Autism Circuitry
Tressa D. Carroll, BS, MS (cand.), Sr. Research Associate, The Neuroscience Alliance, West Jefferson, Ohio
Brendan T. Carroll, M.D., Associate Professor (Volunteer), Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio
Dr. R. Ankenman M.D., London, Ohio
Pharmachological Treatments and Poly-Pharmacy, using Namenda* and Risperidone* In The Treatment Of Autism.
The Neuroscience Alliance announces that we have discovered what we believe to be the "Switch" that leads to the expression of autism in children with autistic spectrum disorders. Although the causes of autism are quite diverse (genetic, environmental, toxic and developmental) they all must pass through a common pathway that involves the dentate gyrus and related structures. - Tressa and Brendan Carroll
Goal 1: To show that autism is not one illness. To identify one probable mechanism that may lead to the development of the syndrome of autism.
Goal 2: To identify the neuro-circuitry of autism. To do this we will use the model of catatonia.
Goal 3: To address autism from the developmental theory that this syndrome results from abnormalities of brain growth. Specifically it is a failure of apoptosis. This term might be referred to as “mispoptosis”, which leads to an “under pruning of the brain”.
Goal 4: To identify the low level or low activity of cortisol and how that might lead to development of autism and possible treatment.
Goal 5: The understanding of some genetic factors which may act as genetic markers, predisposing a patient to a higher risk of autism.
Goal 6: The connection between the temporal lobe structures’ of “primitive response” through the amygdala to the “mammalian response,” hippocampus, through one of the main connectors the “Dentate Gyrus.” The dentate gyrus contains mossy fibers and granule cells of the cerebellum, with each interconnecting with the purkinje cells via the mossy fiber system.
Goal 7: How the cerebellum is affected in catatonia and ASD.
Goal 8: The ratio of autistic boys to girls is approximately 4:1, a common finding in boys with autism is hypogonadism, how GnRH (gonadotropin) may play a role in fetal development and possible maternal autoimmunity.
What is Autism?
It is a neuropsychiatric disorder that is characterized by a movement disorder, socially aberrant behavior, attachment disturbance and aberrant speech. The DSM-IV defines it in a group of Pervasive Developmental Disorders (PDD). Sometimes these are referred to as autism spectrum disorders (ASD). They include: Autism, PDD, Asperger’s Disorder, Childhood Disintegrative Disorder and Rett’s Disorder. While the causes of ASD remain unknown, Rett’s disorder is an illness caused by a defect in the MeCP2 gene found on the X-chromosome in at least 80% of the identified cases.
Table 1.
Medical Illnesses which are associated with Autistic Spectrum Disorders
Autistic Disorder (AD)
Angelman Syndrome (AS)
Asperger Disorder (AsD)
Childhood Disintegration Disorder (CDD)
Fragile X Syndrome (FXS)
Landau – Kleffner Syndrome (LKS)
Pervasive Developmental Disorder (PDD)
Prader Willi Syndrome (PWS)
Rett Syndrome (RS)
This means that the majority of ASDs have an unknown etiology. There are no screening tests. There genetic component of autism and related disorders has been an area of great focus. This is because of the high heritability of ASDs. The search for the autism susceptibility genes has yielded 10 to 20 different interacting genes. Yet there is no one single gene to explain all cases of autism and ASD. Similarly, the search for functional neuropathology has identified several focal regions of the brain that may play a role in the development of autism. However, since ASDs are related disorders but are not discrete, identified illnesses the cases that are presented for brain imaging or neuropathological examination may be heterogeneous.
Autism and ASDs are defined by the criteria in DSM-IV. The domains of these criteria are impairments in social interaction, communication, motor behaviors and symbolic play. The age of onset is usually by 2 or 3 years, although it may be recognized later.
Early Screening for Autism
Early screening for autism is designed to preserve psychosocial functions through psychosocial therapies. While many of these interventions have shown greater preservation of social function, there is no biological intervention that has demonstrated the improved regulation of brain function.
