Neurological Histopathology and Biological Changes in Autism

Cerebellum. The Purkinje cells contain round,

darkly stained cytoplasmic inclusions (Luxol fast blue and cresyl

violet; bar represents 10 mm.)

Changes seen in Autism

In general there is nothing to see under standard haematoxylin and eosin staining of brain tissue. Complex assessment is necessary to show alterations that are reliable and research has required many samples in order to separate them from the controls. Electron microscropy findings are not good either and not much has been done except in specific cases. Often the findings cannot be repeated because the numbers of deaths is low in this group, and the death is often due to some other cause that may have an effect on the histopathology e.g. seizures. The use of PET, SPECT and MRI scanning in children gives an opportunity to look at the metabolism of the brain and the relative levels of usage of different parts. Currently this is inadequately taken advantage of: probably because of the sheer difficulty of organisation.

However, major groups claim specific changes

Overall changes in brain structure
Histopathology (see neuroimmunology in brain also)
Electron microscopy
Neurobiology
MRI scanning
Positron Emission Tomography
Autoradiography
Electroencephalography
Cerebral blood flow

Overall changes

The changes in growth of the brain and brain parts has been argued over for many years. The use of MRI has given a chance but of course, by the time the child is realised to have autism it is past the age that the scanning might be most useful to give insight in this respect. As a result, many of the results that we see are in slightly older children and compared with controls. The finding of slightly enlarged brains is fairly regular.

As quoted from Pardo and Eberhart:

“One consistent finding in ASD is altered brain growth, which has been extensively documented by Courchesne et al. The clinical onset of autism appears to be preceded by two phases of brain growth abnormalities: a reduced head size at birth, then a sudden and excessive increase between 1–2 months and 6–14 months of age (2,3 4). Furthermore, these reports and other recent neuroimaging studies have shown that an abnormal pattern of brain overgrowth also occurs in areas of the frontal lobe, cerebellum and limbic structures

between 2 and 4 years of age, a pattern that is followed by abnormal slowness in brain growth”(54, 55, 57, 192)

Diagram 1: This comes from Pardo and Eberhart and is an excellent insight into the mechanism by which the ASD may appear. They realise that there may be many individual factors and that they may take place at many separate points in the development of the brain and at different times.

Hardan AY, Girgis RR, Adams J, Gilbert AR, Keshavan MS, Minshew NJ. Abnormal brain size effect on the thalamus in autism Psychiatry Res. 2006 Oct 30;147(2-3):145-51. (Findings from this larger study than previously are consistent with the previous report of an abnormal brain size effect on the thalamus in autism and support the possibility of abnormal connections between cortical and subcortical structures in this disorder. There was no correlation with clinical condition)

Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, Morgan J. Mapping early brain development in autism. Neuron. 2007 Oct 25;56(2):399-413. (this is a complex description of the increased brain size in childhood, and how it appears to come about in various periods. A good review that seems to admit that there may be many formats to the illness as the stimulation or inhibition of the various brain development periods may all be important and effected differently)

Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, Lammers CR, Reiss AL, Amaral DG. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci. 2004 Jul 14;24(28):6392-401

Casanova MF. The neuropathology of autism. Brain Pathol. 2007 Oct;17(4):422-33. Review. (tries to say that much of the pathology that has been put forward has not been found to be reliable). Changes in the size of the brain, particularly the parietal lobes are larger in autism. Modified changes in astrocytes, and brain monocytes (suggesting irritation). Decreased and modified synaptic interactions between neurones, some of which are only visible under electron microscropes.

Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, Gilmore J, Piven J. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years .Arch Gen Psychiatry. 2005 Dec;62(12):1366-76 (Generalized enlargement of gray and white matter cerebral volumes, but not cerebellar volumes, are present at 2 years of age in autism. Indirect evidence suggests that this increased rate of brain growth in autism may have its onset postnatally in the latter part of the first year of life.)

