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
Date posted: 
© 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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Preface

I. BRAIN DAMAGE AT BIRTH
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

II. THE AUDITORY SYSTEM
12 - Metabolic Rank Order
13 - The Auditory System
14 - Auditory Dysfunction

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

IV. CHILDHOOD HANDICAPS
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

V. BRAINSTEM DAMAGE
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
34 - Bibliography
35 - Autism and Complications at Birth
36 - Umbilical Cord Clamping

Summaries

Blood flow is highest in the inferior colliculus
Figure 1: Experiments on cerebral circulation in cats showed greatest perfusion of a radioactive tracer after 60 seconds, thus greatest blood flow, in nuclei of the brainstem auditory pathway. These auditory nuclei are therefore vulnerable during a brief period of circulatory arrest or asphyxia, and also to metabolic disturbances caused by all other etiologic conditions associated with autism.
(from Kety, 1962, with permission from Columbia University Press)

. . . .

Complications at birth have been acknowledged as common among children with autism, but then most often dismissed as part of a genetic predisposition rather than as cause of developmental problems. However, research done long ago with monkeys provides evidence that a few minutes of asphyxia at birth damages brainstem auditory nuclei. Such damage could underlie failure to learn language by ear. Early brainstem damage also disrupts later development of wider areas of the brain. The effects of oxygen insufficiency at birth merit as much attention as the search for genetic causes of autism.

. . . .

Preface
Auditory system impairment is the focus of the viewpoint paper posted on this website in April 2000, and that all "co-morbid" conditions associated with autism can compromise auditory function. In this update I reiterate this view but urge consideration that perinatal complications may be the most important cause of autism; further that the now standard procedure of immediate clamping of the umbilical cord could explain the increased incidence (or prevalence) of autism. Asphyxia and hypoxia damage cell membranes and disrupt the normal blood-brain barrier to substances in the blood like bilirubin. Likewise the mercury preservative (thimerosol) in vaccines may enter and damage the brain in infants compromised by oxygen insufficiency during birth.


. . . .

I. BRAIN DAMAGE AT BIRTH

1 - Asphyxia at Birth
I first learned of the vulnerability of the auditory system to asphyxia at birth when the October 1969 issue of Scientific American arrived in my mailbox [1]. My son Conrad was then five years old and spoke only in parroted phrases. He loved music and sang all his favorite songs played on the radio. But his hearing was not normal. He became confused and upset in noisy environments and was terrified to enter a room where he saw a telephone. Trying to get him to listen to someone on the phone could also be upsetting.


On the other hand Conrad was often unresponsive to sounds that would attract the attention of most people – like something crashing down behind his back or being called by name from across the room.

When I saw the picture of damage to the inferior colliculus in the Scientific American article "Asphyxia at Birth" by William Windle, I gasped; to me damage in this pair of midbrain auditory nuclei could very well explain Conrad's auditory problems and especially why he wasn't learning to speak normally!

The experiments with monkeys on asphyxia at birth were undertaken to investigate cerebral palsy [1, 2]. However, the asphyxiated monkeys did not develop cerebral palsy, and at first no brain damage could be found. Seymour Kety in extensive studies on cerebral circulation had found a few years earlier that the highest blood flow in the brain is to the inferior colliculus [3,4], and suggested to Windle that he look there for damage – and there it was found!




Damage by asphyxia at birth
Figure 2: Damage to the inferior colliculus in a monkey subjected to a brief period of asphyxia at birth and sacrificed at five years of age (from Windle, 1969).

Normal appearance of the inferior colliculus
Figure 3: Appearance of the inferior colliculus in the brain of a normal monkey of the same age (from Windle, 1969).

Figure 1 (up top) is an autoradiogram from Kety's research (in cats) that shows the greatest amount of a radioactive tracer in the inferior colliculus one minute after injection – thus indicating greatest circulation in this small nucleus of the brainstem auditory pathway. Results of the first experiments on blood flow were confirmed using different radioactive tracers [5, 6]. Methods for glucose uptake and measurement of aerobic enzymes later revealed that aerobic metabolism is highest in the inferior colliculus and other brain areas of high circulatory rate [7-14]. Methods for both blood flow and glucose uptake have been widely used in research on neurochemistry [15-25]

Figure 2 (above) shows damage in the inferior colliculi of the brain of a monkey subjected to asphyxia at birth. The inferior colliculi are pitted by cavities (bilaterally) left by cells that disintegrated over the five year lifespan of the monkey. Figure 3 shows by way of contrast the appearance of the inferior colliculus in the brain of a normal monkey of the same age in which the densely packed neurons are intact.
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2 - Hypoxic Birth
In their initial experiments Windle and co-workers pulled a saline-filled rubber sac over the head of infant monkeys at birth and then clamped the umbilical cord [26, 27]. The lungs were thus prevented from taking in air, and blood flow from the placenta was abruptly blocked. The result was a sudden catastrophic cutoff of respiratory gas exchange (asphyxia). That this did not cause cerebral palsy came as a complete surprise!

Still looking for causes of cerebral palsy, Ronald Myers (a member of Windle's team) employed a technique to produce intermittent obstruction of umbilical blood flow late in gestation [2]. This somewhat less catastrophic disruption more closely mimics what happens during a difficult birth, in which a state of partial oxygen insufficiency develops (hypoxia). Even partial interference with oxygen delivery is not healthy, and cerebral palsy and the pattern of cortical damage long associated with cerebral palsy were observed in monkeys subjected to hypoxia in this way.

However, figure 4 is from Myers' 1972 paper, "Two patterns of perinatal brain damage and their conditions of occurrence," and confirms that damage to the inferior colliculus results when oxygen delivery is totally obstructed at birth.


Most vulnerable in Myers' monotonous rank order of brainstem nuclei
Figure 4: Damage to the inferior colliculi in a newborn monkey subjected to 12 minutes of total asphyxia (from Myers, 1972).

In addition to the inferior colliculi, Myers noted a predictable involvement of what he referred to as a "monotonous rank order" of brainstem structures. These included:

  • Superior olives
    (acoustic processing & relay)
  • Trigeminal nerve sensory nuclei
    (5th cranial nerve from face & jaw)
  • Gracile and cuneate nuclei
    (lower & upper body sensory)
  • Vestibular nuclei
    (equilibrium & reflexive orientation)
  • Ventral thalamic nuclei
    (sensory processing & relay from brainstem & cerebellum to cortex)


Miller and Myers (1970, 1972) found the same pattern of brainstem damage also in adult monkeys subjected to cardiac arrest; and, as in the case of infant monkeys, found damage in the cerebral cortex in adult monkeys subjected to partial disruption of circulation [28, 29]. The infant heart withstands asphyxia longer, but the infant brain is no less vulnerable to damage than that of the adult [2]. Furthermore, the difficult to detect pattern of brainstem lesions in newborn monkeys resulted in a disruption of brain development; monkeys kept alive to maturity were found to have neuropathological changes in additional subcortical areas and the cerebral cortex [30].
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3 – Asphyxia Versus Hypoxia
Asphyxia is not just a more severe degree of hypoxia. Asphyxia is a different kind of insult. In situations of reduced blood flow or oxygen insufficiency (hypoxia), protective mechanisms go into effect. For example, respiratory gas exchange (oxygen for carbon dioxide) is a biochemical process that provides immediate adjustment during any hypoxic episode: Except in the lungs, hemoglobin releases oxygen in exchange for carbon dioxide; this mechanism (the Bohr effect) has been understood for nearly a century [31-36]. Organs of highest metabolic rate produce the greatest amount of carbon dioxide end-product; and these organs are first to obtain oxygen from hemoglobin, especially during any episode of oxygen (or circulatory) insufficiency.

The brain is a collection of separate sensory, motor, and association circuits with differing metabolic needs; nuclei within the auditory system have the greatest need for respiratory gas exchange. Thus during chronic compromise of circulation, hemoglobin will give up the oxygen needed by the inferior colliculus first, and then reach the so-called "watershed" areas of the cerebral cortex depleted of what oxygen it carried from the lungs or placenta. Cortical damage is the expected and most usual consequence of this kind of prolonged hypoxia [2].

Kusumoto et al. (1995) used an autoradiographic method to investigate cerebral blood flow in immature gerbils after bilateral occlusion of the carotid arteries [21]. In 2-week old gerbils 5 minutes of bilateral carotid occlusion produced severe forebrain ischemia. By way of contrast, blood flow in the inferior colliculus and nuclei of the pons increased dramatically (in the inferior colliculus from 91 to 124 ml per minute and in the pons from 61 to 90 ml).

Occlusion of the carotid arteries produced a severe but partial blockage of blood flow; otherwise measurement of residual circulation would not have been possible. The forebrain became severely ischemic at the expense of whatever protective mechanism went into effect to increase circulation to the inferior colliculus and nuclei of the pons. The effects of this change in circulation can be compared with the prolonged partial hypoxia Myers (1972) found caused damage to motor areas of the cortex in monkeys [2].

Asphyxia is catastrophic and most often fatal if it persists to the point of cardiac failure. Newborn monkeys could in most cases be resuscitated after up to 20 to 25 minutes of asphyxia [1, 2], but visible damage was evident in the brain if asphyxia lasted for eight to ten minutes. Later developing neuropathological changes were found throughout the brain in monkeys kept alive for several years, even in animals subjected to asphyxia of duration too short to produce visible brainstem lesions [30]. The commonly held assumption that infants withstand asphyxia and hypoxia better than mature individuals would appear to be a dangerous misconception, especially in view of the impact of early impairment on maturation of the brain.
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4 - Human Conditions
Myers rejected the idea that the brainstem pattern of damage had any relevance to what happens in human cases of hypoxic birth. But, figure 5 (below) shows damage of the inferior colliculi found in a human infant who died from accidental suffocation; and symmetric bilateral involvement of brainstem nuclei (including the inferior colliculi) has been noted in at least seven other reports of damage found following death in infancy related to injury at birth [37-43].


Windle proposed that the brainstem pattern of damage might lead to what at that time was called "minimal cerebral dysfunction" [44-46]. But can any damage within the brain be considered minimal? Is brainstem damage any less serious than damage within the cerebral cortex?

Cerebral palsy and mental retardation have always been feared as possible outcomes of a difficult birth. The purpose of fetal monitoring during labor is to avoid or minimize hypoxic episodes. Hypoxia (partial oxygen insufficiency) is surely more common than total asphyxia as inflicted in Windle's initial experiments.

But a few minutes of asphyxia (total cutoff of oxygen) can occur during labor or at birth. For example, if the umbilical cord wraps tightly around the neck, blood flow and oxygen are cutoff until the baby's head is born and the cord can be unwound.

A baby born with the cord around the neck may be depressed from lack of blood supply from the placenta. In such cases the cord should be allowed to refill with blood and not be cut at least until the baby starts breathing.

But, immediate clamping of the umbilical cord has become a standard practice [47-53]. A paper by Saigal and Usher (1977) is often cited as the rationale for immediate clamping of the cord.


Inferior colliculus damage (bottom) in a human infant
Figure 5: Visible damage in the inferior colliculi (bottom) in the brain of a human infant (from Leech & Alvord 1977 [39], with permission from the American Medical Association).