However, while autism may develop between 6 months and 2 years, there is no behavioral strategy to prevent the abnormalities of neural development in autism. While there are studies to show that brain size increases there is no well described mechanism for this phenomena. The increase in head circumference does not lend itself to screening.
For instance the NIH early intervention for autism includes the following:
From NIMH “ASD is defined by a certain set of behaviors that can range from the very mild to the severe. The following possible indicators of ASD were identified on the Public Health Training Network Web cast, Autism Among Us.3 “
Possible Indicators of Autism Spectrum Disorders
Does not babble, point, or make meaningful gestures by 1 year of age
• Does not speak one word by 16 months
• Does not combine two words by 2 years
• Does not respond to name
• Loses language or social skills
Some Other Indicators
• Poor eye contact
• Doesn't seem to know how to play with toys
• Excessively lines up toys or other objects
• Is attached to one particular toy or object
• Doesn't smile
• At times seems to be hearing impaired
• Social Symptoms
• From the start, typically developing infants are social beings. Early in life, they gaze at people, turn toward voices, grasp a finger, and even smile. In contrast, most children with ASD seem to have tremendous difficulty learning to engage in the give-and-take of everyday human interaction. Even in the first few months of life, many do not interact and they avoid eye contact. They seem indifferent to other people, and often seem to prefer being alone. They may resist attention or passively accept hugs and cuddling. Later, they seldom seek comfort or respond to parents' displays of anger or affection in a typical way. Research has suggested that although children with ASD are attached to their parents, their expression of this attachment is unusual and difficult to "read." To parents, it may seem as if their child is not attached at all.
• Parents who looked forward to the joys of cuddling, teaching, and playing with their child may feel crushed by this lack of the expected and typical attachment behavior.
Unfortunately, the state of the art in autism is what it is not. The screening criteria are a list of developmental milestones that the child does not exhibit. The genetic analysis of ASDs tends to confirm that the candidate genes are not involved in most cases. And the DSM-IV criteria tend not to focus the abnormal behaviors. What might be helpful is pathological mechanism that leads to the development of autism and autistic disorders. In addition, it would be helpful to identify the pathway by which autism expresses itself.
Introduction
Autism is the result of unregulated brain growth. Brain growth is limited and directed by apoptosis in the child without autism. In this form of normal brain development, prenatal and postnatal factors directly influence brain connections and circuitry. The role of apoptosis is to “prune” the millions of connections in the brain.
The developing brain is like a rosebush. The bush will continue to grow with many branches. The energy of the bush goes to branches, thorns and leaves. This leaves very little energy for flowers and roots. The un-pruned rosebush is overgrown and begins to rub upon itself, causing damage to stems, reducing shoots and leaves.
Apoptosis acts like carefully wielded pruning shears. It cuts off unproductive stems and branches. It reduces duplication and allows for a more balanced growth with better roots and flowers. In all, the plant becomes more healthy, adaptable and long-lived.
The theory of misapoptosis:
While the theory of apoptosis, this is of programmed cell death has been applied to disorders of aging such as Alzheimer's disease and Parkinson’s disease, it has not been discussed in developmental disorders. We ran a literature search of apoptosis and autism. We did not find a single article to discuss this concept. This may be that apoptosis is essential to normal development. It may be that the brain enters into a period of growth with multiple nerve connections. This may be a necessary phase since the child may need to develop in a variety of potential pathways. Apoptosis may help as a method to select a pathway to the proper development of personality and function.
In order to understand what mispoptosis is, then we must determine what apoptosis is not. Suppose the wrong cells are knocked off or the wrong branches are cut off. Suppose this occurred in the brain, then aberrant neural pathways would result. Suppose there are two pathways on for socially appropriate behavior (e.g. Shaking a hand) one for a socially inappropriate behavior (e.g. sniffing an offered hand). The first pathway is the correct one while the second is slated for elimination by apoptosis. The hypothesis of mispoptosis suggests that the apoptosis of the second pathway is ignored and it persists or the apoptosis is misdirected to the first pathway. The socially inappropriate behavior persists and is incorporated into the child’s repertoire.