Courchesne E. Brain development in autism: early overgrowth followed by premature arrest of growth. Ment Retard Dev Disabil Res Rev. 2004;10(2):106-11. (growth of the brain in various periods and how this may be altered in autism)

Courchesne E, Redcay E, Kennedy DP. The autistic brain: birth through adulthood. Curr Opin Neurol. 2004 Aug;17(4):489-96.

DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, Schultz RT, Crawley J, Young LJ. The developmental neurobiology of autism spectrum disorder. J Neurosci. 2006 Jun 28;26(26):6897-906. Review.

Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304. (To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1.)

Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005 Dec;17(6):485-95

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Histopathology

Decrease in Purkinje cells in the cerebellum: similarly in all ages. Changes in the inferior olive were seen with unusually large neurons in younger brains and neurones smaller than expected in the older brains. Increased packing of neuronal cells in the entorhinal cortex.

Curtailment of maturation of the forebrain limbic system (most consistently the amygdala the hypocampal formation and entorhinal cortex), abnormalities in the cerebellar circuits, and and an unusual pattern of change of post natal brain size. Also age-related neuronal size and number in the Broca diagonal band. Great argument as to reliable changes. They commonly try to work out the point in the development of the brain at which the damage would have taken place to produce the changes seen in individual brain samples. Neuropathological studies in autistic brains have shown small neuronal size and increased cell packing density in a variety of limbic system structures including the hippocampus, a change consistent with curtailment of normal development.

A good review: Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005 Apr-May;23(2-3):183-7. taking over from Bauman ML, Kemper TL. The neuropathology of the autism spectrum disorders: what have we learned? Novartis Found Symp. 2003;251:112-22; discussion 122-8, 281-97

Schmitz C, Rezaie P. The neuropathology of autism: where do we stand? Neuropathol Appl Neurobiol. 2007 Oct 26 (we don’t know enough yet, they say)

Darby JK. Neurpathologic aspects of psychosis in children. J autism Child Schizophr 1976;6:350-3 (he found no reliable changes in 33 autistic brains).

Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008 Mar;31(3):137-45. (he says that it is a heterogenous group with a heterogenous causes of death and so it is not surprising that we cant get specific changes)

Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J. Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei J Comp Neurol. 1996 Jun 24;370(2):247-61. (The human data suggest that the initiating lesion includes the motor cranial nerve nuclei. To test this hypothesis, we first examined motor nuclei in the brainstem of a human autistic case. The autopsy brain exhibited near-complete absence of the facial nucleus and superior olive along with shortening of the brainstem between the trapezoid body and the inferior olive. They also tried giving some rats in utero some valproate to see if the effect was the same: it wasn’t)

Chen X, Liu H, Shim AH, Focia PJ, He X. Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions. Nat Struct Mol Biol. 2007 Dec 16; [Epub ahead of print] . They explain why the neuroligin genetic mutations (as accused in autism) are likely to be associated with specific changes in the ability of neurones to interact.

Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007 Oct 5;318(5847):71-6.

Garber K. Neuroscience. Autism's cause may reside in abnormalities at the synapse. Science. 2007 Jul 13;317(5835):190 (editorial) – this shows how the evidence with neuroligins has been appearing over the last 3 years.

Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304. (Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues.)

Coleman PD, Romano J, Lapham L, Simon W. Cell counts in cerebral cortex of an autistic patient. J Autism Dev Disord. 1985 Sep;15(3):245-55. (‘Numbers of neurons and glia were counted in the cerebral cortex of one well-documented case of autism and two age- and sex-matched controls. Areas in which cell counts were made were primary auditory cortex, Broca's speech area, and auditory association cortex. No consistent differences in cell density were found between the brains of the autistic patient and the control patients.” All they could say was that the glia:neuronal ratio was smaller in the autistic brain than in the two controls. Statistically this would not be adequate.

Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D, Ritvo A. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report. Am J Psychiatry. 1986 Jul;143(7):862-6. (this involved counts of the cell numbers and has been repeated)

Martchek M, Thevarkunnel S, Bauman M, Blatt G, Kemper T. Lack of evidence of neuropathology in the locus coeruleus in autism. Acta Neuropathol. 2006 May;111(5):497-9. Epub 2006 Apr 5.