Saigal and Usher expressed the opinion that too large a transfusion of placental blood could put an infant at risk for polycythemia and jaundice [47]. Research by Windle and coworkers was apparently already part of forgotten history; Lucey et al. (1964) had demonstrated that even very high levels of bilirubin did not cross the blood brain barrier except in monkeys whose brains were already damaged by asphyxia [54].
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5 - Stages of Asphyxia
Myers believed that hypoxia during gestation was a more likely cause of brain impairment than asphyxia at birth, but he nevertheless thoroughly investigated what happens during asphyxia. His data can now be viewed as relevant to what must happen when the umbilical cord is clamped before a newborn infant's lungs are functional – and bring to mind the stages of drowning described by Sebastian Junger in The Perfect Storm [55].

Myers monitored heart rate, blood pressure, oxygen, carbon dioxide, pH, and respiratory efforts during asphyxia and resuscitation. He noted that envelopment of the fetal head and clamping of the umbilical cord led to an immediate increase in blood pressure followed within 20 seconds by a rapid decrease associated with a rapid fall in blood oxygen. Aerobic metabolism is completely halted by a minute and a half.

Myers commented that the early fall in blood oxygen is the most precipitous and dramatic of any of the changes during asphyxia and leads to deterioration of the heart and other organs of the body. Neurons then become dependent on glycogen stores within their surrounding astrocytes. Gasping began six minutes after cord clamping and continued to the fourteenth minute of asphyxia after which the animal entered a terminal state of apnea, becoming pulseless, pale, and flaccid. Windle noted minimal damage in two monkeys asphyxiated for only six minutes [1].

Visible lesions of brainstem nuclei were always seen in monkeys subjected to asphyxia of ten minutes duration in Myers' experiments. But microscopic examination revealed that damage to mitochondria and cell membranes preceded development of visible damage [2]. Damage of cell membranes is the basis for breakdown of the blood-brain barrier that protects against entry of substances like bilirubin from the blood stream. Compromise of brain and other organs clearly precedes the occurrence of visible damage.

Progressive long-term signs of damage throughout the brain were found by Faro and Windle (1969) in monkeys kept alive for several months or years following asphyxia [30]. Respiratory distress due to lung damage from asphyxia also led to more widespread damage. Damage from oxygen insufficiency is not ordinarily as "monotonously" predictable as found in the early experiments on asphyxia.

Respect for animal rights would prevent doing further experimentation of this kind with monkeys. But the data obtained deserves renewed attention. Myers demonstrated that prolonged partial disruption of circulation in utero leads to damage of the cerebral cortex and cerebral palsy, and he adamantly rejected the idea that brainstem damage caused by catastrophic asphyxia could be relevant to any human condition. But we are suddenly living in a time of increased developmental disorders, autism, childhood asthma, early gastrointestinal problems, and infant anemia. Immediate clamping of the umbilical cord at birth has become a standard procedure in the past 20 years and should be investigated as possibly contributory to rising rates of these childhood disorders.
[Top]

6 – The Umbilical Cord Lifeline
Clamping the umbilical cord at birth is a human invention. The umbilical cord is an infant's lifeline throughout gestation; it should go without saying that it remains the newborn's lifeline until lung function is established. Clamping the cord before a baby breathes can be expected to result in at least a brief period of oxygen deprivation. Seven to ten minutes of asphyxia resulted in visible damage in the brainstem in newborn monkeys, but Myers (1972) described microscopic changes following asphyxia of lesser duration. In human infants a low Apgar score at five minutes is ominous, and associated with autism [56, 57]. Even the briefest lapse of respiration should be avoided.

Looking back at historical textbooks on obstetrics, waiting at least for the infant to breathe on its own was traditionally always required before cutting the cord [58-65].

For example from 1850 to 1930:
"A strong healthy child, as soon as it is born, will begin to breathe freely, and in most cases cry vigorously. As soon as it has thus given satisfactory proof of its respiratory power, you may at once proceed to separate it from its mother by tying and dividing the umbilical cord." (Swayne 1856, p20)

"As soon as the child cries we may proceed to tie and separate the cord." (Playfair 1880, p283)

"The cord should not be tied until the child has breathed vigorously a few times. When there is no occasion for haste, it is safer to wait until the pulsations of the cord have ceased altogether."
(Lusk 1882, pp214)


"Immediately after its birth the child usually makes an inspiratory movement and then begins to cry. In such circumstances it should be placed between the patient's legs in such a manner to have the cord lax, and thus avoid traction upon it… Normally the cord should not be ligated until it has ceased to pulsate…"
(Williams 4th ed 1917, p342)


"As soon as the lungs begin to function, the circulation through the umbilical arteries normally ceases in from five to fifteen minutes after birth." (Williams 6th ed 1931, p418)

By the 1940s a change of opinion is evident:
"We have adopted an intermediate course, feeling that to always wait for complete cessation of pulsation frequently interferes with the proper conduct of the third stage of labor, and at the same time, that most of the available blood in the cord had been incorporated in the fetal circulation during the few minutes immediately following delivery." (Stander [Williams 8th ed] 1941, p429)

"Whenever possible, clamping or ligating the umbilical cord should be deferred until its pulsations wane or, at least, for one or two minutes…There has been a tendency of late, for a number of reasons, to ignore this precept. In the first place the widespread use of analgesic drugs in labor has resulted in a number of infants whose respiratory efforts are sluggish at birth and whom the obstetrician wishes to turn over immediately to an assistant for aspiration of mucus, and if necessary, resuscitation. This readily leads to the habit of clamping all cords promptly." (Eastman [Williams 10th ed] 1950, p397)

Would Williams recognize the 20th edition of his textbook?
"Although the theoretical risk of circulatory overloading from gross hypervolemia is formidable, especially in preterm and growth-retarded infants, addition of placental blood to the otherwise normal infant's circulation ordinarily does not cause difficulty… Our policy is to clamp the cord after first thoroughly clearing the infant's airway, all of which usually takes about 30 seconds."
(Cunningham et al. [Williams 20th ed] 1997, p336)

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7 - Developmental Delay
Monkeys subjected to asphyxia did not develop cerebral palsy as had been expected. However, monkeys asphyxiated at birth displayed transient difficulties with motor control.


Normal monkey
Figure 6: A normal monkey assumes an alert crouching stance soon after birth (from Windle, 1969).

Asphyxiated monkey
Figure 7: A monkey subjected to asphyxia at birth is hypotonic and unable to control its arms and legs normally
(from Windle, 1969).

Figure 6 illustrates the ability of a normal infant monkey to rise and bear weight on its arms and legs. Figure 7 by way of contrast shows the early motor impairment of a monkey asphyxiated at birth.

Monkeys asphyxiated at birth appeared to "outgrow" this initial hypotonia, but deficits in manual dexterity and memory remained [1, 44-46.]

Human children with early deficits and delay in motor control may be diagnosed as having "hypotonic" cerebral palsy. More often parents are told their child is just a little slow and will outgrow such early problems.

But poor manual dexterity and lack of fine-motor control have been reported as part of "soft neurological signs" in children with autism. Handwriting that is poorly formed, overly large, and often laboriously produced has been noted, even in high-functioning children with Asperger's syndrome (see figure 8 below).

The asphyxiated monkeys were not deaf despite the severe damage in the inferior colliculi.


The loss of neurons evident in figures 2 and 4 above would suggest that sound transmission to the temporal lobes might be totally blocked. However, the monkeys with damage in the inferior colliculi startled at the sound of buzzers, but they did not localize the sound as normal infant monkeys did [45, 46]. Sound localization has been shown to be a major function of the inferior colliculus [66-68]. The startle reaction may be a reflex response mediated by nuclei in the lower brainstem auditory pathway.
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8 – Poor Manual Dexterity
Figure 8 is a letter home from my son Ralf when he was sixteen and at a school for children with learning disabilities (or what Windle referred to as minimal cerebral dysfunction). The handwriting illustrates his limitation in manual dexterity – compared for example with that of a college-bound teenager. Large handwriting (macrographia) has been described in individuals with high-functioning autism [69].

Ralf suffered a traumatic birth and his development, including speech, was alarmingly delayed. We were told not to worry, "He's a boy. Boys are often slow," etc.


My grandmother (living in Florida) arranged an appointment for Ralf to be evaluated by a neurologist when he was still not walking at eighteen months – she planned to come to Boston and take him herself if I would not. Concerns of family members I came to realize are often far more important than the advice of professional experts.

The neurologist told me Ralf had a "mild" form of cerebral palsy, hypotonic cerebral palsy. Then he added the phrase that echoes in my mind still to this day, "He'll never be quite the person he would have been."

Ralf did finally begin walking two months later, and like the asphyxiated monkeys outgrew his early motor problems. I am eternally grateful that he did not have spastic cerebral palsy. Ralf became quite athletic; running, swimming, basketball, and bicycling have given him a great deal of pleasure. But into adulthood his handwriting and other fine motor skills remain deficient.


Letter home from Ralf

Figure 8: Handwriting sample of a 16-year-old with what Windle would have termed "Minimal Cerebral Dysfunction," and residual deficits in manual dexterity.
[Top]

The rest of the world could care less about Ralf's "minimal" handicaps. I am painfully aware that he is not quite the person he would have been. Mostly he is not highly motivated or ambitious, but I know few people as sensitive to others, cheerful, and intent upon enjoying life. A few years ago I saw his "minimal cerebral dysfunction" recorded as PDD NOS. I dislike this label because of the pernicious implication that he and our family carry genes for "autism spectrum" disorder. Monkeys subjected to asphyxia at birth carried no such genes.

Ralf was crying at birth before anyone could answer my question whether the baby was a boy or a girl. A minute or so later the doctor held him up by his feet and announced, "It's a boy!" Ralf was howling and totally pink except for his feet, which were very blue. I suspect that oxygen deficiency occurred during my long difficult labor, and during which he incurred a prominent cephalhematoma. Because Ralf had a large head and forceps were required, I am sure a few minutes of total asphyxia occurred.

Conrad suffered a much more severe asphyxia; he was flaccid and ashen white at birth, and required resuscitation. I am sure Ralf suffered some impairment of function in the inferior colliculi, and that the same long-term progressive damage found in monkeys is the reason he is, as the neurologist told me many years ago, "not quite the person he would have been."

9 - Progressive Degeneration
Signs of on-going progressive neuropathologic changes were observed in monkeys kept alive for months or years following asphyxia at birth, even in monkeys without the characteristic lesions of the inferior colliculi [30]. Asphyxia had to be of seven to eight minutes duration before visible damage of the inferior colliculi was seen. Impairment of function within the inferior colliculus could reasonably be expected in cases where asphyxia was not of long enough duration to produce visible lesions.

Neurotransmitters are produced in the inferior and superior colliculi of immature laboratory animals, which are thought to guide formation of synapses and promote growth of later developing areas of the cerebral cortex [70, 71]. Submicroscopic as well as visible damage within the inferior colliculi might then disable the biochemical mechanisms required for normal maturation of the cerebral cortex. Failure to fully develop frontal lobe cognitive abilities becomes more and more painfully evident as a child with autism or "minimal cerebral dysfunction" matures. [Top]

Neuropathology found following long-term survival after asphyxia at birth involved:


Brainstem

periaqueductal gray

oculomotor nuclei

inferior olives

reticular formation

Cerebellum

diminished Purkinje cells

Subcortical

mammillary bodies

hippocampus

amygdala

Cortical

frontal and parietal cortex

corpus callosum (left-right hemisphere connection)

ventricular enlargement

Anomalies in many of these areas have been reported as part of the neuropathology of autism or its behavioral handicaps [72-82]. Functional impairment of the amygdala, cerebellum, hippocampus, and frontal lobe connections are at the forefront of theories of autistic disorder. Long-term brain changes following asphyxia at birth provide a mechanism by which impairment of these brain areas might come about, without having to hunt for gene loci on chromosomes.
[Top]

10 - Autism and complications at birth
Autism is not generally acknowledged as having anything to do with difficulties at birth. Perinatal problems have been discussed in several papers, but then usually dismissed as minimal or non-specific [57, 83-95]. As Juul-Dam et al. (2001) noted "No presently apparent unifying feature" can be identified as a unique predisposition for autism.

