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Brain differences in autism
1. The cerebellum
Autopsy and MRI studies have repeatedly and consistently found loss of
purkinje and granule cells of the cerebellum in autistic subjects. There
is general agreement that this loss occurs before birth, probably in early
pregnancy. There are two known possible causes: a specific genetic condition
or an immune system response to a toxin or pathogen during pregnancy.
“There is only one discovery in the history of autism research that has
been found to be both unique and specific to the disorder, a loss of cerebellar
Purkinje and granule cells occurring early in brain development and an immature
development of the limbic system.”
(Jansen R.A.; Melatonin, A look at Humoral Factors in the Cerebellum; Autism
and Dev. Disabilities List 1997)
Dr. Courchesne: 'In ten autopsy cases (out of ten), there was Purkinje
cell loss in the cerebellar hemisphere and in five of ten cases there was
Purkinje cell loss in the cerebellar vermis. The magnetic resonance studies
have found that there is a reduction in the size of the neocerebellar vermis
and the neocerebellar hemisphere which is conclusive with the Purkinje cell
loss' (Eric Courchesne, 1991).
'Due to the fact there is no evidence of atrophy or deterioration after
full development and the results of MR images and autopsy studies, it is
now believed that the neocerebellar loss occurs before birth.' (Autism; Audrey
The cerebellum can be divided into the following functional divisions:
- Neocerebellum: This is the phylogenetically newest part. It consists
of the lateral lobes and is involved in fine movements and speech through
major connections with the cerebral cortex.
- Paleocerebellum: Through interconnections with the spinal cord,
this part mediates sequential movements such as walking, running and swimming.
It consists of the anterior and posterior vermis.
The hemispheres are separated from one another by a thin structure called
the vermis, or "worm". The vermis, located in the midline of the cerebellum,
receives auditory and visual information from the techtum. It also receives
cutaneous and kinesthetic information from the spinal chord. The vermis
sends outputs to the fastigial nucleus, which outputs to the vestibular
nucleus and to motor nuclei in the reticular formation.
- Archicerebellum: Its major connections are with the vestibular (balance)
system. It consists of the flocculus, nodule and lingula and mediates
general posture and eye movements.
The cerebellum is involved in a feedback loop for muscle movement. When
the cortex sends a message for motor movement to the lower motor neurons in
the brain stem and spinal cord, it also sends a copy of this message to the
cerebellum. In addition, information gets to the cerebellum from muscle spindles,
joints and tendons. This information (proprioception and kinesthesia) lets
the cerebellum know about the movements that have been executed, so that
it can determine how well motor commands coming from the cortex are being
Basic function of Cerebellum
The role of the cerebellum is primarily in the co-ordination of complex
movements, using imputs from hearing, balance, visual and muscular systems
as well as from higher executive commands and emotional states. The messages
reach the cerebellum through a complex web of millions of climbing fibers,
which pulsate rhythmically, generating an awareness of self in space, of self
in relation to other, of self in motion. The information is channeled along
parallel fibers and purkinje neurons tap into this information, sending back
modulated information to the body and brain, enabling the execution of complex
actions such as speech and non-verbal communication (body language).
Causes and mechanisms of Purkinje cell loss
The indole alkaloids ibogaine and harmaline are beta-carboline derivatives
that cause both hallucinations and tremor. We recently found that ibogaine
induces a marked glial reaction in the cerebellum with activated astrocytes
and microglia aligned in parasagittal stripes within the vermis. Based on
those findings, the present study was conducted to investigate whether ibogaine
may cause neuronal injury or degeneration. The results demonstrate that, after
treatment with ibogaine or harmaline, a subset of Purkinje cells in the vermis
degenerates. We observed a loss of the neuronal proteins microtubule-associated
protein 2 and calbindin co-extensive with loss of Nissl-stained Purkinje
cell bodies. Since these drugs produce sustained activation of inferior olivary
neurons, we hypothesize that release of an excitatory amino acid from climbing
fiber synaptic terminals may lead to excitotoxic degeneration of Purkinje
cells. [Degeneration of Purkinje cells in parasagittal zones of the
cerebellar vermis after treatment with ibogaine or harmaline OHearn E et al,
The pyridine derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
is recognized as a crucial neurotoxin which destroys nigrostriatal dopamine
cells, thereby inducing neurological signs relevant to idiopathic Parkinson's
disease. In the present study, we have revealed MPTP neurotoxicity to cerebellar
Purkinje cells in mice. Systemic MPTP injections to mice resulted in a substantial
loss of Purkinje cells in a dose-dependent fashion. The MPTP-induced Purkinje
cell loss occurred markedly in the crus I and II ansiform lobules and the
paraflocculus. Such a neurotoxic effect was largely prevented by the monoamine
oxidase B inhibitors pargyline and deprenyl, and the dopamine uptake inhibitors
mazindol and benztropine. [MPTP neurotoxicity to cerebellar
Purkinje cells in mice. Takada et al 1993]
Volkensin, a highly toxic protein retrogradely transported through axons,
was used to target primary neuronal death in brainstem precerebellar relays
after injection in the cerebellar cortex of rats. The reaction of astrocytes
and microglia was studied with immunohistochemistry in the inferior olivary
and pontine nuclei from 6 h to 14 days. Neurodegenerative features were evident
since the first hours, especially in the pontine nuclei, and neuronal loss
reached a plateau at 7 days in the inferior olive and at 10 days in the pons.