A Bailey, P Luthert, A Dean, B Harding, I Janota, M Montgomery, M Rutter and P Lantos A clinicopathological study of autism Brain, Vol 121, Issue 5 889-905 (They are less happy with the reliable findings that might be suggested elsewhere and wonder if the changes that they found also in the Purkinje cells of the cerebellum are indeed much to do with the clinical aspects of the condition, which they put towards involvement of the cerebral cortex but with little to be seen under microscoscopy)

van Kooten IA, Palmen SJ, von Cappeln P, Steinbusch HW, Korr H, Heinsen H, Hof PR, van Engeland H, Schmitz C. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain. 2008 Apr;131(Pt 4):987-99. Epub 2008 Mar 10.

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Electron microcroscopy

There appears to be little data of reliable changes in autism that cannot be predicted from standard methods of histopathology (if there are, please contact me!)

Chubykin AA, Liu X, Comoletti D, Tsigelny I, Taylor P, Südhof TC. Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism. J Biol Chem. 2005 Jun 10;280(23):22365-74. (contains the electron microscope viewpoint of the synapse in these genetic mutants)

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Neurobiology and Brain Biochemistry (take into account diagram 1)

Currently inadequately followed but clearly a mechanism to follow the progressive pathology that takes place in the brain of the autistic child and the physiology of the brain in a steady long term condition.

Pardo CA, Eberhart CG. The neurobiology of autism. Brain Pathol. 2007 Oct;17(4):434-47. Review. (they are trying their best to associate the time of onset of the illness with the disease that is seen. From that they try to show why they see different pathology in different cases)

Kleinhans NM, Schweinsburg BC, Cohen DN, Müller RA, Courchesne E. N-acetyl aspartate in autism spectrum disorders: regional effects and relationship to fMRI activation. Brain Res. 2007 Aug 8;1162:85-97. Epub 2007 May 21 (this is an attempt to show changes in the regional effects of the transmitter: and they claim success, which would justify treatment being expected to make effect e.g. memantine)

McDougle CJ, Erickson CA, Stigler KA, Posey DJ. Neurochemistry in the pathophysiology of autism. J Clin Psychiatry. 2005;66 Suppl 10:9-18. Does not actually say what the changes are in the abstract.

Pardo CA, Eberhart CG. The neurobiology of autism. Brain Pathol. 2007 Oct;17(4):434-47. Review. Explains how things are moving much more rapidly and that further neurochemicals may be involved.

Minshew NJ, Williams DL. The new neurobiology of autism: cortex, connectivity, and neuronal organization. Arch Neurol. 2007 Jul;64(7):945-50. Review

Friedman SD, Shaw DW, Artru AA, Dawson G, Petropoulos H, Dager SR. Gray and white matter brain chemistry in young children with autism. Arch Gen Psychiatry. 2006 Jul;63(7):786-94.

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MRI

Magnetic resonance imaging and positron emission tomography. The data has built up and gradually it has become clearer of the size of the brain, the different periods during which changes from controls appear to take place. It is quite clear that the higher technology later in the era has managed to show much more specific changes that are relatively predictable in ASD children. The problem must always be as to whether the changes seen are secondary to chemistry (or some other factor causing damage) or involved with the primary illness. What can be said is that many mental illnesses cannot be shown to have MRI changes at all whereas the finding of these alterations in ASD is itself significant.

Acosta MT, Pearl PL. Imaging data in autism: from structure to malfunction. Semin Pediatr Neurol. 2004 Sep;11(3):205-13. Review. (view of autism as a neurobiological disorder corresponding with different stages and events in brain development. Alterations in volume of the total brain and specifically the cerebellum, frontal lobe, and limbic system have been identified.)

