Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial

Daniel A Rossignol, Lanier W Rossignol, Scott Smith, Cindy Schneider, Sally Logerquist, Anju Usman, Jim Neubrander, Eric M Madren, Gregg Hintz, Barry Grushkin, Elizabeth A Mumper, Daniel A Rossignol, Lanier W Rossignol, Scott Smith, Cindy Schneider, Sally Logerquist, Anju Usman, Jim Neubrander, Eric M Madren, Gregg Hintz, Barry Grushkin, Elizabeth A Mumper

Abstract

Background: Several uncontrolled studies of hyperbaric treatment in children with autism have reported clinical improvements; however, this treatment has not been evaluated to date with a controlled study. We performed a multicenter, randomized, double-blind, controlled trial to assess the efficacy of hyperbaric treatment in children with autism.

Methods: 62 children with autism recruited from 6 centers, ages 2-7 years (mean 4.92 +/- 1.21), were randomly assigned to 40 hourly treatments of either hyperbaric treatment at 1.3 atmosphere (atm) and 24% oxygen ("treatment group", n = 33) or slightly pressurized room air at 1.03 atm and 21% oxygen ("control group", n = 29). Outcome measures included Clinical Global Impression (CGI) scale, Aberrant Behavior Checklist (ABC), and Autism Treatment Evaluation Checklist (ATEC).

Results: After 40 sessions, mean physician CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0008), receptive language (p < 0.0001), social interaction (p = 0.0473), and eye contact (p = 0.0102); 9/30 children (30%) in the treatment group were rated as "very much improved" or "much improved" compared to 2/26 (8%) of controls (p = 0.0471); 24/30 (80%) in the treatment group improved compared to 10/26 (38%) of controls (p = 0.0024). Mean parental CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0336), receptive language (p = 0.0168), and eye contact (p = 0.0322). On the ABC, significant improvements were observed in the treatment group in total score, irritability, stereotypy, hyperactivity, and speech (p < 0.03 for each), but not in the control group. In the treatment group compared to the control group, mean changes on the ABC total score and subscales were similar except a greater number of children improved in irritability (p = 0.0311). On the ATEC, sensory/cognitive awareness significantly improved (p = 0.0367) in the treatment group compared to the control group. Post-hoc analysis indicated that children over age 5 and children with lower initial autism severity had the most robust improvements. Hyperbaric treatment was safe and well-tolerated.

Conclusion: Children with autism who received hyperbaric treatment at 1.3 atm and 24% oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air.

Trial registration: clinicaltrials.gov NCT00335790.

Figures

Figure 1
Figure 1
Consolidated Standards of Reporting Trials (CONSORT) flow diagram.
Figure 2
Figure 2
Absolute change compared to baseline on the mean CGI overall functioning score in the treatment and control groups as rated separately by physicians and parents. * p < 0.001; ** p < 0.05.
Figure 3
Figure 3
Changes compared to baseline on the ABC total score and subscales (percentage change) in the treatment and control groups. *** p < 0.1.
Figure 4
Figure 4
Changes compared to baseline on the ATEC total score and subscales (percentage change) in the treatment and control groups. ** p < 0.05.

