Autism and gastrointestinal issues
A common medical finding in autism is gastrointestinal disfunction; studies vary, indicating between 20%-90% may be affected. The most common findings are diarrhea and constipation. Toe walking may indicate constipation.
Gastroesophageal reflux (GERD) is another frequent finding. A hallmark symptom may be pressure seeking on the abdomen or tapping on the chest.
Eosinophilic esophagitis (EoE) could be related to underlying food allergies, and may be causing food selectivity.
Some may have bloating, pain, celiac disease, Crohn's, ileitis, and ulcerative colitis.
There is evidence that for some, night waking and self-injurious behaviors are related to GI distress. Food restriction may indicate an intolerance or undiagnosed allergy.
It is not uncommon for symptoms of constipation to be described as "withholding" and primarily attributed to willful behavior; however, they are more likely based on underlying pathophysiological conditions.
Studies have shown abnormal gut bacteria, increased gut permeability, increased fungal metabolites, intestinal inflammation, impaired carbohydrate breakdown and transport, immunopathological mucosal changes, and altered gene expression.
Some of the most exciting and promising research is emerging from a better understanding of the micro biome and its potential role in autism. Parents have reported improvements after their children are prescribed a course of anti fungal medications, antibiotics, and probiotics.
Proper identification and treatment of underlying GI issues may greatly improve an individual's quality of life and may even ameliorate symptoms associated with autism.
"Accumulating evidences showed modulation of the gut microbiota is a potential therapy in children with ASD. Probiotics, prebiotics, fecal microbiota transplantation (FMT) and diet have getting considerable attention (Table1). Probiotics may prevent intestinal inflammatory diseases by regulating intestinal tight junction protein expression and barrier function. The use of heat-killed probiotics may provide therapeutic benefit while minimizing adverse effects."
Li, Qinrui et al. “The Gut Microbiota and Autism Spectrum Disorders.” Frontiers in Cellular Neuroscience 11 (2017): 120.
"Our dataset of autistic subjects displayed a different fungal community structure compared to neurotypical subjects. In particular, the genus Candida was one of the most abundant taxa in the gut mycobiota of this study cohort, being two times more abundant in AD than in NT. To the best of our knowledge, this is the first time that alterations of the intestinal fungal microbiota are associated with ASDs. Although Candida is one of the most common and abundant genus of the human gut mycobiota [50, 51], its implication in phenomena of fungal dysbiosis have been reported in several GI and inflammatory conditions [52–54] as well as in Rett syndrome . It is therefore possible that alteration of the intestinal fungal population driven by an expansion of Candida in the gut mycobiota of autistic individuals may negatively impact on GI abnormalities through cytokine dysregulation."
Strati, Francesco et al. “New Evidences on the Altered Gut Microbiota in Autism Spectrum Disorders.” Microbiome 5 (2017): 24. PMC.
"High frequency of gastrointestinal yeast presence in ASD subjects was shown through a simple cultural approach (Candida spp. in 57.5 % of ASDs and no controls); the identification of aggressive form (pseudo-hyphae presenting) of Candida spp. at light microscope means that adhesion to intestinal mucosa is facilitated. Dysbiosis appears sustained by lowered Lactobacillus spp. and decreased number of Clostridium spp. Absence of C. difficilis and its toxins in both ASDs and controls is also shown. Low-mild gut inflammation and augmented intestinal permeability were demonstrated together with the presence of GI symptoms. Significant linear correlation was found between disease severity (CARs score) and calprotectin and Clostridium spp. presence. Also GI symptoms, such as constipation and alternating bowel, did correlate (multivariate analyses) with the increased permeability to lactulose. The present data provide rationale basis to a possible specific therapeutic intervention in restoring gut homeostasis in ASDs."
Iovene et al, (2017). Intestinal dysbiosis and yeast isolation in stool of subjects with autism spectrum disorders. Mycopathologia 182, 349–363.
"While the number of participants with significant upper gastrointestinal tract problems was small in this sample, 42.5% of participants met criteria for functional constipation, a disorder of the lower gastrointestinal tract. Heart rate variability, a measure of parasympathetic modulation of cardiac activity, was found to be positively associated with lower gastrointestinal tract symptomatology at baseline. This relationship was particularly strong for participants with co-occurring diagnoses of anxiety disorder and for those with a history of regressive ASD or loss of previously acquired skills. These findings suggest that autonomic function and gastrointestinal problems are intertwined in children with ASD; although it is not possible to assess causality in this data set. Future work should examine the impact of treatment of gastrointestinal problems on autonomic function and anxiety, as well as the impact of anxiety treatment on gastrointestinal problems. Clinicians should be aware that gastrointestinal problems, anxiety, and autonomic dysfunction may cluster in children with ASD and should be addressed in a multidisciplinary treatment plan."