But oxygen insufficiency is the major "unifying feature" of all complications at birth. Respiration is the most immediate and essential need of all life forms dependent upon oxygen. Asphyxia at birth results in selective damage within the brainstem auditory pathway, and auditory dysfunction is a characteristic of autistic disorder. Failure to learn language by ear, as normal children all do, is the most serious obstacle to further development for children with autism. Asphyxia at birth warrants investigation as a cause of autism as much as if not before consideration of genetics, infections, or exposure to toxic substances.

Some researchers have argued that complications at birth are due to a pre-existing problem with the infant or mother. But damage to the inferior colliculi had nothing to do with any pre-existing problem of monkeys subjected to asphyxia at birth.


Cephalhematoma
Figure 9: Cephalhematoma, bruising of head caused by dystocia or difficult passage through the maternal pelvis
(from Towbin, 1970).

One monkey followed by Faro and Windle (1969) had been a breech birth and suffered asphyxia, and damage to the inferior colliculi, because of difficulty extracting the head [30]. Birth can be a hazardous experience, but malpresentation and dystocia should not be viewed as unpreventable pre-existing (genetic) causes of brain damage.

The inferior colliculi are small nuclei in the tectum (roof) of the midbrain, and although prominent these lesions were overlooked in the search for anticipated involvement of the cerebral cortex in the asphyxiated monkeys.

Neuropathology is not easily detected in autism. Pathology has been reported in brains from some autistic individuals, which included some of the rank-order of brainstem nuclei Myers found damaged by asphyxia [72-82], as well as the brain structures affected by progressive "trans-neuronal" degeneration [30].

Only Williams et al. (1980) reported looking for damage in the inferior colliculi in one case of autism in which asphyxia at birth had been suspected as a possible cause [72].


But the article by Willams et al. is a prime example of the difficulty finding visible signs of brain impairment: Reduced Purkinje cell density was noted in the cerebellum of a male patient who had a chronic seizure disorder and died at age twelve. This patient also had reduced pyramidal cell dendrites in the midfrontal gyrus. The same pyramidal cell abnormality was seen in the brain of a 27-year old autistic subject who belatedly was found to have phenylketonuria (PKU), and this was the only abnormality found!

Figure 9 is a drawing from an article by Towbin (1970) in a textbook of neuropathology [96]. The drawing bears such a striking resemblance to my son Ralf that I contacted Dr. Towbin, who told me the drawing was made in September 1962 in the newborn nursery at the Boston Lying-In Hospital. That is when and where Ralf was born, and if figure 9 is not a drawing of him, it looks just like him, even today in adulthood. His eyes were swollen shut right after birth (more so than shown in the picture), and he still bears a scar under his right eye from use of forceps.

I was told my difficult delivery with Ralf was because he was a "brow presentation." The article by Towbin and many chapters in textbooks of obstetrics describe the dangers of malpresentation at birth.
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11 - Mercury and Other Toxic Factors
Windle and coworkers found that bilirubin levels (from jaundice) can be very high and not cross the blood brain barrier (BBB), and therefore not damage the brain. In experiments with newborn monkeys, bilirubin was found to enter brain tissue only in those animals also subjected to asphyxia [54]. Compromise of the BBB by asphyxia may be part of a protective response to increase blood flow and help get oxygen into neurons.


But compromise of the BBB by asphyxia also allows bilirubin or any other toxic substance in the blood to get into brain tissue and damage it further. Thus administration of hepatitis B (or any other) vaccine in the newborn nursery may likewise compound the effects of asphyxia incurred during complications at birth.

Many parents are convinced that the mercury preservative in vaccines caused their child to develop autism [97-101]. The auditory system is damaged by mercury poisoning in Minamata disease [102]. Loss of BBB integrity could allow the small amounts of mercury preservative in vaccines to get into brain tissue just as happens with bilirubin, especially vaccines given in the first hours or days after birth.


Kernicterus
Figure 10: Kernicterus (bilirubin staining of subcortical nuclei) found only in monkeys subjected to asphyxia (from Windle, 1969).

Figure 10 shows staining by bilirubin of nuclei in the basal ganglia (subcortical motor nuclei) in a monkey subjected to asphyxia at birth. How can it be safe to assume that the immature brain is more resistant to oxygen insufficiency? Changes in the blood-brain barrier caused by asphyxia are not visible, and disruption of metabolic systems that precede the appearance of visible damage may still lead to serious impairment of function.


. . . .

[Top]
II. THE AUDITORY SYSTEM

12 - Metabolic Rank Order
Myers (1972) described involvement of a "monotonous rank order" of brainstem nuclei in the pattern of damage caused by asphyxia at birth. This rank order is comparable to the metabolic rank order of brainstem nuclei revealed by the autoradiographic techniques for measuring cerebral blood flow and metabolism.

The autoradiogram picture in Figure 1 (top of webpage) is part of data gathered in experiments done nearly half a century ago (Landau et al. 1955) to investigate cerebral circulation [3]. A radioactive tracer was injected into a laboratory animal (cats were used in this initial investigation). Distribution of the tracer was measured one minute later.


Table 1: Cerebral Blood Flow in Cats
Brain Structurecc/gm/minBrain System
Inferior colliculus1.80auditory
Sensory-motor cortex1.38
Auditory cortex1.30
Visual cortex1.25
Medial geniculate1.22auditory
Lateral geniculate1.21visual
Superior colliculus1.15visual
Caudate1.10subcortical motor
Thalamus1.03
Association cortex0.88
Cerebellar nuclei0.87
Cerebellar white matter0.24
Cerebral white matter0.23
Spinal cord white matter0.14

Table 2: Deoxyglucose Uptake
Brain StructureMonkeyAlbino RatBrain System

SD 1-4SD 2-7
Inferior colliculus103197auditory
Auditory cortex79162
Vestibular nucleus66128
Medial geniculate65131auditory
Superior olivary nucleus63133auditory
Visual cortex59107
Mammillary body57121limbic
Superior colliculus5595visual
Thalamus, lateral nucleus54116
Caudate-putamen52110subcortical motor
Cochlear nucleus51113auditory
Cerebellar nuclei45100
Sensorimotor cortex44120
Lateral geniculate3996visual
Hippocampus3979limbic
Cerebellar cortex3157
Cerebellar white matter1237

The most intense radioactivity can be seen in the inferior colliculi, the superior olives, and nuclei of the lateral lemniscal tracts that connect these brainstem auditory nuclei.

Blood flow values (measured from autoradiogram slices through the entire brain) are shown in Table 1. The inferior (auditory) colliculus can be seen to be at the top of a rank order of brain areas of high circulatory rate in cats. These include sensory and motor areas of the cortex, the auditory and visual geniculate nuclei of the thalamus, the superior (visual) colliculus, and the caudate nucleus (in the subcortical motor system).

In figure 1, the higher density of tracer in the brainstem auditory pathway compared with that in the cortex gives some idea of what the numerical differences mean.

Blood flow was investigated using metabolically inert tracers. A radioactive analogue of glucose (deoxyglucose) was employed later because it enters the brain like glucose but is not further metabolized [7]. Data for deoxyglucose uptake is shown in Table 2 for both monkeys and laboratory rats.

Fluoro-deoxyglucose was adopted soon thereafter for use in positron emission tomography (PET) studies in human subjects [8]. PET scanning has been used to try to identify neuropathology in cases of autism, but no consistent anomalies have been reported yet [103-110].

The original deoxyglucose method has been widely used in animal research studies, and a rank-order for glucose uptake similar to that for blood flow has been confirmed many times over in many different laboratories [15-25].

Data for capillary density, and glucose transport protein (GLUT1) further indicate that high blood flow supports greater glucose utilization for aerobic metabolism [9-11].


Measurements of the aerobic enzymes alpha-ketoglutarate and cytochrome oxidase further confirm that high blood flow supports aerobic metabolism, which is highest in the same hierarchy of brain areas [12-14].

The auditory system is susceptible to injury because its components have greater metabolic needs than most other areas of the brain. On the other hand this most active system is clearly often spared. But after a few minutes of sudden total circulatory arrest, and if resuscitation is possible, the inferior colliculus incurs severe damage. This has been found true in adult human cases as well as children [111-117].
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13 - The Auditory System
Figure 11 is a diagram of the auditory system that shows the location of the darkly labeled structures in figure 1.


The auditory system may have special importance for the brain as a whole. Fisch (1970) pointed out that the auditory system is always active, even during sleep [118] -- this is why we use alarm clocks to wake up!

The auditory system evolved as an alerting mechanism for visual attention, and there is evidence that the inferior (auditory) and superior (visual) colliculi in the midbrain tectum might have special importance for general awareness and consciousness [119, 120].

In experiments with cats Sprague et al. (1961) severed the lateral lemniscal tracts and described a behavioral change they felt was reminiscent of autistic children [121].


Diagram of the auditory system
Figure 11: Diagram of the auditory system from the ears (via the cochlear nerves) to the auditory receptive areas of the temporal lobes (via the temporal radiations).

Roth and Barlow (1961) employed an autoradiographic technique modeled after that used for measuring blood flow to investigate distribution of drugs in the brain [122]. They found that the fast-acting anesthetic thiopental was quickly distributed to the inferior colliculus. Thiopental is used for rapid induction of general anesthesia (loss of consciousness). That thiopental goes directly to the inferior colliculi suggests that high metabolic rate in this pair of auditory nuclei may be important for maintaining the conscious state.

Deafness is not a handicap of consciousness or general awareness. But deafness is the result of impairment at the level of the cochlear nucleus, or mechanical components of the ears. Autism is a handicap of general awareness, or of multiple attention deficits at least. Lack of social awareness and diminished capacity for "shared attention" are manifestations of environmental obliviousness in children with autism. That these characteristics may stem from impairment of midbrain auditory alerting functions is worth exploring.
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14 - Auditory Dysfunction
That autistic children are hypersensitive, hyper-reactive, and confused by some sounds is common knowledge (though largely based on anecdotal accounts). Normal children carry on conversations in school cafeterias and gymnasiums as easily as anywhere else, even with music blaring from the loudspeakers. An autistic child in such a noisy setting may exhibit extreme distress. My son Conrad would cover his ears and often refuse to go into a room where he saw a telephone – another anecdotal account. But anecdotes should be collected and taken more seriously as sources of useful data.

A parent on an internet email exchange (autism@list.feat.org, 3 Oct 2002) asked for advice on what to do about classroom aides who were controlling his 13-year-old son's behavior by holding him down in front of a vacuum cleaner. An outpouring of sympathy, outrage, similar stories, and ways to help overcome the child's fear followed. Kanner (1943) described two of the eleven children in his original report as being afraid of the vacuum cleaner, one so much that she would not go near the closet where it was kept [123]. Analysis of sound patterns emitted by vacuum cleaners, ability to recognize words and other sounds with component sounds as background noise, and research on auditory evoked potentials to signals of interest presented in noisy surroundings might yield useful data.