Astrocytic activation, revealed by glial fibrillary acidic protein immunoreactivity,
was concomitant with early signs of neuronal death and gradually increased.
Microglia activation, revealed by OX-42 immunoreactivity, was evident at
2 days and became rapidly intense in precerebellar relays. At 1 week, marked
ED-1 immunoreactivity also revealed phagocytic features of microglia, which
persisted during the second week. In addition, major histocompatibility
complex antigens (MHC) class I and II were induced in cells exhibiting microglial
features. In the inferior olive, MHC I immunoreactivity was evident since
4 days and persisted at 14 days, whereas MHC II induction was intense at
7 days and subsided at 2 weeks. In the pontine nuclei high expression of
both MHC antigens persisted instead at 14 days, probably reflecting the progression
of neuronal death. Thus, targeted lethal injury of central neurons elicited
prompt activation of both astrocytes and microglia; the marked microglia
activation resulted in phagocytic features and immunophenotypic changes,
with a temporal regulation that paralleled the evolution of neurodegenerative
phenomena. [Glial reaction to volkensin-induced selective degeneration
of central neurons. Cevolani et al 1990]
Mechanisms of Neuronal Injury; Excitotoxicity; Purkinje Cell Degeneration;
Neurodegenerative Diseases: Spinocerebellar Ataxias
We are interested in mechanisms of excitotoxic neuronal injury and in developing
methods for neuroprotective intervention. Purkinje cells are integrative
neurons of the cerebellar cortex and are highly susceptible to a variety of
insults, both experimental and clinical. The explanation for the heightened
susceptibility of these neurons remains uncertain. We have developed an in
vivo animal model of Purkinje cell degeneration in which neurotoxic alkaloids,
including ibogaine and harmaline, cause prolonged activation of inferior olive
neurons that results in trans-synaptic, excitotoxic degeneration of Purkinje
cells. Climbing fiber axons from inferior olive neurons are glutamatergic
and innervate Purkinje cells in a uniquely dense fashion, a factor which
may underlie the susceptibility of Purkinje cells to injury. Through pharmacologic
modulation of drug-induced Purkinje cell degeneration we are focusing on
the contribution of specific glutamate receptor subtypes and on signal transduction
mechanisms that lead to Purkinje cell death. Identification of neuronal
events in this injury cascade may provide therapeutic targets to ameliorate
neuronal damage. An associated interest is in relating mechanisms of neuronal
injury to clinical neurologic disease in human patients. In collaboration
with Russell Margolis and Christopher Ross at Johns Hopkins, we are evaluating
patients with neurodegenerative conditions affecting the cerebellum, e.g.,
the spinocerebellar ataxias. Our goals include relating genetic abnormalities,
such as expanded trinucleotide repeats, to cellular mechanisms that result
in neuronal degeneration. (Elizabeth O'Hearn, M.D., Assistant Professor of
Neurology, Johns Hopkins University School of Medicine, Department of Neurology,
Meyer 6-119b, 600 N. Wolfe Street, Baltimore, MD 21287)
O'Hearn, E. and M.E. Molliver. (1997) The olivocerebellar projection
mediates ibogaine-induced degeneration of Purkinje cells: a model of
indirect, trans-synaptic excitotoxicity. J.Neurosci. 17(22):8828-8841.
O'Hearn, E. and M.E. Molliver. (1999) Neurotoxins and neuronal
death an animal model of excitotoxicity. In V.E. Koliatsos and R.R. Ratan,
Eds., Cell Death and Diseases of the Nervous System, Humana
Press, Towata, NJ, pp. 221-245.