Ferguson, et al; Psychophysiological Associations with Gastrointestinal Symptomatology in Autism Spectrum Disorder; Autism Res. 2017 February ; 10(2): 276–288. doi:10.1002/aur.1646.
"Recent studies have shown altered levels of Bacteroidetes and Firmicutes phyla with abundance in Clostridium phyla, highlighting the dysregulation of the gut-microbiota in autistic children and therefore establishing a strong link between gut microbiota and ASD.242-245 An increase in microbiota diversity has been reported in autistic children with Bacteroidetes was found to be in abundance in severe autistic cases and with a significant difference in the Actinobacteria and Proteobacteria phyla. Other gut commensals altered in autism are Bifidobacterium, Lactobacillus, Prevotella, and Ruminococcus genus."
Sandu, K. et al. Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry.
Translational Research Volume 179, January 2017, Pages 223-244
"Our study compared mucosa-associated microbial communities in children with ASD with previous reports characterizing stool in this population. Furthermore, we investigated whether mucosa-associated microbes correlated with altered tryptophan–serotonin metabolism and cytokine networks in clinically distinct patient cohorts. Here, we report a unique mucosa-associated microbiome signature in children with ASD that correlates significantly with quantitative cytokine and tryptophan measurements, as well as clinical symptoms. This analysis shows functional associations that distinguish both the clinical group and GI symptoms. Because mucosal-associated microbes remain poorly defined in ASD, we advance this field by linking both previously reported and new gut-microbe interactions as possible drivers of disease-associated signaling networks in ASD and in functional abdominal pain."
Luna, Ruth Ann et al. “Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder.” Cellular and Molecular Gastroenterology and Hepatology 3.2 (2017): 218–230. PMC.
"Emerging research is finding that the enteric microbiome and its metabolic by-products, including PPA, play a major role in normal brain and behavioral development and are altered in persons with ASD. Interestingly, neurodevelopmental abnormalities, which include ASD features, are seen in individuals with impaired PPA metabolism.PPA has been shown to be elevated in the stool from individuals with ASD but not in every study. Adams et al. speculated that the lower incidence of SCFAs in the stool in their study could be consistent with the PPA theory, as this could potentially mean that more SCFAs are being absorbed and entering the blood stream and exacerbating ASD symptoms...The PPA theory of ASD suggests that ASD may be a result of disturbances in the enteric microbiome resulting in the production of elevated levels of PPA in genetically susceptible individuals during a critical neurodevelopmental period. Microbes that produce PPA, including Clostridia, Bacteroides, and Desulfovibrio species, are reported to be in abundance in ASD patient cohorts. PPA as well as other SCFAs can alter diverse metabolic and immune pathways, gene expression, and synaptic plasticity in a manner that is consistent with findings of ASD. The PPA theory of ASD may also offer a potential explanation of why certain diet manipulations may provide therapeutic benefit for certain children with ASD, as modifying the gut ecosystem through dietary changes may influence the taxa represented in the microbiome and the SCFAs they produce."
Slattery, John, Derrick F. MacFabe, and Richard E. Frye. “The Significance of the Enteric Microbiome on the Development of Childhood Disease: A Review of Prebiotic and Probiotic Therapies in Disorders of Childhood.” Clinical Medicine Insights. Pediatrics 10 (2016): 91–107.
"Individuals with ASD and significant lower GI tract symptoms displayed a greater stress response, as indicated by higher levels of salivary cortisol, than those with few or no lower GI tract symptoms...The presence of regressive autism significantly modified the relationship between post-stress cortisol and lower GI tract symptoms, suggesting increased risk for lower GI symptoms in those with ASD who lose previously acquired skills."
Ferguson, Bradley J. et al. “Associations between Cytokines, Endocrine Stress Response, and Gastrointestinal Symptoms in Autism Spectrum Disorder.” Brain, behavior, and immunity 58 (2016): 57–62.
"Recent reports suggest that Candida, particularly Candida albicans, growth in intestines may cause lower absorption of carbohydrates and minerals and higher toxin levels which are thought to contribute autistic behaviors. The aim of this study was to identify the 3-year deposited yeasts isolated from stool samples of children with diagnosed or suspected ASD and to determine in vitro activity of nystatin and fluconazole against these isolates using Clinical Laboratory Standards Institute M27-A3 guidelines. A 17-year retrospective assessment was also done using our laboratory records. Among the species identified, intrinsically fluconazole-resistant Candida krusei (19.8 %) and Candida glabrata (14.8 %) with elevated MICs were remarkable. Overall, C. albicans (57.4 %) was the most commonly isolated species in 17 years. The species identification and/or antifungal susceptibility tests have to be performed using the strain isolated from stool sample, to select the appropriate antifungal agent, if antimycotic therapy is needed."