Garber HJ, Ritvo ER, Chiu LC, Griswold VJ, Kashanian A, Freeman BJ, Oldendorf WH. A magnetic resonance imaging study of autism: normal fourth ventricle size and absence of pathology. Am J Psychiatry. 1989 Apr;146(4):532-4. (showed no difference between the autistics and the controls)

Bloss CS, Courchesne E. MRI neuroanatomy in young girls with autism: a preliminary study. J Am Acad Child Adolesc Psychiatry. 2007 Apr;46(4):515-23. (Girls with autism exhibited nearly every size-related abnormality exhibited by boys with autism. Furthermore, additional sites of abnormality were observed in girls, including enlargement in temporal white and grey matter volumes and reduction in cerebellar grey matter volume. Significant correlations were observed between age and white matter volumes (e.g., cerebral white matter rs = 0.950) for the girls with autism, whereas no significant age-structure size relationships were observed for the boys with autism.)

Wassink TH, Hazlett HC, Epping EA, Arndt S, Dager SR, Schellenberg GD, Dawson G, Piven J. Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism .Arch Gen Psychiatry. 2007 Jun;64(6):709-17

(They found that 5-HTTLPR genotype influenced gray matter volumes of the cerebral cortex (F(2,23) = 7.29, P = .004) and of 3 lobe-based subregions in the UNC sample of 29 children (frontal lobe gray matter: F(2,23) = 6.36, P = .01). The 5-HTTLPR short allele appeared to be additively associated with increasing gray matter volumes, an observation affirmed by tests of linear genotype effects (cortical gray matter: F(1,24) = 14.11, P = .001; frontal lobe gray matter: F(1,24) = 13.20, P = .001). Genotype did not influence cerebellar volumes. This was not measured with respect to platelet serotonin but the results seem reasonable. Checking the change using histopathology?: a very difficult process and ethically difficult also). The significance of the gene for serotonin transport see serotonin.

Akshoomoff N, Lord C, Lincoln AJ, Courchesne RY, Carper RA, Townsend J, Courchesne E. Outcome classification of preschool children with autism spectrum disorders using MRI brain measures. J Am Acad Child Adolesc Psychiatry. 2004 Mar;43(3):349-57 (indicate that variability in cerebellar and cerebral size is correlated with diagnostic and functional outcome in very young children with ASD, but they did not try this with older children, which it is unlikely to be of value to indicate)

Gaffrey MS, Kleinhans NM, Haist F, Akshoomoff N, Campbell A, Courchesne E, Müller RA. Atypical [corrected] participation of visual cortex during word processing in autism: an fMRI study of semantic decision. Neuropsychologia. 2007 Apr 9;45(8):1672-84. Epub 2007 Jan 16. (functional MRI (fMRI) scanning was carried out while the patient was actually performing an action involving being shown something and responding. The autistic patients showed unreliable, and poor response but it was different amongst the patients. The authors decided that it was difficult to interpret)

Belmonte MK, Mazziotta JC, Minshew NJ, Evans AC, Courchesne E, Dager SR, Bookheimer SY, Aylward EH, Amaral DG, Cantor RM, Chugani DC, Dale AM, Davatzikos C, Gerig G, Herbert MR, Lainhart JE, Murphy DG, Piven J, Reiss AL, Schultz RT, Zeffiro TA, Levi-Pearl S, Lajonchere C, Colamarino SA. Offering to share: how to put heads together in autism neuroimaging. J Autism Dev Disord. 2008 Jan;38(1):2-13. Epub 2007 Mar 9.

Redcay E, Courchesne E. When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol Psychiatry. 2005 Jul 1;58(1):1-9.

Courchesne E, Pierce K. Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int J Dev Neurosci. 2005 Apr-May;23(2-3):153-70. Review.

Courchesne E. Brain development in autism: early overgrowth followed by premature arrest of growth. Ment Retard Dev Disabil Res Rev. 2004;10(2):106-11. Review

Müller RA, Kleinhans N, Pierce K, Kemmotsu N, Courchesne E. Functional MRI of motor sequence acquisition: effects of learning stage and performance Brain Res Cogn Brain Res. 2002 Aug;14(2):277-93 (superior parietal and occipital regions are most intensely involved in visually driven explicit digit sequence learning during early stages and low performance, whereas later stages of acquisition and higher levels of performance are characterized by stronger recruitment of prefrontal and mediotemporal regions.)

Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism. JAMA. 2003 Jul 16;290(3):337-44.

Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA, Tigue ZD, Chisum HJ, Moses P, Pierce K, Lord C, Lincoln AJ, Pizzo S, Schreibman L, Haas RH, Akshoomoff NA, Courchesne RY. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology. 2001 Jul 24;57(2):245-54. (Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism)

Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, Gilmore J, Piven J. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry. 2005 Dec;62(12):1366-76. (Generalized enlargement of gray and white matter cerebral volumes, but not cerebellar volumes, are present at 2 years of age in autism)

Hazlett HC, Poe MD, Gerig G, Smith RG, Piven J. Cortical gray and white brain tissue volume in adolescents and adults with autism. Biol Psychiatry. 2006 Jan 1;59(1):1-6. Epub 2005 Sep 1. (These findings give evidence for left-lateralized gray tissue enlargement in adolescents and adults with autism, and demonstrate a regional pattern of cortical lobe volumes underlying this effect.)

Zilbovicius M, Meresse I, Chabane N, Brunelle F, Samson Y, Boddaert N. Autism, the superior temporal sulcus and social perception. Trends Neurosci. 2006 Jul;29(7):359-66. Epub 2006 Jun 27. Review (this goes over the scanning factors that suggest the involvement of the sulcus)

Boddaert N, Chabane N, Gervais H, Good CD, Bourgeois M, Plumet MH, Barthélémy C, Mouren MC, Artiges E, Samson Y, Brunelle F, Frackowiak RS, Zilbovicius M. Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study.

Neuroimage. 2004 Sep;23(1):364-9.

Gervais H, Belin P, Boddaert N, Leboyer M, Coez A, Sfaello I, Barthélémy C, Brunelle F, Samson Y, Zilbovicius M. Abnormal cortical voice processing in autism. Nat Neurosci. 2004 Aug;7(8):801-2. Epub 2004 Jul 18. (this is done using functional magnetic resonance and trying to see which parts of the brain are active when specific action of the brain takes place)

Boddaert N, Zilbovicius M. Functional neuroimaging and childhood autism. Pediatr Radiol. 2002 Jan;32(1):1-7. Epub 2001 Nov 13. (Functional brain imaging, such as positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional MRI (fMRI) have added a new perspective to the study of normal and pathological brain functions. In autism, functional studies have been performed at rest or during activation. However, first-generation functional imaging devices were not sensitive enough to detect any consistent dysfunction. Recently, with improved technology, two independent groups have reported bilateral hypoperfusion of the temporal lobes in autistic children. In addition, activation studies, using perceptive and cognitive paradigms, have shown an abnormal pattern of cortical activation in autistic patients. These results suggest that different connections between particular cortical regions could exist in autism. They are admitting that we simply don’t know much just yet but their finding must fit in somehow with other groups)

Boger-Megiddo I, Shaw DW, Friedman SD, Sparks BF, Artru AA, Giedd JN, Dawson G, Dager SR. Corpus callosum morphometrics in young children with autism spectrum disorder. J Autism Dev Disord. 2006 Aug;36(6):733-9. (they could show decreased inter-hemipheric connections by a decreased in size of the cc)

Munson J, Dawson G, Abbott R, Faja S, Webb SJ, Friedman SD, Shaw D, Artru A, Dager SR. Amygdalar volume and behavioral development in autism. Arch Gen Psychiatry. 2006 Jun;63(6):686-93 (Larger right amygdalar volume was associated with more severe social and communication impairments at ages 3 and 4 years. Larger right amygdalar volume also was predictive of poorer social and communication abilities at age 6 years)

Dager SR, Wang L, Friedman SD, Shaw DW, Constantino JN, Artru AA, Dawson G, Csernansky JG. Shape mapping of the hippocampus in young children with autism spectrum disorder. AJNR Am J Neuroradiol. 2007 Apr;28(4):672-7. (using 3D MRI images they could show that children with ASD exhibited an alteration of hippocampal shape consistent with inward deformation of the subiculum. This pattern of hippocampal-shape deformations in the children with ASD was accentuated in the more severely affected subgroup of children with AD and was associated with deficits on neuropsychologic tests of medial temporal lobe but not prefrontal function.)