Research to date on auditory evoked potentials suggests that acoustic signals from ear to temporal lobes may be slowed or distorted in some children with autism [124-134]. These investigations have been controversial but they do provide indication of auditory dysfunction. Further, monkeys asphyxiated at birth were not deaf, but measurement of auditory evoked potentials revealed a delay in auditory signal transmission similar to that found in some children with autism [135].

Confusion in noisy environments points to problems processing multiple incoming sounds, and suggests that alternatives to simple click and tone stimuli should be used in testing for disorders of hearing. For example, tests of word recognition in quiet (WRIQ) and word recognition in noise (WRIN) described by Church et al. (1997) could be used to assess verbal children and even adapted for use with low functioning children with autism [136].

Researchers at the molecular level have found that inhibitory as well as excitatory neurotransmitters work together to modulate responses of neurons that detect sound onset; ongoing signals of the same frequency and intensity are detected but not transmitted further [137, 138]. The hypersensitivity to sounds displayed by some autistic children may represent loss of inhibitory function – why the sound of a vacuum cleaner might be distressing beyond the imagination of most of us. Inability to distinguish sound onset then relegate it to background awareness could also be part of the difficulty in recognizing boundaries between words and syllables in spoken language.

Caspary et al (1995) provided data showing decline with advancing age of neurotransmitter function in the inferior colliculus that may lead to loss of the capacity to detect and extract meaningful signals from background noise [139]. They pointed out that this leads to difficulty following a conversation in a noisy environment and may be the reason some elderly people withdraw from participation in society. The same or similar disability may lead children with autism to avoid social contact.
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. . . .

III. LANGUAGE


15 - Language by Ear
Language evolved in the human brain with the temporal-to-frontal lobe circuit in the cerebral cortex. Language is a higher cortical function. However, language learning begins before maturation of the cortical language areas is complete. Children learn language "by ear."


Maturation of brain circuits takes place as myelin sheaths form around axons of neurons. The brainstem auditory pathway is myelinated and functional earlier than any other system in the human brain [140-142].

Figure 12 is from the brain of a human infant born prematurely at 29 gestational weeks (29gw) who survived eight postnatal days (8pnd). The dark stain for myelinated fibers in the auditory pathway dominate the brainstem almost to the exclusion of other neural systems (ICol, inferior colliculus; LLm, lateral lemniscus; MLF, medial longitudinal fasciculus; MLm, medial lemniscus).

It is at 29 gestational weeks that the human fetus first responds to sounds [142].

A maturational timetable can be viewed by clicking the link above to The Auditory System. Myelination of the acoustic radiations to the temporal lobes continues up to three or four years of age. But children normally start learning to speak between the ages of one to two.

Brown and Bellugi (1964) determined that young children normally recognize stressed syllables as a prominent feature of speech around them.


Myelination at 29 gestational weeks
Figure 12: The brainstem auditory pathway is myelinated earlier in the human fetus than any other circuit of the brain.
(from Yakovlev & Lecours, 1967, with permission from Blackwell Scientific Publications).

Detection of stressed syllables leads to a predictable first stage of language development known as "telegraphic speech" in which a child makes use of single syllable units of meaning and rearranges these newly acquired units of meaning to fit new contexts [143-145].

Inability to recognize syllable and word boundaries has been identified as a problem in some children with autism [146]. Use of phrase fragments rather than syllabic units is characteristic of the echolalic speech of autistic children. Phrase fragments are not as easily rearranged as syllabic units to fit new contexts.
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16 - Verbal Auditory Agnosia
Everyone agrees learning a language by ear is best, but after the first decade of life this becomes more and more difficult. Normal young children can learn a second language, without accent. The ability to hear syllable and word boundaries decreases with age. There is evidence that the auditory system ages faster than other areas of the brain because of its high metabolic rate [147]. Impairment of the inferior colliculus by asphyxia at birth may be like premature aging, and make it as difficult for a child so handicapped to detect syllable and word boundaries as it is for an adult trying to learn a foreign language.

Rapin (1997) suggested that inability to distinguish syllable and word boundaries in rapid streams of speech may be the basis of the language disorder in some children with autism; she referred to this as "verbal auditory agnosia" [146]. Agnosia is a failure of recognition without loss of sensory function. Most children with autism have hearing seemingly adequate for learning language, but agnosia ought to be more fully explored.

Agnosia for speech or "word deafness" (loss of ability to comprehend spoken language) has been reported in three previously normal adults following injury of the inferior colliculi in the midbrain auditory pathway [148-150].


17 - Echolalic Speech
Telegraphic speech includes use of elemental units of meaning rearranged to fit new contexts. Some examples are phrases like "Mommy go store" or "Apple, I want." Use of elemental units of meaning (morphemes) reveals a child's ability to parse what he hears. Command of morphemic components facilitates re-wording and comprehension of grammatical structures.

Speech productions of an autistic child on the other hand at best consist of phrase fragments used badly out of context. This is echolalic speech, use of parroted "sound bytes," which Kanner (1946) referred to as "irrelevant and metaphorical language" [151]. No rewording to fit new contexts takes place. "Pronoun reversal" is part of the failure to re-word, as is frequent use of the prosodic intonation for a question.

"You don't want to go swimming?" is not intended as a question, but as a statement by the child that he doesn't want to go in the water. "You want an apple?" is equivalent to the telegraphic request "Apple, I want." "Is that yours?" is equivalent to a normal young child's statement, "That mine."
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Bedtime ritual
Figure 13:Conrad and Ralf getting ready for bedtime stories (after getting the toothpaste unstuck).

18 - Echolalic Speech is Pragmatic
Reliance on echolalic sound-bytes impedes recognition of morphemic units or grammatical structures. But echolalic speech is not irrelevant and metaphorical. Echoed phrases are used with pragmatic purpose, for communication or expression of feelings. Often only the intimate caregiver can explain the utterances of an autistic child.

"What's the matter, did your wagon get stuck?" was a phrase my son Conrad used in any frustrating situation. His grandmother did not understand why he should say this when he was having trouble squeezing toothpaste out of the tube.



"He speaks perfectly well," my mother said, "He just doesn't make any sense!"

I had to explain to her where this peculiar phrase came from. At least a few weeks (if not months) earlier Conrad was pulling his little wagon along the fence in our backyard, and started to cry when it got stuck on the root of a shrub.

His brother Ralf went running to help calling out, "What's the matter, did your wagon get stuck?"

Conrad remembered this as the best fit he had for any context of frustration, or as Roger Brown (1975) said, it was the equivalent of saying "Damn" [145].

Ralf and Conrad's little brown wagon
Figure 14: Ralf and the wagon that got stuck.
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. . . .

IV. CHILDHOOD HANDICAPS

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).
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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.
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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].

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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."
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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].

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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].

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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.
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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].

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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.
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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.
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. . . .

V. BRAINSTEM DAMAGE

28 - Variable Vulnerability
Preservation of function in the auditory system is apparently important for survival and homeostasis. Mechanisms that increase blood flow under adverse conditions protect the auditory system in most circumstances, as shown by research using the autoradiographic methods for blood flow and deoxyglucose uptake For example the nerve gas Soman administered to laboratory animals in sub-toxic doses stimulated increased blood flow, with the greatest increase in the inferior colliculus [233-235].

Adjustment of aerobic metabolism as well as increased blood flow takes place with use of alcohol and other drugs. Research on the effects of amphetamine drugs revealed increased blood flow and metabolism in the inferior colliculus and visual cortex with metabolic depression elsewhere in the brain [236].

Grünwald et al. (1993) found that administration of one dose of alcohol to laboratory rats depressed glucose utilization throughout the brain, and this was most pronounced in the auditory system [24]. Increasing doses of alcohol given over a three week period increased deoxyglucose uptake in the inferior colliculus in dramatic contrast to lowered uptake in other areas of the brain. But an additional dose given two hours before measurement of deoxyglucose led to depressed uptake in the inferior colliculus.

If increased metabolism leads to auditory sensitivity that is diminished by an additional dose of alcohol, this might provide one explanation for addiction. In any event it provides an example of how metabolism as well as blood flow adapts to substances like alcohol.

Neuropathology caused by alcohol intoxication has long been known (as Wernicke's encephalopathy, in Wernicke-Korskoff syndrome), and the mammillary bodies are most predictably involved [237-241]. The mammillary bodies are among the brain areas of high glucose utilization as can be seen in table 2. Protective mechanisms that spare the inferior colliculi may then make slightly less active nuclei like the mammillary bodies most vulnerable to compromise.

Damage to the cerebral cortex is the most common consequence of oxygen deficiency. Clamping the carotid arteries of neonatal gerbils led to decreased blood flow to the forebrain but increased circulation in the inferior colliculi from collateral blood vessels [21]. Partial obstruction of placental blood flow to fetal monkeys produced damage in the cerebral cortex and cerebral palsy [2].
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29 - Patterns of Damage

(1) Cortical and brainstem patterns
Damage caused by partial oxygen insufficiency (hypoxia) and total oxygen cutoff (asphyxia) is not a matter of degree. That brainstem damage is sometimes seen in human cases of circulatory arrest or suffocation has been a puzzle and topic of discussion in the medical literature [111-117].

Neubuerger (1954) investigated neuropathology in cases of cardiac arrest during surgery; most resulted in damage to the cerebral cortex, but Neubuerger expressed surprise that the location of lesions showed more variety than expected [111]. He made special note of one case in which there was, "...involvement of centers usually affected in Wernicke's disease, especially the mammillary bodies and posterior colliculi..." This was a person who died, at age 72, of respiratory failure during surgery. Artificial respiration and heart massage were performed with spontaneous heart beats obtained after eight minutes and spontaeous respiration after eighteen minutes. The patient, however, remained in a coma until death one week later. This can be viewed as a case of sudden catastrophic asphyxia, comparable to asphyxia at birth as produced in the experiments begun five years later by Ranck and Windle 1959 [26].

Gilles (1963) described symmetrical damage of brainstem nuclei in three individuals who survived episodes of cardiac arrest but later succumbed [113]. In two of the cases, normally expected damage was found in the cerebral cortex, thalamus, and cerebellar cortex. In addition, brainstem lesions of sensory and motor nuclei of several cranial nerves including the third (oculomotor), the inferior colliculi, cell groups in the reticular formation, and the lateral cuneate nuclei were found. The third case was an eighteen-month-old child who drowned but was resuscitated. In this case, the cerebral and cerebellar cortex remained intact.

Gilles noted the similarity of the brainstem pattern of damage to that found after experimental asphyxia of newborn monkeys and in human cases of kernicterus (bilirubin staining, or jaundice, of subcortical nuclei), and he suggested that brainstem "aphasias," such as in Moebius syndrome [242] might be related to temporary cardiac arrest in the prenatal or perinatal period. Moebius syndrome is another condition associated with Autism [243, 244], and it appears to be related to brainstem pathology [245-248], caused in some cases by prenatal exposure to the drug misoprostol [249].
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(2) Wernicke-like or "circulatory arrest" encephalopathy
Brierley (1961) described, "Wernicke-like" lesions in the mammillary bodies as well as severe cell loss and gliosis in the inferior colliculi" in the brain of a two-year old child who suffered cardiac arrest of ten to fifteen minutes duration from anesthesia used for repair of a hernia [112]. Brierley also noted the striking similarity of this pattern of damage to that reported by Ranck and Windle.

