Publications, 1975-2008

Simon EN (2008)
Can language and reading proficiency be followed into the school years for
infants born in poor condition? Am J Obstet Gynecol. 2008 Feb;198(2):243;
author reply 243-4.

This is a letter I wrote in response to an article by Bahl et al.
(Neurodevelopmental
outcome at 5 years after operative delivery in the second stage of labor:
a cohort study. Am J Obstet Gynecol 2007;197:147.e1-6.).  Development of
264 children (67 percent of 393) who required operative delivery was followed
for their first five years.  Rates of developmental problems were reported to be
low.  I commended the authors for undertaking their investigation of long-term
outcomes, and asked if follow-up for learning disabilities could be continued
into the school years, especially for the 17 percent reported to be in poor
condition after birth.  The authors concurred with my recommendation, but
pointed out the difficulty getting funding for long-term follow-up studies.
--

Simon EN (2007)
Auditory system damage and anoxic birth. Arch Pediatr Adolesc Med. 2007
Nov;161(11):1106; author reply 1106-7.

This is a letter I wrote in response to an article by Kolevzon et al. (Prenatal and
perinatal risk factors for autism: a review and integration of findings. Arch
Pediatr Adolesc Med. 2007 Apr;161(4):326-33).  Intrapartum hypoxia was noted
as a significant obstetric predisposition for autism.  The authors' reply pointed
out how little is known about autism and hearing impairment.
--

Simon EN (2006)
Comment on "Asperger syndrome: Familial, pre- and perinatal factors" by
Gillberg and Cederlund. J Autism Dev Disord. 2006 Feb;36(2):291-2. [letter].

This was a response to two articles by these authors that reported perinatal
problems in children with Asperger syndrome. More than half the children
described had not been talking in full sentences by the age of two. I pointed out
that while many children with Asperger syndrome appear to have a superior
command of language, they often make idiosyncratic use of phrases tangential,
at best, to conversational context. Once again I urged consideration of auditory
system impairment resulting from anoxia at birth as contributory to
developmental language disorder across the autism spectrum.
--

Simon EN (2005)
Auditory agnosia caused by a tectal germinoma. Neurology, 2005 Jul
26;65(2):339 [letter].

This letter is online (with a reply from the authors) at
http://www.neurology.org/cgi/eletters/63/12/2387; it was submitted in response
to a case report, of a 14-year-old boy who lost the ability to understand spoken
language because of neoplastic growth that invaded the auditory tectum. This
is one of several reports that have appeared since 1991 in which injury of the
inferior colliculi was revealed by use of MRI.
--

Simon EN (2004)
Autism as a birth defect. Birth Defects Res Part A Clin Mol Teratol, 2004
Jun;70(6):416 [letter].

Environmental factors associated with autism can produce variants of
Wernicke's encephalopathy with involvement of oculomotor and facial nuclei,
diminished Purkinje cells in the cerebellum, and brainstem nuclei like the
inferior olives and relay nuclei of the auditory pathway. Impairment within the
auditory system merits investigation as a primary site of injury potentially
underlying the developmental language disorder of children with autism.
--

Simon EN (2004)
The lessons of MMR. Lancet, 2004 May 1;363(9419):1473-4 [letter].

This letter was sent in response to an excellent commentary by Lancet Editor
Richard Horton, The Lessons of MMR (Lancet, 06 March 2004, pp747-749), in
which he pointed out that one consequence of the MMR controversy had been
a redirection of public attention to autism, a condition sadly neglected by
medicine. The hope I expressed was that attention to this horrible disorder
might continue in more productive ways. I could never join the parental chorus
of fury over MMR, the end result going no further than "the brain," viewed as a
homogeneous organ. How impairment of specific brain systems underlying (first
and foremost) developmental language disorder should in my opinion be the
focus of public-funded research.
--

Simon N. (2000)
Autism's home in the brain. Neurology. 2000 Jan 11;54(1):269-70. PMID:
10636173; UI: 20100128.

This letter was in response to four articles on autism in the March 23, 1999
issue of Neurology. The letter is accompanied by replies from the authors. Each
of the four papers had proposed impairment of different systems in the brain.
Comment on the four papers brought up for discussion whether the proposed
impairments might all stem from perinatal disruption of aerobic metabolism by
anoxia, infections, or exposure to toxic substances during gestation. Beyond
knowing that neurological functions are impaired, the mechanism of damage
must be sought, and include all known etiologies of autism.
--

Simon N. (1999)
Auditory dysfunction in autism: a submicroscopic form of Wernicke's
encephalopathy? J Autism Dev Disord. 1999 Oct;29(5):426-7. PMID: 10587890;
UI: 20055202.