References

    1. APA . Diagnostic and statistical manual of mental disorders. 4. Washington, DC: American Psychiatric Association; 1994.
    1. Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children. JAMA. 2001;285:3093–3099. doi: 10.1001/jama.285.24.3093.
    1. Bertrand J, Mars A, Boyle C, Bove F, Yeargin-Allsopp M, Decoufle P. Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation. Pediatrics. 2001;108:1155–1161. doi: 10.1542/peds.108.5.1155.
    1. Baird G, Charman T, Baron-Cohen S, Cox A, Swettenham J, Wheelwright S, Drew A. A screening instrument for autism at 18 months of age: a 6-year follow-up study. J Am Acad Child Adolesc Psychiatry. 2000;39:694–702. doi: 10.1097/00004583-200006000-00007.
    1. Rice C. Prevalence of autism spectrum disorders–autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR. 2007;56:12–28.
    1. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004;113:e472–486. doi: 10.1542/peds.113.5.e472.
    1. Rossignol DA, Rossignol LW, James SJ, Melnyk S, Mumper E. The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: an open-label pilot study. BMC Pediatr. 2007;7:36. doi: 10.1186/1471-2431-7-36.
    1. Feldmeier JJ, Chairman and Editor . Hyperbaric oxygen 2003: indications and results: the hyperbaric oxygen therapy committee report. Kensington, MD: Undersea and Hyperbaric Medicine Society; 2003.
    1. Leach RM, Rees PJ, Wilmshurst P. Hyperbaric oxygen therapy. BMJ. 1998;317:1140–1143.
    1. Stoller KP. Quantification of neurocognitive changes before, during, and after hyperbaric oxygen therapy in a case of fetal alcohol syndrome. Pediatrics. 2005;116:e586–591. doi: 10.1542/peds.2004-2851.
    1. Montgomery D, Goldberg J, Amar M, Lacroix V, Lecomte J, Lambert J, Vanasse M, Marois P. Effects of hyperbaric oxygen therapy on children with spastic diplegic cerebral palsy: a pilot project. Undersea Hyperb Med. 1999;26:235–242.
    1. Collet JP, Vanasse M, Marois P, Amar M, Goldberg J, Lambert J, Lassonde M, Hardy P, Fortin J, Tremblay SD, et al. Hyperbaric oxygen for children with cerebral palsy: a randomised multicentre trial. HBO-CP Research Group. Lancet. 2001;357:582–586. doi: 10.1016/S0140-6736(00)04054-X.
    1. Rockswold GL, Ford SE, Anderson DC, Bergman TA, Sherman RE. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J Neurosurg. 1992;76:929–934.
    1. Golden ZL, Neubauer R, Golden CJ, Greene L, Marsh J, Mleko A. Improvement in cerebral metabolism in chronic brain injury after hyperbaric oxygen therapy. Int J Neurosci. 2002;112:119–131. doi: 10.1080/00207450212027.
    1. Hardy P, Johnston KM, De Beaumont L, Montgomery DL, Lecomte JM, Soucy JP, Bourbonnais D, Lassonde M. Pilot case study of the therapeutic potential of hyperbaric oxygen therapy on chronic brain injury. J Neurol Sci. 2007;253:94–105. doi: 10.1016/j.jns.2006.12.005.
    1. Shi XY, Tang ZQ, Sun D, He XJ. Evaluation of hyperbaric oxygen treatment of neuropsychiatric disorders following traumatic brain injury. Chin Med J (Engl) 2006;119:1978–1982.
    1. Rossignol DA, Rossignol LW. Hyperbaric oxygen therapy may improve symptoms in autistic children. Med Hypotheses. 2006;67:216–228. doi: 10.1016/j.mehy.2006.02.009.
    1. Al-Waili NS, Butler GJ. Effects of hyperbaric oxygen on inflammatory response to wound and trauma: possible mechanism of action. Scientific World Journal. 2006;6:425–441.
    1. Buchman AL, Fife C, Torres C, Smith L, Aristizibal J. Hyperbaric oxygen therapy for severe ulcerative colitis. J Clin Gastroenterol. 2001;33:337–339. doi: 10.1097/00004836-200110000-00018.
    1. Takeshima F, Makiyama K, Doi T. Hyperbaric oxygen as adjunct therapy for Crohn's intractable enteric ulcer. Am J Gastroenterol. 1999;94:3374–3375. doi: 10.1111/j.1572-0241.1999.03374.x.
