cord was not tied until ten minutes after birth. It may be time to consider whether postnatal anemia isn't a greater risk for more infants than polycythemia and jaundice [223].


26 – Autism in Twins
Autism is not 100 percent concordant in identical twins. The finding of even one pair of identical twins who are discordant for any disorder provides the counterexample that disproves a simple genetic etiology.

Folstein and Rutter (1977) investigated cases of autism occurring in twins [224]. Eleven pairs were identical (monozygotic), and ten fraternal (dizygotic). Concordance for autism was found in 4 of the 11pairs of monozygotic twins (36 percent) and no concordance was found in the dizygotic pairs. Thus of 21 twin pairs, 17 were discordant for autism; and in 12 of these autism was associated with an event likely to cause brain damage. Case reports are provided and worth reviewing:

  • Of the identical twin pairs concordant for autism, all four are male and complications of pregnancy were noted in each case. For example, the mother of one pair went into labor of 24 hours duration six weeks early, and each twin was a breech birth. Another mother of a concordant pair had labor induced at 39 weeks gestation because of pre-eclamptic toxemia; the second twin was born 30 minutes after the first due to uterine inertia. He suffered fetal distress, and did not breathe until 7 minutes after birth; autism and cognitive disability were more severe in this second-born twin than in his brother. The differences are more striking than the similarities in each of the four twin pairs deemed concordant for autism.
  • Three of the five identical twins discordant for autism were female. One of the female twins who became autistic was a breech birth with delayed breathing; her umbilical cord was described as very narrow and white. One of the male twins with autism also had a cleft palate, which suggests prenatal exposure to alcohol or other drugs.
  • Of the non-identical twin pairs, three of the mothers were Rh-negative. The three twin pairs of these mothers were all male. The only twins concordant for cognitive disorder were born to one of these mothers; she did not have Rh-factor antibodies but bilirubin rose to 10 mg in the neonatal period of the twin who became autistic. Exchange transfusions were performed in both twins of one Rh-negative mother. Of the third Rh-negative mother, only the twin who later became autistic had an exchange transfusion at birth.

It is difficult not to question the role of perinatal compromise in all of the cases described by Folstein and Rutter. The most obvious genetic predisposition is the occurrence of Rh-negative blood type in three of the mothers.

Norman (1982) noted that perinatal hazards are increased for twins and suggested that therefore twins are an imperfect model for genetic versus environmental studies of things like intelligence [225]. That concordance is higher in identical than fraternal twins reflects factors such as the limited capacity of a shared placenta to withstand environmental hazards like anoxia or prenatal infections. Davis et al. (1995) found that twins who both develop schizophrenia were more likely to have shared a single placenta and chorionic sack in utero [226]. Autism becomes evident years earlier than schizophrenic disorders and is therefore even more likely related to prenatal environment, and autism may yet prove to be part of the schizophrenia spectrum

Ritvo et al. (1985) reported concordance for autism in 22 of 23 identical twin pairs (95.7 percent) and in 4 of 17 fraternal twin pairs (23.5 percent) [227]. The discordant identical twins were male, age 8, with a normal sister, one year younger. Of the 22 pairs of identical twins concordant for autism, 5 were female, comparable to the 4:1 ratio of males to females reported for autism occurring in the general population.

In the study of Ritvo et al., concordance for autism among the 17 pairs of fraternal twins was high, occurring in 4 pairs. Of the 13 pairs of fraternal twins discordant for autism, 5 were male-female twins and the autistic twin was male in 2 pairs. Both of the male-female twin pairs, in which the male was autistic, had male siblings who were autistic. Of the 8 same-sex twin pairs discordant for autism, only one was female.

Steffenburg et al. (1989) investigated occurrence of autism in same-sexed twins under the age of 25 [85]. They found 21 twin pairs, 11 monozygotic (including one set of identical triplets) and 10 dizygotic. Concordance for autism was 91 percent in the monozygotic pairs. Concordance for autism was not found in the dizygotic pairs, but concordance for cognitive disorder was 30 percent. In the twin pairs discordant for autism, autism was associated with greater perinatal stress. Steffenburg et al. concluded that autism sometimes has a hereditary component, and that perinatal stress is involved in some cases. Case reports were not provided.