Autistic behaviors have been observed in children with genetic disorders and
infections that damage the brain. Some children exposed to alcohol during
gestation have also been found deficient in reciprocal social interactions and
with impaired language development. Alcohol affects brainstem nuclei and the
cerebellum in a pattern of damage known as Wernicke's encephalopathy.
Involvement of many of the same areas has been noted in brains from
individuals with autism. The auditory system is prominently affected in
Wernicke's encephalopathy and auditory dysfunction may underly the language
disorder of autistic children. Impairment of metabolism in the brain areas
affected by Wernicke's encephalopathy may be shared in common by all of the
etiologies of autism.
--

Simon N. (1999)
The auditory system, brain maturation, and development in autistic children. J
Autism Dev Disord. 1999 Feb;29(1):94-5. PMID: 10098000; UI: 99198073.

Brainstem auditory nuclei are the earliest to mature in the human fetal brain.
There is evidence that neurochemical events in the developing auditory system
may stimulate growth of higher cognitive centers in the cerebral cortex. Damage
to brainstem auditory nuclei has been found in infants who died during the
perinatal period. The suggestion is made that early impairment of the auditory
system might also interfere with subsequent stages of development in autistic
children. Echolalic autistic children do not reword what they have heard but
recite whole phrases from memory to express their needs. Many of the
etiological factors that lead to autism are known to affect the auditory system
and may be responsible for this language decoding disorder.
--

Simon N. (1998)
Hemoglobin and the brain: a piece of the autism puzzle? J Autism Dev Disord.
1998 Dec;28(6):579-80. PMID: 9932245; UI: 99131037.

Multiple etiologies of autism spectrum disorders have been identified. It is
proposed here that the "Bohr effect" of hemoglobin might explain why motor
disabilities are more likely to result from conditions that partially disrupt
metabolism in the brain, while impairment of brainstem sensory systems could
be expected as the outcome following brief periods during which metabolic
processes are totally blocked.
--

Simon N. (1997)
Autism and the inferior colliculus. J Autism Dev Disord. 1997 Aug;27(4):494-6.
PMID: 9261672; UI: 97404978.

The inferior colliculus has the highest rate of metabolism of any structure in the
brain. It is therefore vulnerable in some circumstances to the effects of genetic
metabolic disorders, toxic substances, infections, nutritional deficiencies, and
anoxia, many of which have been associated with autism as etiologic factors. It
is suggested that dysfunction within this brainstem area should be explored for
its potential relevance to etiology of the core syndrome of autism, and a few
citations to the literature on cerebral metabolism are given.
--

Simon N. (1990)
Infantile autism and Wernicke's encephalopathy. Med Hypotheses. 1990
Jul;32(3):169-72. Review. PMID: 2204786; UI: 90377023.

In this paper I discuss evidence that brain damage in infantile autism may
involve the same complex of brainstem nuclei that are damaged by alcohol
abuse, thiamine deficiency, and asphyxia. These are metabolically the most
active structures in the brain, which makes them vulnerable to many injurious
factors. It is my belief that the high metabolic rate in the brainstem nuclei could
support a control function for multiplexing of neural pathways, and that if this
control is lost it may result in the defects of awareness and responsiveness
seen in autistic children.
--

Simon N. (1978)
Kaspar Hauser's recovery and autopsy: a perspective on neurological and
sociological requirements for language development. J Autism Child Schizophr.
1978 Jun;8(2):209-17. PMID: 353024; UI: 78218009.

Reprinted in S. Chess and A. Thomas (eds.) Annual Progress in Child
Psychiatry and Child Development 1979, Vol. 12, Chapter 11, pp. 215-224,
Brunner/Mazel: New York, 1979.

Also reprinted in J. Money and G. Williams (eds.) Traumatic Abuse and Neglect
of Children at Home, Chapter 6, pp 56-62. Johns Hopkins Press: Baltimore,
1979.

The feral children literature has frequently been cited for relevance to
understanding historical antecedents of autism. Kaspar Hauser, who appeared
in Nuremberg, Germany in 1828, is one of these children, raised under
conditions of extreme deprivation. His case history and gradual acquisition of
language after age 17 years are summarized. There is strong evidence that he
was the prince of Baden, abducted from his cradle in 1812. Findings of
postmortem examination, conducted after his assassination, are discussed.
Hauser's postadolescent recovery of language contradicts the notion of a
"critical period" for language development.
--

Simon N, Volicer L. (1976)
Neonatal asphyxia in the rat: greater vulnerability of males and persistent
effects on brain monoamine synthesis. J Neurochem. 1976 May;26(5):893-900.
PMID: 946815; UI: 76192939.

In the rat, neonatal asphyxia produced by suffocation did not leave permanent
visible lesions in the brain, nor did it result in permanent motor impairment,
although a delay in the development of some reflexes was observed. A
transient retardation of body and brain growth, which was more pronounced in
males, was found. By 5-6 weeks of age, body and brain weights of asphyxiated
rats were no longer significantly different from control animals. However, an
increase in brain norepinephrine synthesis was found to persist after
maturation. An alteration of serotonin metabolism was found after maturation
only in asphyxiated males. The possibility that neonatal asphyxia in the rat is a
model for abnormal development of monoamine metabolism, relevant to early
childhood behavior disorders such as infantile autism or the syndrome of
minimal brain dysfunction is discussed.
--

Simon N. (1975)
Echolalic speech in childhood autism. Consideration of possible underlying loci
of brain damage. Arch Gen Psychiatry. 1975 Nov;32(11):1439-46. PMID:
812450; UI: 76087034.