    1. Heuser G, Heuser SA, Rodelander D, Aguilera O, Uszler M. Treatment of neurologically impaired adults and children with "mild" hyperbaric oxygenation (1.3 atm and 24% oxygen) In: Joiner JT, editor. Hyperbaric oxygenation for cerebral palsy and the brain-injured child. Flagstaff, Arizona: Best Publications; 2002.
    1. Rossignol DA. The use of hyperbaric oxygen therapy in autism. In: Zhang JH, editor. Hyperbaric oxygen for neurological disorders. Flagstaff, AZ: Best Publishing Company; 2008. pp. 209–258.
    1. Granowitz EV, Skulsky EJ, Benson RM, Wright J, Garb JL, Cohen ER, Smithline EC, Brown RB. Exposure to increased pressure or hyperbaric oxygen suppresses interferon-gamma secretion in whole blood cultures of healthy humans. Undersea Hyperb Med. 2002;29:216–225.
    1. Rossignol DA. Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism. Med Hypotheses. 2007;68:1208–1227. doi: 10.1016/j.mehy.2006.09.064.
    1. Weisz G, Lavy A, Adir Y, Melamed Y, Rubin D, Eidelman S, Pollack S. Modification of in vivo and in vitro TNF-alpha, IL-1, and IL-6 secretion by circulating monocytes during hyperbaric oxygen treatment in patients with perianal Crohn's disease. J Clin Immunol. 1997;17:154–159. doi: 10.1023/A:1027378532003.
    1. Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999;134:607–613. doi: 10.1016/S0022-3476(99)70248-9.
    1. Ohnishi T, Matsuda H, Hashimoto T, Kunihiro T, Nishikawa M, Uema T, Sasaki M. Abnormal regional cerebral blood flow in childhood autism. Brain. 2000;123:1838–1844. doi: 10.1093/brain/123.9.1838.
    1. Zilbovicius M, Boddaert N, Belin P, Poline JB, Remy P, Mangin JF, Thivard L, Barthelemy C, Samson Y. Temporal lobe dysfunction in childhood autism: a PET study. Positron emission tomography. Am J Psychiatry. 2000;157:1988–1993. doi: 10.1176/appi.ajp.157.12.1988.
    1. Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology. 2002;46:76–84. doi: 10.1159/000065416.
    1. Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, et al. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry. 2002;7:375–382. doi: 10.1038/sj.mp.4001077.
    1. Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004;24:664–673. doi: 10.1007/s10875-004-6241-6.
    1. Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51:77–85. doi: 10.1159/000084164.
    1. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67–81. doi: 10.1002/ana.20315.
    1. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007;36:361–365. doi: 10.1016/j.pediatrneurol.2007.01.012.
    1. Chungpaibulpatana J, Sumpatanarax T, Thadakul N, Chantharatreerat C, Konkaew M, Aroonlimsawas M. Hyperbaric oxygen therapy in Thai autistic children. J Med Assoc Thai. 2008;91:1232–1238.
    1. Ashamalla HL, Thom SR, Goldwein JW. Hyperbaric oxygen therapy for the treatment of radiation-induced sequelae in children. The University of Pennsylvania experience. Cancer. 1996;77:2407–2412. doi: 10.1002/(SICI)1097-0142(19960601)77:11<2407::AID-CNCR33>;2-Z.
    1. Annane D, Depondt J, Aubert P, Villart M, Gehanno P, Gajdos P, Chevret S. Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial from the ORN96 study group. J Clin Oncol. 2004;22:4893–4900. doi: 10.1200/JCO.2004.09.006.
    1. Clarke RE, Tenorio LM, Hussey JR, Toklu AS, Cone DL, Hinojosa JG, Desai SP, Dominguez Parra L, Rodrigues SD, Long RJ, et al. Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up. Int J Radiat Oncol Biol Phys. 2008;72:134–143.
    1. Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985;89:485–491.
    1. Autism Treatment Evaluation Checklist (ATEC): Reliabilities and Score Distributions. 2000.
    1. Guy W. Clinical Global Impression. Rockville, MD; 1976.
    1. Cohen J. Statistical power analysis for the behavioral sciences. second. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods. 2007;39:175–191.
    1. Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66:3–8.
    1. Sandler AD, Sutton KA, DeWeese J, Girardi MA, Sheppard V, Bodfish JW. Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J Med. 1999;341:1801–1806. doi: 10.1056/NEJM199912093412404.