Hippocampus
The mechanism by which a limbic and cerebellar destruction would occur is through the granule cell – (See granule cell cycle) we have postulated a single cell type responsible for loss of purkinje cells, smaller cerebellar volumes and smaller dentate and hippocampal volumes. The concept of a cerebellar limbic loop is important. Certainly it may be a secondary coexistent or result loop to the cerebral loop of catatonia. One of the difficulties is that its capacity to compensate for injuries early in development. Consequently, testing for cerebellar abnormalities does not always detect cerebellar damage on exam. If we examine the functional homology between the cortical catatonia loop and the cerebellum we find thalamic and parietal areas involved in both. In catatonia, the deficit termination of movement is localized in the posterior parietal area, but the cerebellum may play a role in this function. Also lack of checking may also be part of the anosognosic of the position of rest. In fact in testing for one, the examiner may be testing both, the parietal and cerebellar integration. - Tressa Carroll, et al 2005
McGinty & Friedman 1988- "Opiods in the Hippocampus" Hippocampal structure and circuitry-It is a curved structure which must be sectioned in the frontal plane rostrally and in the horizontal plane caudally in order to retain the characteristic "laminar" relationship between the major cellular layers throughout the structure. The relationship is in the frontal section through the dorsal HF (Hippocampal Formation + Dentate Gyrus). The basic route of information flow through the HF, which is most relevant to the location of opioid-containing neurons, is via a trisynaptic excitatory chain. This chain originates in the entorhinal cortex, which projects highly processed, polymodal sensory information from the entire cerebral cortex through the perforant pathway to the granule cells in the dentate gyrus of the HF.
The granule cells are the second link in the chain; they protect their axons, the mossy fibers, to the proximal apical dendrites of the pyramidal cells in the stratum lucidum of the CA3 (inferior) region of the HF. The CA3 pyramids, are the third link, not only project their axons out of the HF but also send a branch (The Schaffer Collateral) to the pyramidal cell dendrites in the stratum radiatum of the CA1(superior) region of the HF, in turn, the CA1 pyramids project axons out of the HF primarily through the fornix. Inhibition mediated by (GABA) and/or peptide-containing interneurons (basket cells) whose axons surround the granule and pyramidal cells is a major control of HF excitability. Without this tonic inhibition, seizures would be free to march through the uninhibited hippocampus via the trisynaptic excitatory chain. - McGinty, Friedman 88.
McGinty, "What We Know and Still Need To Learn About Opiods In The Hippocampus" The role of the hippocampus in overall brain function, Chavkin, et al and Segal report their most recent data on the mediation of a specific component of opioid excitation of pyramidal cells in CA1 by receptors for the excitatory amino acid N-methyl-D-aspartate (NMDA). Activation of NMDA receptors occurs in long-term potentiation, the putative substrate for hippocampal learning and memory processing. The Hebbian synapse is evoked by associating afferent stimulation with depolarization of CA1 pyramidal cells. Thus by enhancing the activity of excitatory neurotransmitters, possibly by decreasing GABA-mediated inhibitory tone at specific synapses, opioid peptides may be essential to the very fabric of the hippocampal synaptic plasticity in which memory is stored through changes in the efficacy of transmission among elements.
How cortisol & cytokine imbalance may lead to autism
Cortisol and other glucocorticoids act on cells in the hippocampus, dentate gyrus and elsewhere to facilitate planned apoptosis. In the developing brain there are several ways in which cortisol and related hormones can be prevented from reaching the developing brain. Specifically, we identify prenatal factors including 1) placental factors, 2) maternal cortisol binding proteins, 3) interference with signal transmission in the developing brain, 4) abnormal levels of cytokines and 5) possible maternal immune response to embryonic GnRH. It may be that a failure of any one or all of these may lead to the failure of apoptosis or misapoptosis. In the post-natal period the infants adrenocortical, pituitary and hypothalamic factors become important. The post natal developing brain still needs planned apoptosis. Since the data on increased head circumference and presumably the failure of apoptosis, cortisol and cytokines most likely play a role here (Akshoomoff, et al 2002). Cortisol and cytokines are responsible for: 1) facilitation of planned apoptosis, 2) to provide the careful balance of hormones in the brain and 3) to protect against aberrant immune system responses.