Greenberg et al (2001) noted a higher concordance of autism in fraternal twins than would be expected in the general population, and this indicates environmental influences are more significant than genetic factors [93]. If environmental factors were not involved, the concordance rate for fraternal twins should not be greater than between single-born siblings in families in which autism has occurred more than once.

Autism has been found as a complication of phenylketonuria, and other genetic disorders. But some of the medical conditions associated with autism may have been mistakenly thought of as genetic. For example Migeon et al. (1995) and Subramaniam et al. (1997) described a pair of identical twin girls in which one had Rett syndrome but the other was developing normally still at the age of six [228, 229]; and Feekery et al. (1993) reported Landau-Kleffner syndrome in one but not the other of identical twins [230].


27 – Male-Female Differences
In my own dissertation research, I with my advisor, Ladislav Volicer, investigated the long-term effects of neonatal asphyxia in laboratory rats. The major findings of this research have been published (Simon and Volicer 1976) [231].

Newborn rat pups were subjected to asphyxia by suffocation in small air-tight vials until gasping efforts ceased (45 minutes to two hours). Pups were pale and flaccid when removed from the vials; they were resuscitated using a slow stream of air to the nose and mouth and massaging the chest. Only about half of the experimental animals survived and they were lethargic during the first 24 hours following resuscitation. Most did not gain the normal amount of weight and many lost weight during the first 24 hours; animals with weight loss exceeding 0.5 to 1.0 grams or that appeared jaundiced (with yellow discoloration of the skin) often died during the first two days. Control animals gained about one gram during the first 24 hours after birth.

Male/Female weight-gain differences
Figure 17: Weight differences between control and asphyxiated male (solid line) and female (broken line) pairs during the first week after neonatal suffocation
(from Simon and Volicer 1976).

No focal lesions or visible disruption of neural pathways in the brain could be detected, although development of some reflexes was delayed. Increased synthesis of norepinephrine in the brain was found at 5 to 6 weeks of age in rats subjected to neonatal suffocation; alteration in serotonin synthesis was found in male rats only. Monoamine metabolism was just coming to the forefront during the 1970s, which is why I investigated the effect of asphyxia on these systems.

Perhaps more important, as it turns out, was the startling discovery of growth retardation that was significant for male animals only. The initial failure of weight gain may have resulted from lethargy and lack of initiative to suckle and seek nourishment.

But growth retardation persisted for the first two weeks of life, most noticeably in male rats. Figure 17 is a graph showing differences in weight between pairs of male and pairs of female animals. Brain growth was also retarded in the asphyxiated rats, and to the same degree in both males and females.

We thought that vulnerability to asphyxia might be related to the metabolic requirements of the animal and that this might be related to birth weight and sex. Male animals were significantly heavier at birth (just over 7 grams) than females (just under 7 grams), with standard deviation 0.07 grams. Metabolism would appear to be higher in males than females. Research evidence is not abundant on this subject, but it is common knowledge that males (on average) have greater muscle mass than females and have greater muscular strength. Almost all competitive athletic events have male and female categories, or female champions and record-setters would be few and far between if at all.

Males were more prone to growth retardation than females as a consequence of asphyxia at birth. According to the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV) many developmental disabilities are found more frequently in males than females [232]. Perhaps oxygen insufficiency resulting from perinatal complications should be investigated as the possible cause of other developmental problems.

Metabolism is higher in males than females. Research evidence is not abundant on this subject, but it is common knowledge that males (on average) have greater muscle mass than females and have greater muscular strength. Almost all competitive athletic events have male and female categories, or female champions and record-setters would be few and far between.

Greater metabolic needs imply greater requirement for intact aerobic activity. Thus males are likely to be more vulnerable in situations in which compromise of oxygen delivery is involved.