Gilles (1969) reported three more cases of brainstem damage: In a 17-month-old boy who suffered cardiac arrest during a high fever, a nine-year-old child resuscitated after suffocation under a collapsed earthen bank, and a 22-year-old man who suffered cardiac arrest following a bullet wound to the abdomen [116]. Gilles referred to these cases as examples of "hypotensive brainstem necrosis." Janzer and Friede (1980) suggested "cardiac arrest encephalopathy" as a better term, and reported the brainstem pattern of damage in eight infants and seven adults for all of whom a well documented episode of cardiac arrest had occurred [117].

When circulation and oxygen delivery are completely cut off, metabolism within the brainstem nuclei of high circulatory rate comes to a sudden halt. This clearly happens far less often with survival than circulatory insufficiency or partial disruption of aerobic metabolism. Damage from both partial and total asphyxia can happen, with both cortical and brainstem patterns evident in the brain of any victim of an accident that interferes with respiration.

Asphyxia is not a more severe degree of hypoxia; asphyxia is a different kind of insult. Protective mechanisms go into effect in situations of reduced blood flow or oxygen insufficiency (hypoxia). Expansion of blood vessels (vasodilation) happens with exposure to toxic substances [233-236], and in alcohol intoxication [24]. Increased blood pressure can lead to bursting of capillaries; the "whiskey nose" of some alcoholics is a visible sign of this kind of process. Figure 19 (below) shows "flea-bite" size hemorrhages in the brainstem caused by alcohol intoxication. The "corpus quadrigeminum post" (posterior quadrigeminal body, or inferior colliculus) is indicated as a primary site in which this kind of damage occurs.
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Wernicke's encephalopathy
Figure 19: Wernicke's encephalopathy: Flea-bite size hemorrhages in the brainstem from dilated blood vessels that burst (from Kant 1933, with permission from Springer-Verlag).

30 – Wernicke's Encephalopathy

(1) Hemorrhagic (or vascular) cause?
Brainstem damage caused by alcohol intoxication has long been known as Wernicke's encephalopathy [237-241]. Wernicke (1881) observed this pattern of damage in the brains of two alcoholic men and a young woman who had swallowed sulfuric acid [251]. An English translation of part of Wernicke's paper can be found in the article by Brody and Wilkins (1968) [253].


Wernicke described the damage as hemorrhagic, consisting of pin-point size burst capillaries as shown in the photograph above. Whether Wernicke's encephalopathy is always hemorrhagic has been controversial. Rosenblum and Feigin (1965) reported 41 cases of which 17 had no hemorrhages [252]. Visible petechial hemorrhages were recognized in 5 cases, and 19 revealed hemorrhages only under the microscope; five of these 19 were old hemorrhages recognized only by hemosiderin laden macrophages. Thus only 60 percent of their 43 cases showed any evidence of a hemorrhagic process.

Wernicke cited a paper by Gayet (1875) who described hemorrhagic brainstem damage in a man who survived several months following scalding of his airways in a boiler explosion [250]. Figure 20 predates use of photography, but is a drawing in color showing the areas of hemorrhagic damage in Gayet's patient.

(2) Brain structures involved
The mammillary bodies are usually noted as most severely affected in Wernicke's encephalopathy. But damage in the inferior colliculi is also often prominent [237-241].

Location and severity of the damage is variable because protective mechanisms have time to go into effect whenever a toxic insult does not immediately or totally disrupt aerobic metabolic systems.


Drawing of hemorrhagic brainstem damage (from Gayet 1875)

Figure 20: Drawing of hemorrhagic brainstem damage found by Gayet (1875) in a patient who survived eight months following scalding of the airway in a boiler explosion.

Note the involvement of the cerebellum in Wernicke's encephalopathy [254, 255]. Similar cerebellar pathology is prominent in the few investigations of brains from individuals with autism.

Damage caused by asphyxia at birth should probably be recognized as a variant of Wernicke's encephalopathy. Windle reported that the brainstem lesions caused by asphyxia at birth were not hemorrhagic in origin, which may be why he did not consider the damage caused by asphyxia at birth to be a variant of Wernicke's encephalopathy. But the brainstem structures affected are comparable.
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31 - Suffocation at the Molecular Level
Circulatory arrest and suffocation have an immediate and catastrophic effect on respiratory gas exchange and thence aerobic metabolism. In these circumstances brain structures of high metabolic rate are most vulnerable, evident from experiments on asphyxia in monkeys (newborn and adult) and case reports of damage following resuscitation after cardiac arrest and accidents like drowning [1-2, 29, 111-117]. The same metabolically active brain nuclei are also susceptible to damage or impaired function by chemical substances many of which may selectively disable aerobic metabolic pathways.

(1) Selective disruption of aerobic metabolism:
Troncoso et al. (1981) introduced the substance pyrithiamine as a tool for simulating thiamine deficiency, producing Wernicke's encephalopathy, and as a shortcut for mimicking the effects of chronic alcohol consumption in laboratory animals [256]. Pyrithiamine displaces thiamine (vitamin B1) from the enzyme that activates it as a cofactor for the major (Krebs cycle) pathway of glucose metabolism. Neurological impairment and neuropathology are produced more quickly with pyrithiamine than by administering alcohol to experimental animals [257-261].

Pyrithiamine causes suffocation at the molecular level. Protective mechanisms can have no effect. Hakim (1986) found dramatic increases in cerebral circulation following pyrithiamine administration – a protective response doomed to failure [259]. Blood flow returned to normal levels following administration of thiamine except in the inferior colliculi, mammillary bodies, and thalamic nuclei – an early sign of permanent impairment in these metabolically most active brain nuclei.

Glucose metabolism is blocked by pyrithiamine, thus carbon dioxide is not produced as a stimulus for hemoglobin to release oxygen. Chen et al. (1997) found the inferior colliculi sustained damage before the mammillary bodies or any other of the brainstem nuclei of high metabolic rate in laboratory rats injected with pyrithiamine [261]. The blocking of glucose metabolism by pyrithiamine is one step beyond that of carbon monoxide or cyanide, which displace oxygen on the hemoglobin molecule [33, 34].
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(2) Fast-acting anesthesia:
Roth and Barlow (1961) used an autoradiographic technique modeled after that used for measuring blood flow to investigate distribution of anesthetic agents in the brain [122]. They found distribution in the brain of fast-acting thiopental was different from that of barbiturates, which are slow to take effect but of longer duration. Thiopental was quickly distributed to the inferior colliculi and other nuclei of high blood flow. This finding lends support to the idea of Denny-Brown (1962) that the midbrain tectum (auditory and visual colliculi) is involved in maintaining the conscious state [119].

If the action of thiopental is on a specific neurotransmitter system, it would appear to be one of special importance for consciousness, and one closely coupled to aerobic energy production – the reason for high aerobic metabolism to have evolved in brain nuclei that maintain vigilance for environmental change.

(3) Brain-damaging intoxicants:
Damage of the inferior colliculus has been reported following exposure to several toxic chemicals [262-267]. Fumes from dry-cleaning fluids may reduce oxygen available to the lungs, or like thiopental be quickly distributed to areas of the brain with high blood flow. A confusional delirium afflicting two pressers in a dry-cleaning establishment was described by Bini and Bollea (1947) as comparable to alcohol intoxication [262]. Chronic intoxication lead to coma and death with focal lesions typical of Wernicke's encephalopathy found in the mammillary bodies, floor of the fourth ventricle, and inferior and superior colliculi.

Franken (1959) reported the case of a 28-year-old man exposed over a two-year period in his work filling fire extinguishers with methyl bromide [263]. He developed transient alterations in consciousness and involuntary jerking of his legs; he died two days after acute intoxication by a large amount of methyl bromide. Franken described brain lesions of the Wernicke-encephalitic type involving both posterior quadrigeminal bodies (the inferior colliculi). Goulon et sl. (1975) and Squier et al. (1992) reported additional cases of disability and death following acute exposure to methyl bromide, with Wernicke-like patterns with prominent involvement of the inferior colliculi [264, 265].

Cavanagh (1992) commented on the paper by Squier et al. and pointed out other toxic substances (6-amino-nicotinamide, misonidazole, metronidazole, and mono- and dinitro-benzene) that act by disabling the biochemical pathways of energy generation and produce symmetrical brainstem damage similar to that caused by methyl bromide [266]. Cavanagh and Nolan (1993) described the same pathology in laboratory rats caused by alpha-chlorohydrin, which was under investigation for use as a male anti-fertility agent [267]!
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(4) Selective what?
Terms such as "Selective serotonin re-uptake inhibitors" have become part of the common vernacular, and are used to promote sales of drugs touted to improve mental well-being. Caution is warranted. There may be drugs, and even herbal remedies, that impair aerobic metabolism without causing visible damage; unlike alpha-chlorohydrin they may be out there on the market.

Alzheimer dementia as well as autism is on the rise. It might seem prudent to require that all pharmaceutical products be tested for their effects on the brain. The autoradiographic methods for blood flow and deoxyglucose uptake are ideally suited to investigation of metabolic effects of substances that do not produce visible damage. Auditory system and aerobic metabolic impairments have been detected in Alzheimer patients [14, 268].

(5) Mercury and lead poisoning:
Bertoni and Sprenkle (1989) used the deoxyglucose method to investigate how lead compounds affect the brain. They found decreased glucose uptake throughout the brain seven hours after administration of lead acetate, but this was most pronounced in structures of the auditory system: Inferior colliculus, superior olive, cochlear nucleus, lateral lemniscus, and auditory cortex [18]. Bertoni and Sprenkle proposed that lead may poison the energy-activating enzyme Na,K-ATPase.

Oyanagi et al. (1989) reported auditory system involvement as part of the neuropathology of mercury poisoning in 14 victims of Minamata disease (or Hunter-Russell syndrome), a condition that includes impairment of hearing and speech [102]. The evidence that mercury and lead affect the auditory system suggests that they may be disruptive to aerobic metabolism or a neurotransmitter system dependent upon a steady energy supply. How heavy metals interfere with aerobic metabolism is not as clear-cut as in the case of pyrithiamine.

The mercury preservative (Thimerosol) in vaccines is widely claimed to be a cause of autism [97-101]. The mercury theory is controversial because it has been formulated largely by parents who report having seen regression into autism following vaccination of their child. Lead poisoning has been reported as a co-morbid condition in some children with autism[174-176].
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(6) Mitochondrial damage:
Aerobic metabolism takes place within the mitochondria of cells. Any substance disruptive to any component of mitochondria (cell walls, cristae, enzyme complexes, ribosomes, or DNA) will impede aerobic metabolism. Mitochondria have their own double stranded circular DNA similar to that of primitive bacteria [274, 276]. Mitochondria are thought possibly to have been a primeval infecting organism that turned out to be symbiotic for multicellular life forms because of the efficiency of their aerobic pathways for energy production [270, 277].

Mitochondrial genes encode RNA sequences for ribosomes, where peptides are assembled to become components of the enzymes that catalyze oxidative metabolism [274, 276]. Genes within chromosomes of cell nuclei encode additional RNA and peptide sub-units for the mitochondrial enzyme system. Mitochondria are duplicated from the maternal egg because sperm cells do not contain mitochondria [277]. Chromosomal genes are derived from both parents, and are far less vulnerable to mutations because protective enzymes that repair chromosomal DNA evolved later in cells with nuclei.