Hrdlicka M. Structural neuroimaging in autism. (Review) Neuro Endocrinol Lett. 2008 Jun 25;29(3). This attempts to go over all the MRI scanning that has taken place and indicate when and how the changes appear to take place.

Gabis L, Huang W, Azizian A, Devincent C, Tudorica A, Kesner-Baruch Y, Roche P, Pomeroy J. 1H-Magnetic Resonance Spectroscopy Markers of Cognitive and Language Ability in Clinical Subtypes of Autism Spectrum Disorders. J Child Neurol. 2008 May 16. (significantly lower N-acetyl-aspartate/creatine ratios bilaterally in the hippocampus-amygdala but not cerebellum, whereas myo-inositol/creatine was significantly increased in all measured regions)

Cleavinger HB, Bigler ED, Johnson JL, Lu J, McMahon W, Lainhart JE. Quantitative magnetic resonance image analysis of the cerebellum in macrocephalic and normocephalic children and adults with autism. J Int Neuropsychol Soc. 2008 May;14(3):401-13. (They found that there was little difference between that found in the autistic and control sample: so it was difficult)

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Positron Emission Scanning (PET – positron emission tomography)

This is may be carried out by the injection of water that has an oxygen atom that has an atomic weight of 15 and hence is emitting positrons. Parts of the brain that are most being used will have more of this in that they will be provided with more blood and uptake of water. Using computer techniques to show a difference between different periods it is possible to show which parts of the brain are most active. Other labelled molecules can be used to show how they are being used similarly to very specific substrates (e.g. the labelled tryptophan to follow serotonin manufacture). Currently in autism this technique is under-assessed.

The picture shows a PET scan from Castelli et al. indicating the areas of the brain that are used to a greater degree during the testing that they carried out. The white lines are arrows pointing to the areas of the brain that showing excess activity.

Castelli F, Frith C, Happé F, Frith U. Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes. Brain. 2002 Aug;125(Pt 8):1839-49. (changes from control in the handling by the brain of random vs non-random shapes. They showed medial prefrontal and amygdaloid area deficits during these)

Guilloteau D, Chalon S. PET and SPECT exploration of central monoaminergic transporters for the development of new drugs and treatments in brain disorders. Curr Pharm Des. 2005;11(25):3237-45. (this is more of a suggestion of work that could be done rather than some that has already results to state): similarly Sundaram SK, Chugani HT, Chugani DC. Positron emission tomography methods with potential for increased understanding of mental retardation and developmental disabilities. Ment Retard Dev Disabil Res Rev. 2005;11(4):325-30

Hall GB, Szechtman H, Nahmias C. Enhanced salience and emotion recognition in Autism: a PET study. Am J Psychiatry. 2003 Aug;160(8):1439-41 (they managed to show that there was a change in the PET demonstrable activity in the brain of autistic wrt controls when recognising or taking in emotional interaction. They admitted that this was difficult and required further work. It had been done as a test of limbic activity, which had been shown in other groups using PET).

Chandana SR, Behen ME, Juhász C, Muzik O, Rothermel RD, Mangner TJ, Chakraborty PK, Chugani HT, Chugani DC. Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci. 2005 Apr-May;23(2-3):171-82. (they had shown previously that there was variation and particular increase in serotonin production in specific areas of the brain. I this paper they show that this varies over time and that this will change in a predictive manner for the patient). See: Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children .Ann Neurol. 1999 Mar;45(3):287-95. and Pfund Z, Chugani DC, Muzik O, Juhász C, Behen ME, Lee J, Chakraborty P, Mangner T, Chugani HT. Alpha[11C] methyl-L-typtophan positron emission tomography in patients with alternating hemiplegia of childhood. J Child Neurol. 2002 Apr;17(4):253-60.