We propose that there is a possible maternal immune response to GnRH from the embryo. GnRH does pass through the blood brain barrier, the number of boys to girls with autism is a 4:1 ratio and a common symptom of autism is hypogonadism (Gupta, 2000). We feel the study of placental immunities, from birth to 4 years, might prove fruitful.
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In conclusion, autism is not one illness; it has many different variables, from the genetic (long arm of chromosome 15q, WNT-2, RELN), neurobiological signs (possible, maternal auto-immune response to GnRH in utero, a cytokine connection, IL-1 and IL-10, interleukins) and neuroanatomical differences (hypoplasia was seen in the posterior cerebellar vermis; dentate gyrus, amygdala and purkinje cells, hyperplasia was seen in the, temporal, parietal, occipital and frontal lobes). Given these many variables, it is understandable how autism can have such a wide range of functionality. Autism parallels catatonia in motor signs, most likely due to the same dysfunction in the GABAa and GABAb receptors. Ankenman (2005) theorized that a possible hyperglutaminiergic response was responsible for the extreme need for isolation in some with autism. Dr. Ankenman used his theory and treated the patients with memantine and risperidone at very low doses. He reported success and described this treatment as “taking them out of their own world and bringing them into Disneyland” using it for only a few weeks with behavioral therapies.
References
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Carroll BT, Thomas C, Jayanti K , et al. Treating persistent catatonia when benzodiazepines fail. Current Psychiatry 4:22-33, 2005
Dhossche & Stanfill (2004) – Could ECT be effective in autism? Medical Hypotheses 63,371-376
Dhossche D, (2004) – Autism as early expression of catatonia.
Med Sci Monit, 2004; 10(3):RA31-39
Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. Cambridge University Press: Cambridge, UK. 2003
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Dept. of Anatomy and Cell Biology, E. Carolina Univ. School of Medicine, Greenville, NC
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Catatonia and Autism
The two papers that first described autism identify its’ core elements. Kanner described autism as deficits in social engagement, communication and range of behavioral repertoire. Asperger described a sub group of children with high intellect specific circumscribed and motor skills (Dhossche). Meanwhile, Kahlbaum’s description of Catatonia was made in adults in the sanitarium, seventy years earlier. (Kahlbaum 1871) He identified a motor syndrome with 11 signs (immobility, staring, Mutism, rigidity, withdrawal- refusal to eat and drink, posturing, grimacing, negativism, waxy flexibility, echolalia, Echoproxia, stereotypy and verbigeration.) The age influenced the description of these disorders. Kahlbaum practiced in the 19th century when child psychiatry was not well described. In fact, Kahlbaum had developed the first child psychiatric ward.
Table 2. Comparison of Autism and Childhood Catatonia
(Adapted from Dhossche, Medical Science Monitor)
Autism CDD Catatonia
Age at Onset 3 10 Adolescent/Adult
Regression 30% Massive Regression ++
Abnormal speech/Mutism ++/- ++/- +++
Mannerisms/stereotypes + + +
Negativism + + +
Echolalia/Echoproxia + + +/-
Social Impairment + + +
Lack of Empathy + + ?
Abnormal Gaze or Staring + + +
Posturing + + +
Positivism / Automatic Obedience ? ? +
Hyperkinesis + ++ +
By the 1940’s, child psychiatry was a recognized medical sub-specialty. The discipline of child psychiatry identified disorders specific to the age group with developmental aspects. It turns out that autism and catatonia differ in age of onset, but share motor signs. However, there was one school of thought that identified motor phenomena as essential to the classification of endogenous psychoses. The Wernicke Kliest – Leonhard School of Psychiatry which identified motility psychoses. Specifically, Leonhard described childhood catatonia.