Mitrochondrial DNA is especially susceptible to mutagenic agents, and antibiotic drugs can damage mitochondria because of their similarity to bacterial organisms [271, 275]. Antibiotics are less and less effective against bacteria, which mutate and produce resistant strains. But damage to mitochondria may be a more urgent reason to avoid overuse of antibiotic medications. Mutations of mitochondrial DNA can lead to serious mitochondrial disorders. The kidneys and auditory system are most susceptible; nephrotoxicity and ototoxicity are common side effects of many drugs.

Matrilineal transmission of deafness induced by widespread use of streptomycin has been reported [272, 273]. Toxic chemicals used as herbicides and pesticides have long been known to cause neurodegenerative disorders; methyl bromide was used for this purpose as well as in fire extinguishers. DeJong (1944) reported the neurotoxicity of methyl bromide [269], which later was found to cause a brainstem pattern of damage similar to that caused by asphyxia [262-265]. Other chemical substances have been found to be mutagenic to mitochondrial DNA and are known to cause symptoms similar to those of Parkinsonism and Huntington’s chorea [271, 275]. [Top]

32 - Thiamine Deficiency
Suffocation at the molecular level also occurs in cases of severe thiamine (vitamin B1) deficiency. Beriberi is an illness that developed in countries where rice was a dietary staple after whole-grain rice was replaced by refined white rice [282, 284].

Causes ranging from infection, toxic contamination of water, dietary deficiency of protein, to racial predispositions were sought, but adding back to rice "polishings" containing the germ removed during refining was found to immediately ameliorate the symptoms of this illness. Diligent research finally led to isolation of thiamine as the essential molecular component that would prevent illness [281].

Thiamine is an essential cofactor for enzymes that catalyze glucose metabolism, and is now therefore classified as a vitamin. Thiamine is needed only in small amounts but it has a high turnover rate and needs to be replaced at least daily. Neurological signs gave evidence of brain involvement in beriberi. Peripheral "polyneuritis," disorders of eye movements, staggering gait, disorientation, and drowsiness were noted to be similar to the problems of chronic alcoholics, and thiamine deficiency was found to produce the same bilaterally symmetric lesions of brainstem nuclei characteristic of Wernicke's encephalopathy [283].


Inferior colliculus damage caused by thiamine (vitamin B1) deficiency
Figure 21: Damage to the inferior colliculi in a human patient maintained on prolonged parenteral feeding lacking vitamin B1 (from Vortmeyer et al. 1992).

Calingasan et al (1994) measured distribution of the major thiamine-dependent enzyme, alpha-ketoglutarate dehydrogenase, and found the highest amounts in regions of the brain that are predilection sites for Wernicke’s encephalopathy [12].

Brain damage in alcoholism is widely regarded as due to thiamine deficiency in part because alcohol damages the gastro-intestinal system, which disrupts absorption of nutrients. Thiamine is used in detoxification treatment of alcoholics, and an analogue of thiamine appears to be helpful to some children with autism. Its use should perhaps be considered in autistic children with gastrointestinal disorders. One pilot study with thiamine tetrahydrofurfuryl disulfide appears to have helped some children [285].


Figure 21 shows severe damage to the inferior colliculi in a terminally ill patient maintained on total parenteral nutrition (TPN) in which thiamine was lacking [286], and this was not a unique case [287]!

The damage in figure 21 is hemorrhagic but otherwise strikingly similar to the pattern of damage caused by asphyxia at birth. Wernicke's encephalopathy has been observed in animals inadvertently maintained on diets lacking thiamine [288, 290] and in experimental thiamine deficiency [289, 291]. Damage to the inferior colliculi was found most prominent in animals, in contrast to more severe involvement of the mammillary bodies in human cases of chronic alcohol use.

Damage caused by long-term escalating abuse of alcohol is serious, but not as catastrophic as sudden total deprivation of the essential aerobic coenzyme thiamine. Protective mechanisms spare the inferior colliculus and leave the mammillary bodies more vulnerable to repeated damage during the lifespan of a person addicted to alcohol.
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33 - Brain-Gut Relationship
Chronic alcohol use damages the esophagus, intestinal tract, and liver. Liver encephalopathy or cirrhosis is the terminal stage of alcoholism. Alcohol in excess directly damages these organs. But considering the speed with which mental changes and inebriation occur following use of alcohol, it seems clear that alcohol's first target is the brain.

Toxic impairment of the brain involves brainstem centers, and involuntary functions such as intestinal peristalsis depend upon intact brainstem circuits that control the autonomic nervous system [292]. Thus the gut is as dependent upon integrity of brainstem function as the brain is on absorption of essential nutrients like thiamine.

Myers referred to the brainstem pattern of damage by asphyxia at birth as a "monotonous rank-order of brainstem nuclei." This pattern of damage did not produce cerebral palsy, but it is a pattern of damage no less serious. Impaired autonomic function caused by brainstem damage should be investigated as possibly contributive to the gastrointestinal problems of some children with autism.

Korsakoff (1889) observed the signs of neurological impairments (oculomotor, ataxia, and mental confusion) described by Wernicke not only in cases of chronic alcoholism, but also during the course of infections and cancerous cachexia (or wasting which may also have involved thiamine deficiency) [293]. Korsakoff provided description of 14 cases of non-alcoholic origin. Among these were post-partum illnesses, typhoid, tuberculosis, tapeworm, diabetes, pneumonia, jaundice, and intestinal disorders. In addition to early acute symptoms similar to those reported by Wernicke, Korsakoff is best remembered for describing the long-term course leading to memory impairment.

Neubuerger (1937) discussed the possibility that "auto-toxic" substances could be produced in senile and diseased organs, and that these auto-toxins were the reason Wernicke's encephalopathy developed in the brain [294]. The brain-gut relationship continues to be described [295-298].

Morley (2003) has noted that immediate clamping of the umbilical cord at birth can leave the infant in a state of hypovolemic shock, which in turn triggers generalized vasoconstriction that shifts blood flow from less vital organs to the heart and brain [299]. Hankins et al. (2002) provided evidence that asphyxia from placental abruption or umbilical cord prolapse during labor results in injury to the liver, kidneys, and heart as well as the brain [300]. Autism is associated with complications at birth, and some children with autism may then begin life with multiple organ injury as well as damage of brainstem autonomic centers.
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. . . .

VI. REFERENCES

34 - Bibliography

Asphyxia and Hypoxia at Birth
  1. Windle, W. F. (1969). Brain damage by asphyxia at birth. Scientific American, 221(#4), 76-84.
  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: Asphyxia at birth, Hypoxic birth, Asphyxia vs hypoxia, Umbilical cord lifeline,
    Developmental delay, Increased incidence, Worth remembering, Hemoglobin,
    Variable vulnerability, Molecular suffocation, [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.
  4. Kety SS (1962) Regional neurochemistry and its application to brain function. In French, JD, ed, Frontiers in Brain Research. New York: Columbia University Press, pp 97-120.
  5. Reivich M, Jehle J, Sokoloff L, Kety SS (1969) Measurement of regional cerebral blood flow with antipyrine-14C in awake cats. Journal Of Applied Physiology 27:296-300.
  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.
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    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.
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    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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  12. Calingasan NY, Baker H, Sheu KF, Gibson GE (1994) Distribution of the alpha-ketoglutarate dehydrogenase complex in rat brain. Journal Of Comparative Neurology 346:461-479.
    Back to: Metabolic Rank Order, Thiamine Deficiency, [Top]

  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
  14. Gonzalez-Lima F, Valla J, Matos-Collazo S (1997) Quantitative cytochemistry of cytochrome oxidase and cellular morphometry of the human inferior colliculus in control and Alzheimer's patients. Brain Research 752:117-126.
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    Research on Blood Flow and Glucose Uptake
  15. Sokoloff L (1981) Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. Journal of Cerebral Blood Flow and Metabolism 1:7-36.
  16. Hakim AM and Pappius HM (1981) The effect of thiamine deficiency on local cerebral glucose utilization. Annals of Neurology 9:334-339.
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  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.
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  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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  21. Kusumoto, M., Arai, H., Mori, K., & Sato, K. (1995). Resistance to cerebral ischemia in developing gerbils. Journal of Cerebral Blood Flow and Metabolism, 15, 886-891.
    Back to: Asphyxia Vs Hypoxia, Variable Vulnerability, [Top]

  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.
  23. Burchfield DJ, Abrams RM (1993). Cocaine depresses cerebral glucose utilization in fetal sheep. Developmental Brain Research 73:283-288.
  24. Grünwald F, Schröck H, Biersack HJ, Kuschinsky W (1993) Changes in local cerebral glucose utilization in the awake rat during acute and chronic administration of ethanol. Journal of Nuclear Medicine 34:793-798.
    Back to: Variable Vulnerability, Patterns of Damage, [Top]

  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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    Infectious Encephalitis
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    Lead Poisoning
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    Seizure Disorder/ Neurologic Damage
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    Intestinal Inflammation
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    Genetic/Metabolic Predispositions for Autism:
    Neurolipidosis
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    Tuberous Sclerosis
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    Neurofibromatosis
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    Phenyhlketonuria
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  193. Williams RS, Hauser S, Purpura DP, deLong GR, Swisher CN (1980) Autism and mental retardation: Neuropathologic studies performed in four retarded persons with autistic behavior. Archives of Neurology 37:748-753.
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    Fragile X Syndrome
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    Leber's Congenital Amaurosis
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    Adenylosuccinate Lyase Defect
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    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
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    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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    Infant Anemia
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    Hierarchy of Human Needs
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    Biochemistry Textbooks
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    Polycythemia
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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
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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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    Neonatal Asphyxia in Laboratory Rats
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    Categories of Mental Disorders
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    Adjustments Under Adverse Conditions
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    Neuropathology in Alcoholism (Wernicke's Encephalopathy)
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    Moebius Syndrome (Bilateral Facial Palsy)
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  248. Matsunaga Y, Amamoto N, Kondoh T, Ohtsuka Y, Miyazoe H, Kamimura N, Matsumoto T, Tsuji Y (1998) A severe case of Moebius syndrome with calcification on the fourth ventricular floor. Journal of Human Genetics 43:62-4.
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    Wernicke-Gayet Encephalopathy
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    Pyrithiamine Enzyme Poison
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    Toxic fumes, Methyl Bromide, and Alpha-chlorohydrin
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    Auditory System Impairment in Alzheimer Dementia
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    Mitochondria and their vulnerability
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    Disruption of Mitochondrial Function
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    Thiamine Deficiency
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    Thiamine Treatment
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    Thiamine Deficiency in Total Parenteral Nutrition
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    Thiamine Deficiency in Animals
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    Brainstem Control of Autonomic Functions
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    Wernicke's Encephalopathy in Gastrointestinal Disorders
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  296. Butterworth RF. Pathophysiology of alcoholic brain damage: synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease. Metab Brain Dis. 1995 Mar;10(1):1-8.
  297. Kril JJ. Neuropathology of thiamine deficiency disorders. Metab Brain Dis. 1996 Mar;11(1):9-17.
  298. Holzer P, Michl T, Danzer M, Jocic M, Schicho R, Lippe IT. Surveillance of the gastrointestinal mucosa by sensory neurons. J Physiol Pharmacol 2001 Dec;52(4 Pt 1):505-21.
    Back to: Brain Gut Relationship, [Top]

    Hypovolemic Shock at Birth
  299. Morley GM (2003) Neonatal Resuscitation: Life that Failed. http://www.obgyn.net/pb/pb.asp?page=/pb/articles/neonatal-resuscitation
  300. Hankins GD, Koen S, Gei AF, Lopez SM, Van Hook JW, Anderson GD (2002) Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy. Obstetrics and gynecology 99:688-91.
    Back to: Brain Gut Relationship, [Top]

35 – Autism and Complications at Birth


  • "… 5 items were found to significantly predict group membership (prescriptions taken during pregnancy, length of labor, viral infection, abnormal presentation at delivery, and low birth weight)."
    Wilkerson DS, Volpe AG, Dean RS, Titus JB. Perinatal complications as predictors of infantile autism. Int J Neurosci. 2002 Sep;112(9):1085-98.