Conrad in the lab with mom
Figure 18: Conrad in the lab with mom and newborn rat pups.

Growth retardation of male laboratory rats indicates they were more severely affected by asphyxia. The inferior colliculi and other brainstem nuclei are likely affected sooner in males than females; thus impairment should occur with a shorter period of asphyxia.

Again, before complex hypotheses are investigated in search for the brain disorder in autism, the most basic requirement for aerobic organisms deserves thorough study. Damage of the auditory system by asphyxia at birth is worth further research as cause of developmental language disorder.

. . . .


34 - Bibliography

Asphyxia and Hypoxia at Birth
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  2. Myers RE (1972) Two patterns of perinatal brain damage and their conditions of occurrence. American Journal of Obstetrics and Gynecology 112:246-276.
    Back to: Increased incidence, Worth remembering, Hemoglobin, [Top]

    Cerebral Blood Flow
  3. Landau WM, Freygang WH, Rowland LP, Sokoloff L, Kety SS (1955) The local circulation of the living brain; values in the unanesthetized and anesthetized cat. Transactions of the American Neurological Association 80:125-129.
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  6. Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L (1978) Measurement of local cerebral blood flow with iodo-14-C-antipyrine. American Journal of Physiology, 234, H59-H66.

    Measures of Aerobic Metabolism (Deoxyglucose Uptake)
  7. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. Journal of Neurochemistry 28:897-916.
  8. Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Casella V, Fowler J, Gallagher B, Hoffman E, Alavi A, Sokoloff L (1977) Measurement of local cerebral glucose metabolism in man with 18F-2-fluoro-2-deoxy-d-glucose. Acta Neurologica Scandinavica. Supplementum 64:190-1

    Correlates of High Deoxyglucose Uptake
  9. Gross PM, Sposito NM, Pettersen SE, Panton DG, Fenstermacher JD. Topography of capillary density, glucose metabolism, and microvascular function within the rat inferior colliculus. J Cereb Blood Flow Metab. 1987 Apr;7(2):154-60.
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  11. Zeller K, Rahner-Welsch S, Kuschinsky W (1997) Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. Journal of Cerebral Blood Flow and Metabolism 17:204-209.
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  13. Hovda DA, Chugani HT, Villablanca JR, Badie B, Sutton RL (1992) Maturation of cerebral oxidative metabolism in the cat: a cytochrome oxidase histochemistry study. Journal of Cerebral Blood Flow and Metabolism 12:1039-1048
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    Research on Blood Flow and Glucose Uptake
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  17. Vingan RD, Dow-Edwards ML, Riley EP (1986) Cerebral metabolic alterations in rats following prenatal alcohol exposure: a deoxyglucose study. Alcoholism, Clinical and Experimental Research 10:22-26.
  18. Bertoni JM and Sprenkle PM (1989) Lead acutely reduces glucose utilization in the rat brain especially in higher auditory centers. Neurotoxicology 9:235-242.

  19. Nehlig A, Pereira de Vasconcelos A, Boyet S (1989) Postnatal changes in local cerebral blood flow measured by the quantitative autoradiographic [14C]iodoantipyrine technique in freely moving rats. Journal of Cerebral Blood Flow and Metabolism 9:579-588.
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  22. Chugani HT, Hovda DA, Villablanca JR, Phelps ME, Xu, W-F (1991) Metabolic maturation of the brain: a study of local cerebral glucose utilization in the developing cat. Journal of Cerebral Blood Flow and Metabolism 11:35-47.
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  25. Antonelli PJ, Gerhardt KJ, Abrams RM, Huang X. Fetal central auditory system metabolic response to cochlear implant stimulation. Otolaryngol Head Neck Surg. 2002 Sep;127(3):131-7.

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    Lead Poisoning
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    Seizure Disorder/ Neurologic Damage
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  178. daSilva EA, Chugani DC, Muzik O, Chugani HT (1997) Landau-Kleffner syndrome: metabolic abnormalities in temporal lobe are a common feature. Journal of Child Neurology 12:489-495.