    1. King BH, Wright DM, Handen BL, Sikich L, Zimmerman AW, McMahon W, Cantwell E, Davanzo PA, Dourish CT, Dykens EM, et al. Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Adolesc Psychiatry. 2001;40:658–665. doi: 10.1097/00004583-200106000-00010.
    1. Shiratsuch H, Basson MD. Differential regulation of monocyte/macrophage cytokine production by pressure. Am J Surg. 2005;190:757–762. doi: 10.1016/j.amjsurg.2005.07.016.
    1. Jyonouchi H, Sun S, Le H. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol. 2001;120:170–179. doi: 10.1016/S0165-5728(01)00421-0.
    1. Boddaert N, Chabane N, Barthelemy C, Bourgeois M, Poline JB, Brunelle F, Samson Y, Zilbovicius M. [Bitemporal lobe dysfunction in infantile autism: positron emission tomography study] J Radiol. 2002;83:1829–1833.
    1. Fox PT, Raichle ME. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci USA. 1986;83:1140–1144. doi: 10.1073/pnas.83.4.1140.
    1. Parri R, Crunelli V. An astrocyte bridge from synapse to blood flow. Nat Neurosci. 2003;6:5–6. doi: 10.1038/nn0103-5.
    1. Starkstein SE, Vazquez S, Vrancic D, Nanclares V, Manes F, Piven J, Plebst C. SPECT findings in mentally retarded autistic individuals. J Neuropsychiatry Clin Neurosci. 2000;12:370–375.
    1. Kaya M, Karasalihoglu S, Ustun F, Gultekin A, Cermik TF, Fazlioglu Y, Ture M, Yigitbasi ON, Berkarda S. The relationship between 99mTc-HMPAO brain SPECT and the scores of real life rating scale in autistic children. Brain Dev. 2002;24:77–81. doi: 10.1016/S0387-7604(02)00006-2.
    1. Wilcox J, Tsuang MT, Ledger E, Algeo J, Schnurr T. Brain perfusion in autism varies with age. Neuropsychobiology. 2002;46:13–16. doi: 10.1159/000063570.
    1. Gendry Meresse I, Zilbovicius M, Boddaert N, Robel L, Philippe A, Sfaello I, Laurier L, Brunelle F, Samson Y, Mouren MC, et al. Autism severity and temporal lobe functional abnormalities. Ann Neurol. 2005;58:466–469. doi: 10.1002/ana.20597.
    1. Connolly AM, Chez M, Streif EM, Keeling RM, Golumbek PT, Kwon JM, Riviello JJ, Robinson RG, Neuman RJ, Deuel RM. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biol Psychiatry. 2006;59:354–363. doi: 10.1016/j.biopsych.2005.07.004.
    1. Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005;73:379–384. doi: 10.1016/j.plefa.2005.06.002.
    1. Pratico D, Lawson JA, Rokach J, FitzGerald GA. The isoprostanes in biology and medicine. Trends Endocrinol Metab. 2001;12:243–247. doi: 10.1016/S1043-2760(01)00411-8.
    1. Yao Y, Walsh WJ, McGinnis WR, Pratico D. Altered vascular phenotype in autism: correlation with oxidative stress. Arch Neurol. 2006;63:1161–1164. doi: 10.1001/archneur.63.8.1161.
    1. Fatemi SH, Halt AR, Stary JM, Realmuto GM, Jalali-Mousavi M. Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum. Neuroreport. 2001;12:929–933. doi: 10.1097/00001756-200104170-00013.
    1. Fatemi SH, Halt AR. Altered levels of Bcl2 and p53 proteins in parietal cortex reflect deranged apoptotic regulation in autism. Synapse. 2001;42:281–284. doi: 10.1002/syn.10002.
    1. Fatemi SH, Stary JM, Halt AR, Realmuto GR. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord. 2001;31:529–535. doi: 10.1023/A:1013234708757.
    1. Araghi-Niknam M, Fatemi SH. Levels of Bcl-2 and P53 are altered in superior frontal and cerebellar cortices of autistic subjects. Cell Mol Neurobiol. 2003;23:945–952. doi: 10.1023/B:CEMN.0000005322.27203.73.
    1. Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ, Jr, Giaccia AJ. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol. 1994;14:6264–6277.
    1. Shimizu S, Eguchi Y, Kamiike W, Itoh Y, Hasegawa J, Yamabe K, Otsuki Y, Matsuda H, Tsujimoto Y. Induction of apoptosis as well as necrosis by hypoxia and predominant prevention of apoptosis by Bcl-2 and Bcl-XL. Cancer Res. 1996;56:2161–2166.