It is the concept of childhood catatonia that exemplifies this approach to diagnosis. We owe a debt of gratitude to Dirk Dhossche, M.D, PhD. He has provided the foundation of this medical proposal. Dhossche puts forth the hypothesis that some patients with autism are actually expressing an early onset form of periodic catatonia. He identifies multiple similarities between autism disorders and catatonia. While the extended discussion of autism and catatonia is beyond the scope of this paper we refer you to Dhossche’s articles. This includes but is not limited to:
1. Overlap of psychomotor symptoms
2. Dysfunction of the GABA system
3. Small cerebellar structure
4. Genetic linkage to the long arm of chromosome 15
The Neural Circuit
Recently, the neural circuitry that underlies catatonia has been described by Northoff (2002). If we accept that autism and catatonia share psychomotor phenomena then it is likely that a similar neural circuit is important in autism.
The implication of this model is that it departs from the site specific search for etiology. Since alteration anywhere along the circuit may cause autism.
Implications of this model
1. Identifies a circuit (a neuroanatomy)
2. Identifies a neurochemistry including GABA, Dopamine and Glutamate
3. Permits multiple genetic etiologies
4. Allows for associated conditions (e.g. Angelman Syndrome) to be included on lists of autism disorder etiology.
5. Recognizes the motor phenomena of autism as declarative of the developmental/ psychosocial impairment.
6. Helps to explain the benefit of certain medications on autistic motor symptoms specifically GABAergic agonists, atypical antipsychotics and NMDA antagonists. This may also support the possibility that ECT could be effective in autism (Dhossche & Stanfill, 2004)
7. Identify the circuit that may emerge as the outcome of the mispoptosis of autism spectrum disorder.
8. Identifies autism as a movement disorder and motility psychoses.
The implication of this model is that it departs from the site specific search for etiology. Since alteration anywhere along the circuit may cause autism.
Implications of this model
9. Identifies a circuit (a neuroanatomy)
10. Identifies a neurochemistry including GABA, Dopamine and Glutamate
11. Permits multiple genetic etiologies
12. Allows for associated conditions (e.g. Angelman Syndrome) to be included on lists of autism disorder etiology.
13. Recognizes the motor phenomena of autism as declarative of the developmental/ psychosocial impairment.
14. Helps to explain the benefit of certain medications on autistic motor symptoms specifically GABAergic agonists, atypical antipsychotics and NMDA antagonists. This may also support the possibility that ECT could be effective in autism (Dhossche & Stanfill, 2004)
15. Identify the circuit that may emerge as the outcome of the mispoptosis of autism spectrum disorder.
16. Identifies autism as a movement disorder and motility psychoses.
Mechanisms for the Development of Autism Spectrum Disorders
If we apply the neural circuitry of catatonia to autistic spectrum disorder then we will need to present a mechanism by which this aberrant circuit and aberrant functioning of this circuit can occur.
We propose that the catatonia neural circuit is present at certain points of development. Examples include posturing, echolalia and Gegenhalten which occur in infant development. They serve important roles in the course of development but disappear after a certain developmental period. If they persist, then their continued occurrence raises concerns about the possibility of a pervasive development disorder.
Yet, the most interesting theory to explain autism in recent years has been on of brain overgrowth leading to autism. This data was collected from head circumference of autistic individuals when compared to normal control children.
This period of overgrowth was observed between ages 2 – 5 years. Head circumference corresponded to normal controls before and after this period. It is important to point out that studies to examine this crucial period at the neuroscopic and macroscopic level are only now convincing.
The overgrowth hypothesis may not apply to all autistic spectrum disorders but it may lead to an important understanding of a possible mechanism of autism that is the failure of apoptosis.