Other disorders of Cerebellar degeneration
1. “Primary degeneration of the granular layer of the cerebellum is an autosomal
recessive disorder exhibiting characteristic clinical features:
hypotonia, strabismus, delayed motor development, nonprogressive ataxia,
delayed language development with dysarthria and mental retardation.”
[Primary degeneration of the granular layer of the cerebellum. A study of
14 patients and review of the literature. Pascual Castroviejo et al; 1994]
2. “The period of rapid brain growth that occurs relatively late in development
has been shown to be vulnerable to alcohol-induced brain growth deficits
and neuron loss in rats using repeated daily exposure to alcohol. Exposure
to high peak BACs, even for a relatively short period during the brain growth
spurt, constitutes a substantial risk to the developing brain, and even a
moderate exposure may result in loss of more vulnerable neurons.”
[A single day of alcohol exposure during the brain growth spurt induces
brain weight restriction and cerebellar Purkinje cell loss. Goodlett CR et
3. “The cerebellar cortex in patients with autosomal dominant and recessive
ataxia was studied by Golgi impregnation and immunocytochemistry in order
to gain further insight into the pathogenesis of neuronal atrophy which
accompanies these disorders.
Purkinje cell atrophy progressed from loss and simplification of the dendritic
tree to disappearance of the cell body. While these cells appeared to be
especially vulnerable, other neurons of the molecular and granular layers
were not exempt. There was evidence that at least some extracerebellar afferents,
such as mossy fibers, were also affected by the disease process.”
[The Purkinje cell and its afferents in human hereditary ataxia. Koeppen
4. “We studied the nervous systems and tumors of two patients with anti-Yo-associated
paraneoplastic cerebellar degeneration (PCD). In both patients the underlying
tumor was an ovarian adenocarcinoma that expressed Yo antigens and contained
extensive infiltrates of lymphocytes and plasma cells. The major central nervous
system findings were a complete loss of cerebellar Purkinje cells with Bergmann
astrogliosis.” [Inflammatory infiltrates and complete absence of Purkinje
cells in anti-Yo-associated paraneoplastic cerebellar degeneration. Verschuuren
J etal; 1996]
Characteristics of Cerebellar dysfunction
a. Disequilibrium - Falling: forward, backward, laterally when standing;
unsteady, staggering gait; sensations of spinning and nausea.
b. Muscle tone disturbance - Softness of muscle bellies on palpation; decreased
tendon reflexes; asthenia (muscles tire easily). Pendular
swinging of dependent limb segment after displacement.
c. Movement disorders:
I. Incoordination of movements - Ataxia, asynergia - decreased
capability for smooth, cooperative, segmental action between a
d. Speech deficits - Slow onset, slurring, jerky, intermittent sound productions
with explosive nature: "scanning speech".
series of muscle groups.
II. Decomposition of movements - Complex movement performed as a sequence
of irregular disjointed episodes.
III. Adiadochokinesis - Inability to rapidly pronate and supinate.
IV. Dysmetria - Inability to correctly judge distances. Tested by reaching
out and touching an object ("prepointing; pastpointing")
V. Inability to trace a specific course with finger or heel (e.g., right
heel to left knee).
VI. Staggering gait - Tendency to fall, particularly with closed eyes.
VII. Intention tremor - Tremor when voluntary movement is attempted.
e. Cerebellar nystagmus - Inability to fixate on object. Conjugate drift
of eyes away from it, with rapid return. May be positional (more
pronounced when body adopts a particular posture), or directional (increasing
when subject attempts to gaze in particular direction).
1. Microtubule-associated protein 1C (MAP 1C) is now
defined as brain cytoplasmic dynein. Dynein is localized in purkinje cells
of cerebellum and axons of central and peripheral nervous systems.
Yoshida T. et al; 1992
2. Circulating autoantibodies to neuronal and glial filament
proteins in autism; Singh V.K. et al; Dept. of Psychiatry, Univ. of Michigan,
Ann Arbor, USA; Pediatr Neurol 1997
3. Development of the brainstem and cerebellum in autistic
children; Hashimoto T. et al; Dept. of Ped., Univ. of Tokushima Sch. of Med.;
No To Hattatsu 1994
4. Glutaredoxin protects cerebellar granule neurons from
dopamine-induced apoptosis by dual activation of the ras-phosphoinositide
3-kinase and jun n-terminal kinase pathways. Daily D. et al , Dept. of
Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv Univ.,
Ramat Aviv, Tel Aviv, Israel. J Biol Chem 2001