Kantarcioglu, A.S., Kiraz, N. & Aydin, A. Mycopathologia (2016) 181: 1. https://doi.org/10.1007/s11046-015-9949-3
"In two separate case/control cohorts, we demonstrate overlap of 59 differentially expressed transcripts unique to inflamed ileocolonic tissues from ASD children with gastrointestinal symptoms. Nine of these 59 transcripts were also differentially expressed in the peripheral blood of ASDIC+ children from the second cohort. These nine transcripts could represent a putative blood-based biomarker for ASD-associated ileocolonic inflammation. Validation of these preliminary findings using two additional control cohorts (ASD without GI symptoms; TD without GI symptoms) and a larger ASDIC+ cohort are underway."
Walker, Stephen J. et al. “A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis.” Scientific Reports 6 (2016): 35820. PMC.
"Pediatric patients with chronic abdominal pain who present no “red flag” features are the most frequent cause of diagnostic dilemmas for both general practitioners and gastroenterologists, as they have equivocal indications of invasive diagnostics. Measurements of FCC facilitate differentiation between IBD, other inflammatory gastrointestinal disorders, and functional gastrointestinal disorders.
In pediatric population and particularly in young children, it is very important to reduce the use of invasive diagnostic procedures, such as gastroscopy or colonoscopy. High FCC may indicate the need for invasive diagnostics, while low values of this parameter suggest absence of pathologic lesions in the gastrointestinal mucosa ...Unlike commonly used markers of inflammation, such as ESR, CRP, or elevated leukocyte or platelet counts, FCC allows for narrowing the search for inflammatory lesions to the gastrointestinal tract. Therefore it is very useful in differentiation between functional gastrointestinal disorders and inflammatory gastrointestinal disorders [8, 21, 28, 30, 37]. The NPV values approaching 90% make it possible to use FCC as a screening test to exclude organic causes of abdominal pain in children, thus allowing avoiding further invasive diagnostics [38, 39]."
Pieczarkowski, Stanisław et al. “Diagnostic Value of Fecal Calprotectin (S100 A8/A9) Test in Children with Chronic Abdominal Pain.” Gastroenterology Research and Practice 2016 (2016): 8089217. PMC.
"This review outlines basic science and clinical evidence that enteric short-chain fatty acids (SCFAs), present in diet and also produced by opportunistic gut bacteria following fermentation of dietary carbohydrates, may be environmental triggers in ASD. Of note, propionic acid, a major SCFA produced by ASD-associated gastrointestinal bacteria (clostridia, bacteroides, desulfovibrio) and also a common food preservative, can produce reversible behavioral, electrographic, neuroinflammatory, metabolic, and epigenetic changes closely resembling those found in ASD when administered to rodents. Major effects of these SCFAs may be through the alteration of mitochondrial function via the citric acid cycle and carnitine metabolism, or the epigenetic modulation of ASD-associated genes, which may be useful clinical biomarkers. It discusses the hypothesis that ASDs are produced by pre- or post-natal alterations in intestinal microbiota in sensitive sub-populations, which may have major implications in ASD cause, diagnosis, prevention, and treatment...Common infections, chronic antibiotics, and clostridia colonization contribute to carnitine collapse, colitis, convulsions, and compulsions’ – impairment of carnitine metabolism from a variety of causes may be central to autism pathogenesis and regression"
MacFabe, Derrick F. “Enteric Short-Chain Fatty Acids: Microbial Messengers of Metabolism, Mitochondria, and Mind: Implications in Autism Spectrum Disorders.” Microbial Ecology in Health and Disease 26 (2015): 10.3402/mehd.v26.28177. PMC.
"First, we review the link between GI symptoms and abnormalities in mitochondrial function. Second, we review the evidence supporting the notion that environmental stressors linked to ASD can also adversely affect both mitochondria and GI function. Third, we review the evidence that enteric bacteria that are overrepresented in children with ASD, particularly Clostridia spp., produce short-chain fatty acid metabolites that are potentially toxic to the mitochondria. We provide an example of this gut–brain connection by highlighting the propionic acid rodent model of ASD and the clinical evidence that supports this animal model. Lastly, we discuss the potential therapeutic approaches that could be helpful for GI symptoms in ASD and mitochondrial disorders. To this end, this review aims to help better understand the underlying pathophysiology associated with ASD that may be related to concurrent mitochondrial and GI dysfunction."
