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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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 (for all sections)
34 - Bibliography (for section II)
35 - Autism and Complications at Birth
36 - Umbilical Cord Clamping

Summaries (for all sections)
    Summaries (for section II)

[Site Links]


Overview (The Auditory System):

High aerobic metabolism has been found in a rank-order of brain areas that closely matches sites of highest blood flow, and this same rank-order are most prominently affected by asphyxia at birth.

High metabolic activity in the auditory system appears to serve a function of constant vigilance, even during sleep. The auditory system evolved as an alerting mechanism for visual attention, and research evidence supports a view that auditory and visual centers in the midbrain play a role in general awareness and the conscious state. Abundant evidence from research as well as anecdotal reports indicates auditory system dysfunction in children with autism.


. . . .

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)

. . . .


[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 (above) 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].
[Top]

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.
[Top]

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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. . . .

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.

    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.
    Back to: Figure 1, Metabolic Rank Order, Auditory System, [Top]

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

    Correlates of High Deoxyglucose Uptake
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  13. Hovda DA, Chugani HT, Villablanca JR, Badie B, Sutton RL (1992) Maturation of cerebral oxidative metabolism in the cat: a cytochrome oxidase histochemistry study. Journal of Cerebral Blood Flow and Metabolism 12:1039-1048
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    Research on Blood Flow and Glucose Uptake
  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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    Back to: Metabolic Rank Order, [Top]

  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.

  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.

  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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    Early Research of Windle and Coworkers
  26. Ranck JB, Windle WF (1959). Brain damage in the monkey, Macaca mulatta, by asphyxia neonatorum. Experimental Neurology 1: 130-154.
  27. Jacobson HN & Windle WF (1960) Responses of foetal and new-born monkeys to asphyxia. The Journal of Physiology (London) 153:447-456.

    Circulatory Arrest in Adult Monkeyts
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  29. Miller JR, Myers RE (1972) Neuropathology of systemic circulatory arrest in adult monkeys. Neurology 22:888-904.
    Back to: Metabolic Rank Order, [Top]

    Developmental Degeneration Following Asphyxia
  30. Faro MD & Windle WF (1969) Transneuronal degeneration in brains of monkeys asphyxiated at birth. Experimental Neurology 24:38-53.

    Biochemistry of Respiration
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  32. Tigerstedt R (1911) Christian Bohr: Ein Nachruf. Skandinavishes Archiv fur Physiologie 25:v-xviii.
  33. Edsall JT (1980) Hemoglobin and the origins of the concept of allosterism. Federation Proceedings 39:226-35
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    Brainstem Lesions in Human Infants
  37. Norman MG (1972) Antenatal neuronal loss and gliosis of the reticular formation, thalamus, and hypothalamus. A report of three cases. Neurology (Minneapolis) 22:910-916.
  38. Griffiths AD, Laurence KM (1974) The effect of hypoxia and hypoglycemia on the brain of the newborn human infant. Developmental Medicine and Child Neurology 16:308-319.
  39. Grunnet ML, Curless RG, Bray PF, Jung AL (1974) Brain changes in newborns from an intensive care unit. Developmental Medicine and Child Neurology 16:320-328.
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    Minimal Cerebral Dysfunction?
  44. Windle WF (1969) Asphyxial brain damage at birth, with reference to the minimally affected child. In Perinatal Factors Affecting Humn Development. Pan American Health Organization, proc. spec. session, 8th meeting, pp. 215-221
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    Umbilical Cord Clamping
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    Bilirubin Only Gets into Oxygen-Deprived Tissues
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    Stages of Drowning
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    Low 5-minute Apgar Score
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    Historical Textbooks on Obstetrics
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    Sound Localization
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    Large Handwriting (Macrographia)
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    Neurotrophic Influences on Maturation
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    Brain Abnormalities in Autism
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    Autism and Complications at Birth
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. . . .

Summaries

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.


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