DeVito TJ, Drost DJ, Neufeld RW, Rajakumar N, Pavlosky W, Williamson P, Nicolson R. Evidence for cortical dysfunction in autism: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry. 2007 Feb 15;61(4):465-73 (showing a change in certain aminoacids)

Boddaert N, Barthélémy C, Poline JB, Samson Y, Brunelle F, Zilbovicius M. Autism: functional brain mapping of exceptional calendar capacity. Br J Psychiatry. 2005 Jul;187:83-6. (and attempt for PeT to show which parts of the brain are used by a single patient when carrying out a task for which they are known to be exceptionally brilliant).

Zilbovicius M, Boddaert N, Belin P, Poline JB, Remy P, Mangin JF, Thivard L, Barthélémy C, Samson Y. Temporal lobe dysfunction in childhood autism: a PET study. Positron emission tomography.

Am J Psychiatry. 2000 Dec;157(12):1988-93.

Müller RA, Behen ME, Rothermel RD, Chugani DC, Muzik O, Mangner TJ, Chugani HT. Brain mapping of language and auditory perception in high-functioning autistic adults: a PET study. J Autism Dev Disord. 1999 Feb;29(1):19-31.

Müller RA, Chugani DC, Behen ME, Rothermel RD, Muzik O, Chakraborty PK, Chugani HT. Impairment of dentato-thalamo-cortical pathway in autistic men: language activation data from positron emission tomography. Neurosci Lett. 1998 Mar 27;245(1):1-4.

Friedman SD, Shaw DW, Artru AA, Richards TL, Gardner J, Dawson G, Posse S, Dager SR. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology. 2003 Jan 14;60(1):100-7. (clearly important findings in that they could look for small molecules in the brain. They studied using dual-echo proton echoplanar spectroscopic imaging (32 x 32 matrix-1 cm(3) voxels) to measure brain chemical concentrations and relaxation times. ASD subjects demonstrated reduced N-acetylaspartate (NAA) (-10%), creatine (Cre) (-8%), and myo-inositol (-13%) concentrations compared to Typical Development controls and prolonged NAA T(2r) relative to TD (7%) and Delayed Development (9%) groups. Compared to DD subjects, children with ASD also demonstrated prolonged T(2r) for choline (10%) and Cre (9%). Regional analyses demonstrated subtle patterns of chemical alterations in ASD compared to the TD and DD groups. All very interesting but they did not try to state the reason why these findings might be present)

Friedman SD, Shaw DW, Artru AA, Dawson G, Petropoulos H, Dager SR. Gray and white matter brain chemistry in young children with autism. Arch Gen Psychiatry. 2006 Jul;63(7):786-94. (The children with ASD demonstrated significantlydecreased levels of Choline containing compounds (Cho) (P = .04) and mI (P = .008)and trend-level n-acetyl acetic acid (NAA) (P = .09) in gray matter comparedwith the delayed development group. For white matter, both children with ASDand children with DD showed a similar pattern of NAA and mIlevel decreases (for children with ASD vs children with TD:NAA, P = .03; myo-inositol (mI), P = .04; for childrenwith DD vs children with TD, NAA, P = .03; mI, P = .07).In several analyses, cerebral volume contributed significantlyas a covariate. The children with ASD demonstrated decreased graymatter concentrations of Cho (P<.001), creatine plus phosphocreatine(P = .02), NAA (P = .02), and mI (P = .008)compared with children with TD. This article has a good review of the data by other authors so far.