    1. Nathan C. Immunology: Oxygen and the inflammatory cell. Nature. 2003;422:675–676. doi: 10.1038/422675a.
    1. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645–657. doi: 10.1016/S0092-8674(03)00154-5.
    1. Cramer T, Johnson RS. A novel role for the hypoxia inducible transcription factor HIF-1alpha: critical regulation of inflammatory cell function. Cell Cycle. 2003;2:192–193.
    1. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998;17:3005–3015. doi: 10.1093/emboj/17.11.3005.
    1. Hendry J, DeVito T, Gelman N, Densmore M, Rajakumar N, Pavlosky W, Williamson PC, Thompson PM, Drost DJ, Nicolson R. White matter abnormalities in autism detected through transverse relaxation time imaging. Neuroimage. 2006;29:1049–1057. doi: 10.1016/j.neuroimage.2005.08.039.
    1. Lu G, Qian X, Berezin I, Telford GL, Huizinga JD, Sarna SK. Inflammation modulates in vitro colonic myoelectric and contractile activity and interstitial cells of Cajal. Am J Physiol. 1997;273:G1233–1245.
    1. Ishii Y, Ushida T, Tateishi T, Shimojo H, Miyanaga Y. Effects of different exposures of hyperbaric oxygen on ligament healing in rats. J Orthop Res. 2002;20:353–356. doi: 10.1016/S0736-0266(01)00094-8.
    1. Harrison DK, Abbot NC, Carnochan FM, Beck JS, James PB, McCollum PT. Protective regulation of oxygen uptake as a result of reduced oxygen extraction during chronic inflammation. Adv Exp Med Biol. 1994;345:789–796.
    1. Van de Veire N, De Winter O, Philippé J, De Buyzere M, Bernard D, Langlois M, Gillebert T, De Sutter J. Maximum oxygen uptake at peak exercise in elderly patients with coronary artery disease and preserved left ventricular function: the role of inflammation on top of tissue Doppler-derived systolic and diastolic function. Am Heart J. 2006;152:e291–297. doi: 10.1016/j.ahj.2006.04.029.
    1. Suematsu M, Schmid-Schonbein GW, Chavez-Chavez RH, Yee TT, Tamatani T, Miyasaka M, Delano FA, Zweifach BW. In vivo visualization of oxidative changes in microvessels during neutrophil activation. Am J Physiol. 1993;264:H881–891.
    1. Miljkovic-Lolic M, Silbergleit R, Fiskum G, Rosenthal RE. Neuroprotective effects of hyperbaric oxygen treatment in experimental focal cerebral ischemia are associated with reduced brain leukocyte myeloperoxidase activity. Brain Res. 2003;971:90–94. doi: 10.1016/S0006-8993(03)02364-3.
    1. Sheffield PJ, Davis JC. Application of hyperbaric oxygen therapy in a case of prolonged cerebral hypoxia following rapid decompression. Aviat Space Environ Med. 1976;47:759–762.
    1. Neubauer RA, James P. Cerebral oxygenation and the recoverable brain. Neurol Res. 1998;20:S33–36.
    1. Veltkamp R, Siebing DA, Sun L, Heiland S, Bieber K, Marti HH, Nagel S, Schwab S, Schwaninger M. Hyperbaric oxygen reduces blood-brain barrier damage and edema after transient focal cerebral ischemia. Stroke. 2005;36:1679–1683. doi: 10.1161/01.STR.0000173408.94728.79.
    1. Ostrowski RP, Colohan AR, Zhang JH. Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2005;25:554–571. doi: 10.1038/sj.jcbfm.9600048.
    1. Vlodavsky E, Palzur E, Soustiel JF. Hyperbaric oxygen therapy reduces neuroinflammation and expression of matrix metalloproteinase-9 in the rat model of traumatic brain injury. Neuropathol Appl Neurobiol. 2006;32:40–50. doi: 10.1111/j.1365-2990.2005.00698.x.
    1. Hashimoto T, Sasaki M, Fukumizu M, Hanaoka S, Sugai K, Matsuda H. Single-photon emission computed tomography of the brain in autism: effect of the developmental level. Pediatr Neurol. 2000;23:416–420. doi: 10.1016/S0887-8994(00)00224-1.
    1. Boddaert N, Zilbovicius M. Functional neuroimaging and childhood autism. Pediatr Radiol. 2002;32:1–7. doi: 10.1007/s00247-001-0570-x.
    1. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R, Geier MR. Biomarkers of environmental toxicity and susceptibility in autism. J Neurol Sci. 2008.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