  • "Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results:The risk of autism was associated with daily smoking in early pregnancy (OR = 1.4; CI = 1.1-1.8), maternal birth outside Europe and North America (OR = 3.0; CI = 1.7-5.2), cesarean delivery (OR = 1.6; CI = 1.1-2.3), being small for gestational age (SGA; OR = 2.1; CI = 1.1-3.9), a 5-minute Apgar score below 7 (OR = 3.2, CI = 1.2-8.2), and congenital malformations (OR = 1.8, CI = 1.1-3.1)." Note: The OR and CI were both greatest for 5-min Apgar score below 7.
    Hultman CM, Sparen P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology. 2002 Jul;13(4):417-23.

  • "Children with autism spectrum disorders have lower optimality (higher rates of complications) than unaffected siblings…"
    Zwaigenbaum L, Szatmari P, Jones MB, Bryson SE, MacLean JE, Mahoney WJ, Bartolucci G, Tuff L. Pregnancy and birth complications in autism and liability to the broader autism phenotype. J Am Acad Child Adolesc Psychiatry 2002 May;41(5):572-9

  • "In a sample of families selected because each had exactly two affected sibs, we observed a remarkably high proportion of affected twin pairs, both MZ and DZ…"
    Greenberg DA, Hodge SE, Sowinski J, Nicoll D. Excess of twins among affected sibling pairs with autism: implications for the etiology of autism. Am J Hum Genet 2001 Nov;69(5):1062-7

  • "The highest OR [odds ratio] was found for vaginal breech delivery (OR 6.7), birth weights above 5 kg (OR 6.3), and second born twins (OR 4.1)."
    Thorngren-Jerneck K, Herbst A. Low 5-minute Apgar score: A population-based register study of 1 million term births. Obstet Gynecol 2001;98:65-70

  • "Among the children with a serious medical condition, 34.4% also had ante- or perinatal antecedents. Among the 33% without any medical factor, 77% also had ante- or perinatal antecedents."
    Bodier C, Lenoir P, Malvy J, Barthélemy C, Wiss M, Sauvage D. (2001) Autisme et pathologies associées. Étude clinique de 295 cas de troubles envahissants du developpment. [Autism and associated pathologies. Clinical study of 295 cases involving development disorders] Presse Médicale 2001 Sep 1; 30(24 Pt 1):1199-203.

  • "… specific complications that carried the highest risk of autism and PDD-NOS represented various forms of pathologic processes with no presently apparent unifying feature."
    Juul-Dam N, Townsend J, Courchesne E. Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics. 2001 Apr;107(4):E63.

  • "AD was identified in 18 of the 5,271 children and the incidence was 34 per 10,000 (0.34%). This value was more than twice the highest prevalence value previously reported in Japan. Children with AD had a significantly higher history of the meconium aspiration syndrome (p = .0010) than the controls. Autistic patients had different risk factors than CP." Note: CP (cerebral palsy) occurred in 57 of the 5,271 children.
    Matsuishi T, Yamashita Y, Ohtani Y, Ornitz E, Kuriya N, Murakami Y, Fukuda S, Hashimoto T, Yamashita F. Brief report: incidence of and risk factors for autistic disorder in neonatal intensive care unit survivors. J Autism Dev Disord. 1999 Apr;29(2):161-6

  • "…[obstetric] optimality score (OS), were compared in two groups: 78 families containing an autistic proband (ICD-10 criteria) and 27 families containing a down syndrome (DS) proband… RESULTS: Autistic and DS probands had a significantly elevated OS compared with unaffected siblings, regardless of birth order position. The elevation was mainly due to an increase in mild as opposed to severe obstetric adversities."
    Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A, Rutter M. Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry. 1997 Feb;36(2):272-81

  • "Males with AS showed a trend toward lower Apgar scores at one minute …"
    Ghaziuddin M, Shakal J, Tsai L. Obstetric factors in Asperger syndrome: comparison with high-functioning autism. J Intellect Disabil Res. 1995 Dec;39 ( Pt 6):538-43.

  • "These data provide slight support for the contribution of nonspecific pre- and perinatal factors to other etiological bases of autism."
    Lord C, Mulloy C, Wendelboe M, Schopler E. Pre- and perinatal factors in high-functioning females and males with autism. J Autism Dev Disord. 1991 Jun;21(2):197-209.

  • In most of the pairs discordant for autism, the autistic twin had more perinatal stress.
    Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989 May;30(3):405-16.

  • "Abnormal presentation at birth is the only factor that occurred more frequently for the autistic sample…"
    Levy S, Zoltak B, Saelens T. A comparison of obstetrical records of autistic and nonautistic referrals for psychoeducational evaluations. J Autism Dev Disord. 1988 Dec;18(4):573-81.

Back to: Complications At Birth, [Top]


36 - Umbilical Cord Clamping

Clamping the umbilical cord at birth is a human invention. The umbilical cord is an infant's lifeline throughout gestation; it should go without saying that it remains the newborn's lifeline until lung function is established. Clamping the cord before a baby breathes can be expected to result in at least a brief period of oxygen deprivation.

Looking back at historical textbooks on obstetrics, waiting at least for the infant to breathe on its own was traditionally always required before cutting the cord [58-65].

From 1850 to 1930:
  • "A strong healthy child, as soon as it is born, will begin to breathe freely, and in most cases cry vigorously. As soon as it has thus given satisfactory proof of its respiratory power, you may at once proceed to separate it from its mother by tying and dividing the umbilical cord."
    Swayne JG (1856) Obstetric Aphorisms: For the use of students commencing midwifery practice. London: John Churchill, p 20.
  • "As soon as the child cries we may proceed to tie and separate the cord."
    Playfair WS (1880) A Treatise on the Science and Practice of Midwifery. Philadelphia: Henry C. Lea, p 283
  • "The cord should not be tied until the child has breathed vigorously a few times. When there is no occasion for haste, it is safer to wait until the pulsations of the cord have ceased altogether."
    Lusk WT (1882) The Science and Art of Midwifery. New York: D Appleton and Company, pp 214-215
  • "Immediately after its birth the child usually makes an inspiratory movement and then begins to cry. In such circumstances it should be placed between the patient's legs in such a manner to have the cord lax, and thus avoid traction upon it… Normally the cord should not be ligated until it has ceased to pulsate…"
    Williams JW (1917) Obstetrics: A Text-Book for the Use of Students and Practicioners, Fourth Edition. New York & London: D. Appleton and Company, pp 342-343
  • "As soon as the lungs begin to function, the circulation through the umbilical arteries normally ceases in from five to fifteen minutes after birth."
    Williams JW (1930) Obstetrics: A Text-Book for the Use of Students and Practicioners, Sixth Edition. New York: D. Appleton-Century, pp 418-419

By the 1940s a change of opinion is evident:

  • "We have adopted an intermediate course, feeling that to always wait for complete cessation of pulsation frequently interferes with the proper conduct of the third stage of labor, and at the same time, that most of the available blood in the cord had been incorporated in the fetal circulation during the few minutes immediately following delivery."
    Stander HJ (1941) Williams Obstetrics, Eighth Edition. New York, London: D. Appleton-Century company, pp 429-430.

  • "Whenever possible, clamping or ligating the umbilical cord should be deferred until its pulsations wane or, at least, for one or two minutes…
    There has been a tendency of late, for a number of reasons, to ignore this precept. In the first place the widespread use of analgesic drugs in labor has resulted in a number of infants whose respiratory efforts are sluggish at birth and whom the obstetrician wishes to turn over immediately to an assistant for aspiration of mucus, and if necessary, resuscitation. This readily leads to the habit of clamping all cords promptly."

    Eastman HJ (1950) Williams Obstetrics, Tenth Edition. New York: Appleton-Century-Crofts , pp 397-398

Would Williams recognize the 20th edition of his textbook?

  • "Although the theoretical risk of circulatory overloading from gross hypervolemia is formidable, especially in preterm and growth-retarded infants, addition of placental blood to the otherwise normal infant's circulation ordinarily does not cause difficulty… Our policy is to clamp the cord after first thoroughly clearing the infant's airway, all of which usually takes about 30 seconds."
    Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LC, Hankins GDV, Clark SL, Williams JW, (1997) Williams Obstetrics, Twentieth Edition. Stamford, Conn: Appleton & Lange, pp 336-337.


Preventing jaundice

  • It appears that Saigal et al (1972) and Saigal & Usher (1977) may have initiated the fear that delayed clamping of the umbilical cord could result in circulatory overload, polycythemia (too many red blood cells) and jaundice. But polycythemia is more often a physiological response to abnormalities like methemoglobinemia, which results from a genetic or drug-induced abnormality of the hemoglobin molecule.

    Saigal S, O'Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and hyperbilirubinemia in the premature. Pediatrics. 1972 Mar;49(3):406-19.

    Saigal S, Usher RH. Symptomatic neonatal plethora. Biol Neonate. 1977;32(1-2):62-72.

  • Jellett (1910) in a 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."

    Jellett cited research apparently well known in 1910: White (1785, 1773) 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?"

    Jellett further cited research by Schmidt (1894) in which it was 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.

    Jellett H (1910) A Manual of Midwifery for Students and Practitioners. New York: William Wood & Company.

    White C (1773) A Treatise on the Management of Pregnant and Lying-In Women. Science History Publications/ Watson Publishing International, Canton MA, 1987.


A Radical Change

Whatever its motivation, the now routine clamping of the umbilical cord within 30 seconds following birth is a radical change from traditional practice. If an infant is breathing on its own at the time of cord clamping, the most important transition from fetal to neonatal life has taken place (see Mercer & Skovgaard, 2002). This transition has not taken place in an infant in need of resuscitation. It may be only a small minority of infants who do not breathe immediately at birth, but might this minority account for the increased prevalence of autism or other developmental disabilities?

Mercer JS, Skovgaard RL. Neonatal transitional physiology: a new paradigm. J Perinat Neonatal Nurs. 2002 Mar;15(4):56-75.
[Top]


SUMMARIES

Main Points:

  1. The brainstem auditory pathway is susceptible to damage by all of the known medical conditions associated with autism, because it is the most metabolically active system of the brain.

  2. Protective mechanisms prevent auditory system damage except in catastrophic circumstances like circulatory arrest, suffocation, or poisons that disrupt aerobic metabolism.

  3. Partial oxygen insufficiency during late gestation or birth is one cause of cerebral palsy, whose victims in some cases learn language on time and demonstrate good to excellent cognitive and social skills.

