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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Blood flow is highest in the inferior colliculus
Blood flow in the brain: Autoradiogram of the brain of a cat 60 seconds after injection of a radioactive tracer shows the greatest perfusion (thus greatest blood flow) in nuclei of the brainstem auditory pathway. (From Kety, 1962, with permission from Columbia University Press)

Introduction
Blood flow and metabolism are not uniform throughout the brain. The brain is a collection of separate sensory, motor, and association circuits of differing metabolic activity. Experiments on cerebral circulation were first undertaken 50 years ago in which a radioactive tracer was injected into the bloodstream of cats. After 60 seconds the tracer was found in greatest amounts in nuclei of the brainstem auditory pathway (as is evident in the autoradiogram picture above). Blood flow and aerobic metabolism have since been shown many times over to be highest in the auditory system, and especially in the inferior colliculus (Sokoloff 1981, Zeller et al. 1997).

In experiments on asphyxia at birth in monkeys, selective damage of the inferior colliculus was a surprise finding (see picture below, and compare with the autoradiogram of blood flow above).


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

[Site Links]
Topics (section links):

Introduction

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

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Damage of the inferior colliculus has also been reported in human infants who died in the neonatal period (see lower half of picture to the right).

Damage of the inferior colliculus is almost always part of a brainstem pattern of lesions that includes:

  • 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)

Monkeys kept alive for several months or years following asphyxia at birth showed even more widespread damage involving:

  • Brainstem:
    periaqueductal gray
    oculomotor nuclei
    inferior olives
  • Cerebellum:
    diminished Purkinje cells
  • Subcortical sites:
    mammillary bodies
    hippocampus
    amygdala
  • Cerebral Cortex:
    frontal and parietal lobes
    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, and are at the forefront of theories of autistic disorder. Long-term brain changes following asphyxia at birth indicate a mechanism by which impairment of these brain areas might come about, without having to hunt for gene loci on chromosomes.

Mercury, lead and other toxic substances are known to selectively damage the auditory system. Bilirubin (from neonatal jaundice) however only enters neurons already compromised by asphyxia.


Inferior colliculus damage (bottom) in a human infant
Brain damage in human infants: Also involves the inferior colliculi (bottom) following asphyxia (from Leech & Alvord 1977, with permission from the American Medical Association).
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Kernicterus
Bilirubin staining of brain tissue: Occurred only in monkeys also subjected to asphyxia. Asphyxia breaks down the blood-brain barrier and allows toxic substances like bilirubin (and likely also mercury) to get into neurons (from Windle 1969).

Small amounts of mercury preservative in vaccines given within hours at birth may not be enough to affect most infants, but may exacerbate the effects of asphyxia in those who suffered oxygen insufficiency during a difficult birth.

Failure to learn normal language usage is often the first sign of autism in a physically perfect child whose motor development was normal. Most children learn language by ear, and during the first decade of life as easily master a second language. It comes as shock when a child learns only to parrot phrase fragments. Parents naturally suspect a problem with hearing, even though the child may be hypersensitive to some sounds.
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Complications at birth have been discussed in many papers on autism, but are then often dismissed as mild, non-specific, or having no unifying feature. Oxygen insufficiency is the unifying feature of all complications at birth however, and the effect of asphyxia at birth on the auditory system merits investigation as the cause of autism in some children.

Immediate clamping of the umbilical cord at birth has become a standard practice over the past 20 years, and deserves investigation as a possible cause of the increased incidence (or prevalence) of autism. If the umbilical cord is cut before the infant is breathing, a brief period of asphyxia will occur. This was better understood in the past, as can be seen in the teaching of older textbooks on obstetrics.

References

  1. 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. [back]
  2. 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. [back]
  3. Zeller K, Rahner-Welsch S, Kuschinsky W (1997) Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. Journal of Cerebral Blood Flow and Metabolism 17:204-209. [back]
  4. Myers RE (1972) Two patterns of perinatal brain damage and their conditions of occurrence. American Journal of Obstetrics and Gynecology 112:246-276. [back]
  5. Leech RW, Alvord EC (1977) Anoxic-ischemic encephalopathy in the human neonatal period, the significance of brain stem involvement. Archives of Neurology 34:109-113. [back]
  6. Windle, W. F. (1969). Brain damage by asphyxia at birth. Scientific American, 221(#4), 76-84. [back]
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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]

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.
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