Apoptosis is a cellular process by which the organism prunes off unwanted cells. Apoptosis means “programmed cell death”. For instance, Litvan identified the contributors to cell death in PSP (Progressive Supranuclear Palsy)
These are:
1. Environmental factors(Tetrahydroisoquinolones and hypertension)
2. Mitochondrial abnormality
3. Oxidative stress
4. Abnormal Tau – Microtubule interactions
5. Abnormal axonal transport.
These lead to inflammation and cell death.
Apoptosis utilizes several specific mechanisms:
1. Cellular factors
2. Sub cellular factors
a. Membrane receptors
b. Cytoplasmic receptors
c. Mitochondrial factors
The goal of apoptosis is to promote the pruning of connected cells and cell systems, while preserving the desired cells and cell systems. In the brain this means that cells that form certain pathways will be eliminated while other pathogenesis will not. This process altars the development of new pathogenesis. This dynamic process of pruning and new growth may be going on at times of brain growth. Failure of apoptosis in the fetus, infant or child may result in overgrowth of the brain. If apoptosis is defective then the “wrong” pathogenesis may be preserved while the “developmentally correct” is misguided apoptosis.
As evidence of the theory we list the factors affecting cell death (apoptosis)
Pro-Apoptotic Factors
a. Increased free radicals
b. Decreased Cortisone Binding Globulin
c. BCL-2 - BAX
d. Cortisol
Anti-Apoptotic Factors
a. BCL-2 – BID
b. Cell Protective Factors
Mis-Apoptopic Factors
a. Placental dysfunction (leading to inability to filter cortisol to the fetus)
b. Environmental factors that lead to misguided apoptosis
How Misapoptosis could lead to autistic disorders
The mechanism that we propose may involve novel factors that derail normal developmental pruning by apoptosis. Or it may involve and imbalance between pro-apoptotic and anti-apoptotic factors. In either event this hypothesized mechanism can be tested by animal models that exhibit mammalian attachment as part of their normal development. Allan Schore, PhD, has described two sets of developmental attachments. The more primitive is the reptilian model, in which the organism avoids most social interaction. It avoids eye contact, vocalization and interactive social responses to the other organisms in its environment. To borrow a term for etiology, the organism does not imprint. The more advance is the mammalian model in which the organism engages in social interaction. It maintains eye to eye contact, vocalization and approaches other organism. It is capable for imprinting.
Interestingly, Fricchione has applied a similar evolutionary ethological approach to catatonia.
If our theory is correct then Misapoptosis in the child with autism would lead to the following:
Reduced GABAA activation in the medial and lateral orbital frontal lobes
An overdevelopment of the uncinate fascicles, between the orbitofrontal lobe and the amygdala.
A failure of the connection between the amygdala and the hippocampus.
Redirected dopamine at the D2, receptors in the Basal Ganglia system.
An increased activation between the Basal Ganglia and Thalamus, resulting in over activation of the thalamic-parietal pathways (thalamocortical) with increased glutamate and over activity and dysfunction of the NMDA receptor system.
Over activation of the Posterior Parietal to the supplemental motor area (SMA) and NMDA system.
Over activation of the SMA to Orbitofrontal pathways.
Other areas of secondary dysfunction, e.g. (midbrain, cerebellar and brainstem areas)
To summarize, the neuro chemical implication are:
Low GABA (at GABAA receptors in the orbitofrontal cortex)
Low Dopamine (at D2 receptors in the basal ganglia)
High Glutamate (at the NMDA receptors in the thalamus-parietal, parietal pre-motor and pre-motor orbitofrontal pathways)
High Serotonin activity has previously been found and may be explained by some findings in catatonia.
Implications for therapeutics:
While autism does not respond very well to psychotropic medications, the largest study of autism showed favorable responses to risperidone, when compared to placebo. While this medicine blocks D2 receptors in general it tends to increase dopamine levels in the basal ganglia. It does this by blocking the 5-HT2a receptor to release more dopamine. The 5-HT2a receptor is expressed in the basal ganglia but not in other regions.