  4. Total oxygen deprivation during late gestation or birth selectively damages the inferior colliculi in the midbrain auditory pathway, and is proposed here as a possible cause of the language and auditory attention problems of children with autism.

  5. Damage to the inferior colliculi has been noted in previously normal adults who have lost the ability to understand spoken language [Meyer et al. 1996, Johkura et al. 1998, Masuda et al. 2000].

  6. Verbal auditory agnosia (VAA), an inability to distinguish syllable and word boundaries in rapid streams of speech, has been identified as an underlying problem in some children with autism [Rapin 1997].

  7. Inhibitory neurons in the inferior colliculus appear to stop transmission of ongoing sounds, providing a means for detecting sound onset which may also be involved in detection of syllable and word boundaries.

  8. Difficulty learning a foreign language, without accent, past the first decade of life may indicate that verbal auditory agnosia (VAA) is a normal affliction of aging, and most severe in the elderly who lose the ability to engage in conversation in noisy environments.

  9. Most young children learn language by ear and in a foreign language environment as easily learn a second language.

  10. Abnormalities of the amygdala, hippocampus, mammillary bodies, cerebellum, and inferior olives have been observed in the brain of individuals with autism; all are part of a subcortical pattern of damage caused by asphyxia and toxic substances.

  11. Protective mechanisms may prevent visible damage in the inferior colliculi and allow more noticeable abnormalities in the rank-order of subcortical nuclei that are somewhat less metabolically active.

  12. The subcortical pattern of damage may imply impairment of function within the inferior colliculi even in the absence of visible involvement.

  13. Progressive involvement of the cerebral cortex was observed in monkeys subjected to asphyxia at birth, and indicates a mechanism that could explain failure of frontal lobe maturation in children with autism.

  14. Complications at birth are recognized as common in children with autism but their possible significance underestimated.

  15. Immediate clamping of the umbilical cord has become a standard practice within the past 20 years, but an infant who does not breathe right away will suffer at least a brief but potentially catastrophic period of oxygen deprivation.

  16. In research on asphyxia at birth in monkeys, asphyxia was produced by preventing breathing and clamping the umbilical cord; visible damage of the inferior colliculi occurred in some monkeys subjected to as little as six minutes of asphyxia.

  17. Immediate clamping of the umbilical cord ought to be considered as one possible reason for the increased incidence (or prevalence) of autism evident within the last two decades.
The inferior colliculus is important for understanding speech
Meyer B, Kral T, Zentner J. (1996) Pure word deafness after resection of a tectal plate glioma with preservation of wave V of brain stem auditory evoked potentials. Journal of Neurology, Neurosurgery and Psychiatry. 61:423-424.

Johkura K, Matsumoto S, Hasegawa O, Kuroiwa Y. (1998) Defective auditory recognition after small hemorrhage in the inferior colliculi. Journal of the Neurological Sciences. 161:91-96.

Masuda S, Takeuchi K, Tsuruoka H, Ukai K, Sakakura Y. (2000) Word deafness after resection of a pineal body tumor in the presence of normal wave latencies of the auditory brain stem response. The Annals of otology, rhinology, and laryngology. 2000 Dec;109(12 Pt 1):1107-1112.


Verbal auditory agnosia
Rapin I (1997) Autism. New England Journal of Medicine 337:97-104.

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. . . .

I. BRAIN DAMAGE AT BIRTH

1 - Asphyxia at Birth
Experiments with monkeys on asphyxia at birth were undertaken in the 1950s to investigate ways to prevent cerebral palsy. The outcome was not cerebral palsy, and damage to the brain was confined to the brainstem. The inferior colliculus in the midbrain auditory pathway was always most severely involved. The inferior colliculus had been found in earlier experiments on cerebral circulation to have the highest rate of blood flow in the brain.

2 - Hypoxic Birth
In the initial experiments asphyxia was inflicted by covering the newborn monkey's head and clamping the umbilical cord, producing a sudden catastrophic cutoff of respiratory gas exchange. Cerebral palsy was found in later experiments to result from partial blocking of umbilical blood flow late in gestation. Circulatory insufficiency induced in this way led to widespread damage throughout the brain. Hypoxia is a state of partial oxygen insufficiency. Asphyxia occurs when oxygen delivery is completely blocked and if not fatal results in a predictable pattern of brainstem damage.

3 - Asphyxia Versus Hypoxia
Asphyxia is different from hypoxia. Protective mechanisms go into effect to preserve oxygen delivery to the inferior colliculus during a period of hypoxia. High blood flow to the inferior colliculus supports a high rate of aerobic metabolism, generating high levels of carbon dioxide. Hemoglobin delivers oxygen in exchange for carbon dioxide, an immediate adjustment that ensures continuing support of aerobic metabolism in this nucleus of the auditory system. The rest of the brain then becomes deprived of oxygen, and over time widespread damage occurs.

4 - Human Conditions
Asphyxia causes a sudden and catastrophic cessation of aerobic metabolism that is often fatal. Damage to the inferior colliculus is evident in children and adults who survive for at least several days following resuscitation. In the 1960s damage involving only the brainstem was thought to underlie what was then referred to as "minimal cerebral dysfunction."

5 - Stages of Asphyxia
Monitoring what happens during the stages of asphyxia indicates that the heart, brain, and other organs incur compromise earlier than the time required for visible damage to be evident.

6 - The Umbilical Cord Lifeline
Clamping of the umbilical cord at birth is a human invention and a dangerous procedure if performed on an infant who is not yet breathing. Respiration is the most immediate and essential need of all life forms dependent upon oxygen. Placental respiration must be maintained until an infant's lungs and heart have completed the transition from pre- to postnatal adaptation.

7 - Developmental Delay
Monkeys subjected to asphyxia at birth exhibited muscle weakness and delay in developing motor control; they never overcame poor manual dexterity. The asphyxiated monkeys were not deaf, despite the conspicuous damage to the inferior colliculus, but they did not orient to sounds as normal monkeys did.

8 - Poor Manual Dexterity
Monkeys subjected to asphyxia at birth remained deficient in manual dexterity. Large and laboriously produced handwriting is characteristic of children with developmental delay and children with "high functioning" autism.

9 - Progressive Degeneration
Widespread degeneration was evident in the brains of monkeys who survived several months or years following asphyxia at birth. Anomalies of the same brain areas (cerebellum, amygdala, corpus callosum, etc.) are evident in the brains of individuals who were autistic in childhood.

10 - Autism and Complications at Birth
Many children with autism suffered complications at birth. Oxygen insufficiency is the greatest danger during a difficult birth. Problems during labor and delivery are frequently attributed to pre-existing genetic factors, but monkeys subjected to experimental asphyxia had no pre-existing problems.

11 - Mercury, and Other Toxic Factors
In the experiments with monkeys the effects of high levels of bilirubin (jaundice) were investigated. Bilirubin did not enter brain tissue except in monkeys that had been subjected to asphyxia. Mercury preservatives in vaccines and other substances may also only cross a blood-brain barrier compromised by asphyxia or hypoxia. Does the hepatitis-B vaccine need to be given in the newborn nursery?
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. . . .

II. THE AUDITORY SYSTEM

12 - Metabolic Rank Order
Methods to measure cerebral circulation were extended to measure aerobic metabolism. The same brainstem nuclei with highest blood flow were found by several measures to have highest aerobic metabolism. The inferior colliculus is at the top of the rank order by every measure.

13 - The Auditory System
The inferior colliculus evolved to provide auditory alerting for visual attention. The auditory system is always active, even during sleep. The auditory and visual colliculi of the midbrain tectum may be the locus of consciousness in the brain.

14 - Auditory Dysfunction
Children with autism are often over-sensitive to loud sounds and noisy environments (hyperacusis). Auditory evoked potential testing indicates delay of signal transmission in some children with autism. Auditory dysfunction raises the possibility of auditory system impairment by asphyxia at birth. Asphyxia of duration too brief to produce visible damage may still lead to impairment of neurotransmitter systems in the inferior colliculus.


. . . .

III. LANGUAGE

15 - Language by Ear
Most children learn language by ear. Language learning begins before the language circuits of the temporal and frontal lobes are fully myelinated and mature. Children normally learn language through recognition of stressed syllables, which leads to the well recognized stage of language development known as "telegraphic speech" (baby talk).

16 - Verbal Auditory Agnosia
"Agnosia" is a failure of recognition in the apparent absence of sensory deficit. Agnosia for speech sounds has been reported in some children with autism, and has been termed "verbal auditory agnosia." At least three cases of verbal auditory agnosia have been reported in adults following damage of the inferior colliculus.

17 - Echolalic Speech
Some children with autism begin to use parroted phrase fragments (echolalic speech) at the time most children are at the "telegraphic speech" stage of development. The child who hears syllable boundaries is able to detect small units of meaning (morphemic units), to recognize their recurrence in the speech of those around him, and eventually to rearrange their use in new contexts. Use of phrase fragments indicates failure to detect syllable boundaries, and again raises the issue of auditory dysfunction in autism.

18 - Echolalic Speech is Pragmatic
Kanner (in 1946) referred to the echolalic speech of autistic children as "irrelevant and metaphorical speech." The irrelevant nature of echolalic speech is because of its use out of context; its partial fit to context makes it seem metaphorical. Phrase fragments are not as easily rearranged as morphemic units to fit context. "You don't want to go swimming?" was not a question, but one autistic child's emphatic statement that she didn't want to go in the water; this statement also provides an example of "pronoun reversal."


. . . .

IV. CHILDHOOD HANDICAPS

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
The experiments on asphyxia at birth in monkeys could never be repeated because of animal rights laws. The data remain valid 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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. . . .

V. BRAINSTEM DAMAGE

28 - Variable Vulnerability
Protective mechanisms increase blood flow to the inferior colliculus in any circumstance that leads to impairment of aerobic metabolism. This has been revealed in several experiments with toxic chemicals. Total catastrophic disruption of aerobic metabolism damages the rank order of brainstem nuclei of high metabolic rate. Partial interference with aerobic metabolism spares the inferior colliculus and leads to damage of less metabolically active brain centers.

29 - Patterns of Damage
Circulatory insufficiency most often leads to damage of the cerebral cortex. Brainstem damage with or without involvement of cortical areas has been reported in people resuscitated after drowning, suffocation, or cardiac arrest. Brainstem damage has often been compared with that found in monkeys asphyxiated at birth and also in Wernicke's encephalopathy.

30 - Wernicke's Encephalopathy
Gayet (in 1875) and Wernicke (in 1881) described damage restricted to the brainstem in cases of airway damage, alcoholism, and ingestion of sulfuric acid. This pattern of damage is associated most often with alcoholism and thiamine (vitamin B1) deficiency.

31 - Suffocation at the Molecular Level
An increasing array of toxic substances has been found to interfere partially or catastrophically with aerobic metabolism. Brainstem nuclei are affected in varying degrees.

32 - Thiamine Deficiency
Thiamine (vitamin B1) is an essential cofactor for enzymes of aerobic metabolism. Deficiency of thiamine in the diet or because of malabsorption in gastrointestinal disorders leads to Wernicke's encephalopathy or variants of this pattern of damage.

33 - Brain-Gut Relationship
Autonomic functions such as intestinal peristalsis are controlled by brainstem centers. Damage to these autonomic centers can impair intestinal function. Intestinal dysfunction in turn leads to malabsorption and/or absorption of digestional fragments that should be excluded. Toxic fragments of digestion may be toxic to the brain and further compound the effects of earlier damage.


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