    Intestinal Inflammation
  179. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA (1998) Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet Feb 28;351(9103):637-41.
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    Genetic/Metabolic Predispositions for Autism:
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    Tuberous Sclerosis
  182. Fisher W, Kerbeshian J, Burd L, Kolstoe P. (1986) Tuberous sclerosis and autism. Developmental Medicine and Child Neurology 28:814-815
  183. Bolton PF, Griffiths PD (1997) Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 349(9049):392-395
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  188. Gaffney GR, Kuperman S, Tsai LY, Minchin S. (1989) Forebrain structure in infantile autism. J Am Acad Child Adolesc Psychiatry. 28:534-537.
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  192. Lowe TL, Tanaka K, Seashore MR, Young JG, Cohen DJ (1980). Detection of phenylketonuria in autistic and psychotic children. Journal of the American Medical Association 243:126-128.
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    Fragile X Syndrome
  197. Brown WT, Jenkins EC, Friedman E, Brooks J, Wisniewski K, Raguthu S, French J. (1982) Autism is associated with the fragile-X syndrome. Journal of Autism and Developmental Disorders. 12:303-8.
  198. Folstein SE, Rutter ML (1988) Autism: familial aggregation and genetic implications. Journal of Autism and Developmental Disorders. 18:3-30.

    Leber's Congenital Amaurosis
  199. Rogers SJ, Newhart-Larson S (1989) Characteristics of infantile autism in five children with Leber's congenital amaurosis. Developmental Medicine and Child Neurology 31:598-608
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    Adenylosuccinate Lyase Defect
  201. Jaeken J, Van den Berghe G. (1984) An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids. Lancet. Nov 10;2(8411):1058-61.
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  203. Barshop BA, Alberts AS, Gruber HE. (1989) Kinetic studies of mutant human adenylosuccinase. Biochimica et Biophysica Acta. 999:19-23.
  204. Van den Berghe G, Vincent MF, Jaeken J. (1997) Inborn errors of the purine nucleotide cycle: adenylosuccinase deficiency. Journal of Inherited Metabolic Disease. 20:193-202.

    Lactic Acidosis
  205. Coleman M, Blass JP (1985) Autism and lactic acidosis. Journal of Autism and Developmental Disorders 15 1-8.
  206. Philippart M (1986) Clinical recognition of Rett syndrome. American Journal of Medical Genetics Supplement 1:111-8
  207. Lombard J (1998) Autism: a mitochondrial disorder? Medical Hypotheses 50:497-500.
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    Krebs Cycle (aerobic metabolism) Defects
  208. Shaw W, Kassen E, Chaves E (1995) Increased urinary excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features. Clinical Chemistry 41:1094-1194.

    Mitochondrial Disorders
  209. Fillano JJ, Goldenthal MJ, Rhodes CH, Marin-Garcia J (2002) Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome. J Child Neurol. 2002 Jun;17(6):435-9.
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  211. Fetal to Postnatal Adaptation Mercer JS, Skovgaard RL. Neonatal transitional physiology: a new paradigm. J Perinat Neonatal Nurs. 2002 Mar;15(4):56-75.
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    Infant Anemia
  212. Wilson EE, Windle WF, Alt HL (1941) Deprivation of placental blood as a cause of iron deficiency in infants. Am. J. Dis. Child. 62:320-327.
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    Hierarchy of Human Needs
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    Biochemistry Textbooks
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  218. Beutler E. Genetic disorders of human red blood cells. JAMA. 1975 Sep 15;233(11):1184-8.
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    Autism in Twins
  224. Folstein S, Rutter M (1977) Infantile autism: a genetic study of 21 twin pairs. Journal of Child Psychology and Psychiatry 30:405-416.
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  225. Norman MG (1982) Mechanisms of brain damage in twins. The Canadian journal of neurological sciences 1982 Aug;9(3):339-44
  226. Davis JO, Phelps JA, Bracha HS (1995) Prenatal development of monozygotic twins and concordance for schizophrenia. Schizophrenia Bulletin 21:357-366. Published erratum appears in Schizophrenia Bulletin 21:539.
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  227. Ritvo ER, Freeman BJ, Mason-Brothers A, Mo A, Ritvo AM (1985) Concordance for the syndrome of autism in 40 pairs of afflicted twins. American Journal of Psychiatry 142:74-7
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  228. Migeon BR, Dunn MA, Thomas G, Schmeckpeper BJ, Naidu S (1995) Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome. American Journal of Human Genetics 56:647-53.
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    Neonatal Asphyxia in Laboratory Rats
  231. Simon N, Volicer L (1976) Neonatal asphyxia in the rat: greater vulnerability of males and persistent effects on brain monoamine synthesis. Journal of Neurochemistry 26:893-900.
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    Categories of Mental Disorders
  232. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, DSM-IV. Washington, DC: American Psychiatric Association.
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. . . .