There is a large body of data pointing to GABAA agonists in the treatment of autism. It also points to the use of anticonvulsants. There are no large double-blind studies of the potent GABA promoter, lorazapam in autism. Interestingly, this medication is very effective in catatonia, perhaps more so than other GABAA promoters.
Finally, there is emerging data that Memantine, a non-competitive NMDA antagonist may be helpful in autism. Further study is necessary in this area.
If there is one treatment that affects all three of these pathways – to increase GABA, to increase dopamine in the basal ganglia and decrease glutamate at dysfunctional NMDA receptors it could be tested. Unfortunately, this treatment ECT (electro convulsive therapy) has been considered, but not tested for autism. (See Dirks paper)
The limbic system is another area of the brain in which abnormalities have been found in individuals with autism. Margaret Bauman found increased cell packing density in the limbic systems of people with autism. Anatomic abnormalities were found in autopsies of six people. Courschene and Smith, in MRI studies of the limbic system, found the dentate gyrus to be significantly smaller in people with autism. The dentate gyrus is strongly involved in memory. The dentate gyrus acquires new neurons throughout our lives. An enriched learning environment may increase the number of neurons, while stress may decrease the number. Dr. Courchesne believes that stress related to information processing and sensory processing may cause a reduction in the number of dentate neurons in people with autism. The reduced dentate may be responsible for some individuals with autism having super memories without context. He feels that stress reduction techniques and effective learning methods may spur the development of dentate neurons. In his imaging studies, Dr. Courchesne noted that between the ages of two and five, the dentate grows twice as fast in children with autism. This may be tied to the diagnosis and treatment of these children.
To summarize the Dentate Gyrus.
The areas involved in apoptosis such as the dentate gyrus is of special importance, it links the amygdala to the hippocampus, which is part of the limbic system. “The components of the limbic system mediate memory, social and affective functions that are typically disturbed in autism. A developmental defect in the limbic system has been hypothesized to underlie different autistic symptoms”.- O.Saitoh, C.Karns and E. Courchesne, 2001.
A blind study was created for the measurement and thickness of the AD (dentate gyrus +CA4) Children between 29 months – 5 years who were suspected to have autism had MRI’s taken. 11 children ages 29 months to 5 yrs, 32 children ages 5-12 and 16 adolescents 13 – 42yrs. Then a total of 51 healthy normal controls, ages ranging from 28 months to 43 years had MRI’s taken. The summary of results were that AD was significantly smaller approximately 13 ½% in ages 29 months to 4 years.- O.Saitoh, C.Karns and E. Courchesne.
The MRI evidence show autism is characterized by hypoplasia (undergrowth) of the AD, in addition to hypoplasia in the dentate gyrus- O.Saitoh, C.Karns and E. Courchesne. The human dentate gyrus is one of the last brain regions to receive its final full developmental complement of neurons (Bayer, et al 1993) and immature dentate granule cells are present at 15 months of age (Seress, 1992)
Also immature at birth, are the synaptic connections between the dentate granule cells and their target neurons. The dentate gyrus plays an important role in the temporal lobe for epileptogenesis, a higher prevalence of epilepsy and partial seizures are seen with hypoplasia. - O.Saitoh, C.Karns and E. Courchesne
Pierre Gloor, “The Temporal Lobe and Limbic System, 1997”
The dentate gyrus anatomy consists of the mossy fiber system; it is the next link in the transhippocampal loop, after the entorhinal dentate connection mediated by the perforant path. It represents the second link in the trisynaptic circuit that is the main constituent of this loop. The mossy fibers are formed by the axons originating from the granule cells, which are the main output neurons of the dentate gyrus. Each granule cell gives rise to an axon that passes through the polymorph layer of the dentate gyrus and enters its hilus, then and beyond this area forms typical mossy fibers. It then forms a dense plexus within the dentate hilus. The granule cell axon collaterals make asymmetric excitatory contacts with dendrites of polysynaptic cells within the hilus. (Laatsch, Cowan, 1966, Blackstad & Claiborne et al, 1963.