Figure: A cross sectional with spectrtrographic image indicating specific chemicals and hence can be measured during actions of the brain. (spectrum E shows the different chemical peaks)

Petropoulos H, Friedman SD, Shaw DW, Artru AA, Dawson G, Dager SR. Gray matter abnormalities in autism spectrum disorder revealed by T2 relaxation. Neurology. 2006 Aug 22;67(4):632-6. (they look at the water content during different brain actions)

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Autoradiography

(post mortem: this is a mechanism by which radio-labelled compounds are interacted with sections of brain, and then a photographic plate put next to them to see where in the section the labeling has stuck)

Guptill JT, Booker AB, Gibbs TT, Kemper TL, Bauman ML, Blatt GJ. [3H]-flunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: a multiple concentration autoradiographic study. J Autism Dev Disord. 2007 May;37(5):911-20. (They took the reduction seen in the number of hippocampal benzodiazepine binding sites to suggest alterations in the modulation of GABA(A) receptors in the presence of gamma amino butyric acid (GABA) in the autistic brain, possibly resulting in altered inhibitory functioning of hippocampal circuitry.

Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML. Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord.2001 Dec;31(6):537-43 (they agreed with the results from Guptill above but they could not find any differences with other binding sites: In contrast, the density and distribution of the other six receptors studied (3[H]-80H-DPAT labeled 5-HT1A receptors, 3[H]-ketanserin labeled 5-HT2 receptors, 3[H]-pirenzepine labled M1 receptors, 3[H]-hemicholinium labeled high affinity choline uptake sites, 3[H]-MK801 labeled NMDA receptors, and 3[H]-kainate labeled kainate receptors) in the hippocampus did not demonstrate any statistically significant differences in binding.)

Electroencephalographs

Electrical indication of the changes of the activity of the brain as measured using wires into the scalp.

Reinhold JA, Molloy CA, Manning-Courtney P. Electroencephalogram abnormalities in children with autism spectrum disorders. J Neurosci Nurs. 2005 Jun;37(3):136-8. (EEG studies were conducted on a subgroup of children while following established practice parameters for evaluating children for ASD. Abnormal EEG results were obtained in 85 (27%) of the 316 children evaluatedfor ASD. Within the subset of abnormal results, 64 children had autism, 10 had an ASD or milder presentation, 6 had another developmental disorder, 3 had Rett syndrome, had Down syndrome, and 1 had Wolf-Hirshhorn syndrome. The ASD patients are often assessed using EEG for possibility of epilepsy but it is always difficult to interpret. This study may at least give some kind of level as to what to expect in an ASD patient)

Plioplys AV. Autism: electroencephalogram abnormalities and clinical improvement with valproic acid.Arch Pediatr Adolesc Med. 1994 Feb;148(2):220-2.

Coben R, Clarke AR, Hudspeth W, Barry RJ. EEG power and coherence in autistic spectrum disorder. Clin Neurophysiol. 2008 May;119(5):1002-9. Epub 2008 Mar 10.( These results suggest dysfunctional integration of frontal and posterior brain regions in autistics along with a pattern of neural underconnectivity. It is the largest of the EEG studies but it also shows nothing specific and difficulty in interpretation for specific purposes. The references present in this also show how little work has been done previously in this direction)

Cerebral Blood Flow

This can be used to some degree to show that specific parts of the brain is being used adequately but full interpretation is difficult without specific anatomical changes. This is often measured using PET.

Gendry Meresse I, Zilbovicius M, Boddaert N, Robel L, Philippe A, Sfaello I, Laurier L, Brunelle F, Samson Y, Mouren MC, Chabane N. Autism severity and temporal lobe functional abnormalities. Ann Neurol. 2005 Sep;58(3):466-9. (they looked for a relationship between the cerebral blood flow in different parts of the brain)

Boddaert N, Chabane N, Belin P, Bourgeois M, Royer V, Barthelemy C, Mouren-Simeoni MC, Philippe A, Brunelle F, Samson Y, Zilbovicius M. Perception of complex sounds in autism: abnormal auditory cortical processing in children. Am J Psychiatry. 2004 Nov;161(11):2117-20.

Zilbovicius M, Garreau B, Samson Y, Remy P, Barthélémy C, Syrota A, Lelord G. Delayed maturation of the frontal cortex in childhood autism. Am J Psychiatry. 1995 Feb;152(2):248-52.

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