19 - Auditory and Motor Handicaps
Motor handicaps associated with the brainstem pattern of damage were transient and overcome except for manual dexterity in monkeys subjected to asphyxia at birth. More serious permanent disorders of movement indicate impairment of function in the basal ganglia or cerebral cortex. Most children with autism show signs of both, thus signs of damage caused by both asphyxia and hypoxia. Asphyxia is more likely to occur as the final insult of a difficult hypoxic birth. Signs of auditory dysfunction in children with autism would seem to indicate catastrophic impairment of aerobic metabolism by asphyxia at birth or by any of the other medical conditions associated with autism.

20 - Increased Incidence of Autism
The increased prevalence of autism is more likely due to increased incidence of asphyxia at birth than to increases in the medical conditions associated with autism. Textbooks on obstetrics in the late nineteenth and early twentieth centuries stressed the importance of leaving the umbilical cord intact until the newborn infant is breathing. The modern procedure of immediate umbilical cord clamping needs to be investigated as a possible cause of increased prevalence of auditory dysfunction in children.

21 - Fetal to Postnatal Adaptation
The alveoli of the lungs become functional by perfusion with blood at birth. Resuscitation by ventilation in the intensive care unit often requires use of blood volume expanders. Normal blood volume is best ensured by maintaining placental circulation through the umbilical cord.

22 - Forgotten History
Experimental asphyxiation of newborn monkeys would no longer be permissible. But the findings of past research projects remain important and merit re-examination.

23 - Worth Remembering
Comments made by Windle in 1969 are worth heeding still today, especially:
(a) To clamp the umbilical cord immediately is equivalent to subjecting the infant to a massive hemorrhage.
(b) It is no longer acceptable to assume that the human infant will escape harm from a short exposure to asphyxia at birth.
(c) Although improvement can be expected, we know that the brain of a "recovered" monkey is damaged whereas we only assume that the brain of a "recovered" human infant is normal.

24 - Hemoglobin:
The release of oxygen from hemoglobin provides an explanation for why the effects of hypoxia are so different from those of asphyxia. The quickest adjustment to an environment of oxygen insufficiency is provided by the action of hemoglobin in delivering oxygen first to tissues producing the most carbon dioxide. The inferior colliculus is spared under hypoxic conditions, but first to sustain damage during any catastrophic interference with aerobic metabolism

25 - Postnatal Anemia:
Clamping the umbilical cord at birth is equivalent to subjecting the infant to a massive hemorrhage; this loss of blood was shown over 60 years ago to lead to anemia in infancy. An anemic child is in a state of chronic hypoxia, which will impede normal growth of brain and other organs.

26 - Autism in Twins:
Concordance of autism in identical twins is not 100 percent. Differences between concordant twin pairs are greater than similarities. Twins are more vulnerable to perinatal problems, which is also evident from the larger than would be expected number of non-identical twin pairs in which both are autistic.

27 - Male-Female Differences:
Males have higher metabolic needs than females and are thus more vulnerable to any factor that interferes with aerobic energy production. Males outnumber females in most developmental disorders. Growth retardation was immediately evident in males but not females following neonatal asphyxia in laboratory rats.


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Eileen Nicole Simon

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