The dentate gyrus is rich in NMDA receptors and its cells tend to have a high level of Zn++. This makes the dentate sensitive to glutamate and GABA. It may serve a roll to modulate long term potentiation in the hippocampus.
How cortisol imbalance may lead to autism
The work of A. Schore, leads to a variety of ways that may lead to misapoptosis. We have previously identified these factors. Could cortisol assist to mute or reduce misapoptosis? R. Ankenman, 2005 - Specifically we favor a starting dose of 2.5 mg 2 times in the first week of Namenda, then in the 2nd week 2.5 mg 3 times per week, then in the 3rd week, .5 mg per day for one week. Generally the NMDA antagonist is used for only one to three months. This combined pharmacotherapy should be initiated only after the behavioral stabilization and in the context of on going behavioral intervention therapy of high frequency and intensity.
Our rationale for the use of cortical or similar agents is to favorably influence the apoptosis of the dentate gyrus, which may still be forming connections between 2 and 5 years. This approach could be tried in cases of early detection and poor prognostic features. The risks of steroid therapy vs. the benefits of possibly improving the course and outcome must be carefully considered. In addition, the study of animal models must be conducted to further validate this approach.
How cortisol imbalance may lead to autism
The work of A. Schore, leads to a variety of ways that may lead to misapoptosis. We have previously identified these factors. Could cortisol assist to mute or reduce misapoptosis?
Cortisol and other glucocorticoids act on cells in the hippocampus, dentate gyrus and elsewhere to facilitate planned apoptosis. In the developing brain there are several ways in which cortisol and related hormones can be prevented from reaching the developing brain. Specifically, we identify prenatal factors including 1) Placental Factors, 2) Maternal Cortisol Binding Proteins and 3) Interference with signal transmission in the developing brain. In the prenatal in utero environment maternal, placental and fetal sources of cortisol become important. It may be that a failure of any one or all of these may lead to the failure of apoptosis or misapoptosis. In the post natal period the infants adrenocortical , pituitary and hypothalamic factors become important. The post natal developing brain still needs planned apoptosis. Since the data on increased head circumference and presumably the failure of apoptosis, cortisol most likely plays a role here.
Cortisol’s role is to 1) Facilitate planned apoptosis 2) Provide the proper brain development hormonal environment and 3) protect against aberrant immunologic processes that may lead to unplanned apoptosis and for favor intracellular and mitochondria function that leads to planned apoptosis.
Table 3.
1). Maternal stress studies
2). Placental studies
3). Prenatal influence on steroids and the developing brain
4). Post natal adrenal cortex
5). Post natal pituitary ACTH
6). Hypothalamus - CRF
7). Effect of cortisol on cell nucleus
8). Effect of cortisol on mitochondria
9). Effect of cortisol on cell cytoplasm
10). Cerebellar- limbic circuit and the Purkinje cells
How is the cerebellum affected in catatonia and ASDs?
While Serrano, et al, 2003, Neurology have postulated that autism arises from a cerebellar- limbic loop. They failed to have identified catatonic signs. They concentrated on the cerebellar signs which are difficultly in imitation, difficulty in termination of movements and abnormalities of tone. In catatonia, (Carroll, et al, 2003, Northoff, 2002) Identify a cerebral loop responsible for catatonia but do not discuss the cerebellar mechanisms or pathway. The cerebellum remains an understudied yet important area in both disorders unfortunately; testing for cerebellar function involves identifying neurological soft signs on exam. Specifically these include but are not limited to testing of: 1) Hypotonia 2) Lack of check 3) Pendular reflexes 4) Dysmetria and
5) Asynergia. These focused tests are not performed as part of the standard neurological exam and are not usually performed on uncooperative patients. However cerebellar abnormalities were found in a high frequency in catatonic schizophrenia by (Oertel & Kruger, 1999-2000).
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