Reprinted in S. Chess and A. Thomas (eds.) Annual Progress in Child
Psychiatry and Child Development 1976, Vol. 9, Chapter 25, pp. 471-490,
Brunner/Mazel: New York, 1977.

The speech of echolalic autistic children is (1) specifically lacking in appropriate
use of expressive-intonational features, but (2) the echolalic child's clear
articulation of words and phrases indicates that discrimination of phonemic
features is intact. The impairment in aphasic disorders is just the reverse.
Failure to attend to auditory stimuli and the characteristic language disorder
are among the most consistent findings in autistic children; they could be
related. Discrimination of differential stress emphasis is the way the normal
young child extracts major morphemic word stems and syntactic features from
environmental speech; this may be a primitive perceptual function of brain stem
auditory centers. The brain stem auditory system is especially vulnerable to
perinatal injury. Damage to this system is an example of the kind of lesion that
might lead to behavioral handicaps without neurological signs.
--

Simon EN. (1975)
Long-term Effects of Neonatal Asphyxia in the Rat. Doctoral Dissertation,
Boston University, Boston MA, 1974, 193 pp. University Microfilms, Ann Arbor
MI, Order No. 75-5520.

Neonatal asphyxia in the albino rat was chosen as a possible model for
abnormal development of monoamine metabolism in the brain. This could,
perhaps, have bearing on the etiology of childhood schizophrenia (or early
infantile autism).

Recent research on the effects of asphyxia in the prenatal or perinatal period
has revealed that in several species, including man, the resulting injury to the
central nervous system may be confined to brainstem structures without
involvement of the cerebral hemispheres. Research on monoamines in the
central nervous system indicates that their normal metabolism depends upon
integrity of some of the brainstem areas that are damaged by perinatal
asphyxia.

Infant rats were asphyxiated within 24 hours after a natural birth in 12 cc.
Capacity air-tight vials. Only about half of the asphyxiated animals survived the
first 24 hours after this severe insult. The survivors appeared to be quite
depressed during the first 24 hours after asphyxia; most did not gain a normal
amount of weight during this period and many lost up to half a gram in the first
day. Growth retardation persisted for the first two weeks of life; brain growth
was also retarded, and males were more severely affected than females.

There were delays in development of the grasp reflex and reflex orientation to
gravity on an inclined plane; however no spasticity or noticeable long-term
neurological defect resulted. Histological examination at three to six weeks of
age did not reveal necrosis or degeneration of any brain areas; only patchy
gliosis and sparser distribution of nerve cells in some brain areas could be
observed.

The conversion of radioactive tyrosine and tryptophan to dopamine,
norepinephrine, and serotonin was measured in the brains of control and
neonatally asphyxiated animals between five and six weeks of age. The
precursor amino acids were administered by injection into the tail-vein, and the
animals were sacrificed from 30 to 150 minutes after injection. The brains were
assayed for radioactive and endogenous tyrosine, tryptophan, dopamine,
norepinephrine, and serotonin; a preliminary separation of these five
compounds was made on ion exchange columns, then each compound
subsequently purified and measured individually.

The synthesis rate of norepinephrine from tyrosine in the brain was nearly
doubled in the neonatally asphyxiated group. The synthesis rate of dopamine
was not affected by neonatal asphyxia. The catabolic rate constant for
serotonin was increased in asphyxiated males only, but the synthesis rate was
not affected. There was less penetration of radioactive tryptophan, five minutes
aftere intravenous injection, into the brains of both male and female
asphyxiated animals, while the penetration of radioactive tyrosine was the same
as in a control group.

An increase in the monoamine oxidase enzyme activity of the brain, measured
in vitro, was found in both male and female asphyxiated animals, which may
indicate a tendency for higher catabolism of all monoamines. Tyrosine
hydroxylas activity is normally inhibited by excess norepinephrine in the enzyme
environment, which is the major mechanism controlling synthesis rate. Rapid
catabolism of norepinephrine by increased monoamine oxidase activity may
therefore interfere with the normal regulation of catecholamine synthesis.

The effects of birth asphyxia on neurologic status and behavior appear not to
be lon lasting, and histology reveals no gross structural changes; however,
functional defects persist. Metabolism of neural units and the blood-brain
barrier appear to be permanently altered. It is of possible significance that male
animals were more vulnerable to neonatal asphyxia, as there is a 4:1 greater
preponderance of males over females in the human population who develop
early schizophrenic illness (or infantile autism).