Frye, R. et al. "Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome"
Microbial Ecology in Health and Disease
Volume 26, 2015 - Issue s1: Supplement 1, 2015: The Microbiome in Autism Spectrum Disorder
"Microbiota analysis at the species level demonstrated statistically significant differences in the concentrations of 8 species between children with autism and unaffected comparison subjects...The significant reduction in Enterobacter hormaechei is also of interest. The presence of this organism has been associated with outbreaks of sepsis in neonatal intensive care units: It is known as a small-colony variant that is associated with antibiotic resistance and slow-growing, chronic infections. Could an altered/reduced presence of this organism in children with autism affect the inflammatory/immune response in the gut?"
Timothy Buie, M.D.; Potential Etiologic Factors of Microbiome Disruption in Autism; Clinical Therapeutics/Volume 37, Number 5, 2015
"Our findings from the largest population-based case-control sample to date indicate that GI problems, particularly constipation and diarrhea, affect children with ASD and DD far more often than children with TD. Compared to children with TD, children with ASD and DD were at least three times more likely to experience a higher frequency of most GI symptoms...Our findings in children with ASD demonstrating a consistent relationship between GI symptoms and maladaptive behavior have perhaps the most clinical significance, with possible implications for treatment approaches...However, many ASD children, most especially those who are non-verbal, often do not present with symptoms typically recognized by many primary care physicians or specialists as being GI related, such as self-injurious behavior (SIB) and aggression that may be responses to pain and/or discomfort. Until clinicians and therapists consider a thorough GI history as a possible explanation for adverse behaviors, GI disorders in this population will continue to be over-looked and insufficiently treated. Appropriate treatment of GI symptoms may help alleviate at least some problematic behaviors and improve the quality of life in children with ASD along with their families."
Chaidez, Virginia, Robin L. Hansen, and Irva Hertz-Picciotto. “Gastrointestinal Problems in Children with Autism, Developmental Delays or Typical Development.” Journal of autism and developmental disorders 44.5 (2014): 1117–1127. PMC.
"Based on 16S-rRNA and culture-dependent data, Faecalibacterium and Ruminococcus were present at the highest level in fecal samples of PDD-NOS and HC children. Caloramator, Sarcina and Clostridium genera were the highest in AD children. Compared to HC, the composition of Lachnospiraceae family also differed in PDD-NOS and, especially, AD children. Except for Eubacterium siraeum, the lowest level of Eubacteriaceae was found on fecal samples of AD children. The level of Bacteroidetes genera and some Alistipes and Akkermansia species were almost the highest in PDD-NOS or AD children as well as almost all the identified Sutterellaceae and Enterobacteriaceae were the highest in AD. Compared to HC children, Bifidobacterium species decreased in AD. As shown by Canonical Discriminant Analysis of Principal Coordinates, the levels of free amino acids and volatile organic compounds of fecal samples were markedly affected in PDD-NOS and, especially, AD children. If the gut microbiota differences among AD and PDD-NOS and HC children are one of the concomitant causes or the consequence of autism, they may have implications regarding specific diagnostic test, and/or for treatment and prevention."
De Angelis, Maria et al. “Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified .” Ed. Markus M. Heimesaat. PLoS ONE 8.10 (2013)
"Impaired social interaction, communication and imaginative skills characterize autistic syndromes. In these syndromes urinary peptide abnormalities, derived from gluten, gliadin, and casein, are reported. They reflect processes with opioid effect. The aim of this single blind study was to evaluate effect of gluten and casein-free diet for children with autistic syndromes and urinary peptide abnormalities. A randomly selected diet and control group with 10 children in each group participated. Observations and tests were done before and after a period of 1 year. The development for the group of children on diet was significantly better than for the controls."
Knivsberg AM, Reichelt KL, Hoien T, Nødland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutritional Neuroscience 2013;5:251–61.
"The underlying nature of GI dysfunction in ASDs and its relationship to etiology and ASD symptoms are poorly understood, and systematic research in this area has been limited. There is, however, emerging evidence relevant to ASDs in the areas of immune function, the relationship between signaling pathways of the gut and brain, and genome–GI microbiome interactions. Increasingly, evidence supports a combination of changes in gut microflora, intestinal permeability, inappropriate immune response, activation of specific metabolic pathways, and behavioral changes in genetically predisposed individuals. Integrating findings across these areas into a unifying theory will be critical to understanding the mechanisms and manifestations of GI disorders in ASDs."
Coury, D., et al; Gastrointestinal Conditions in Children With Autism Spectrum Disorder: Developing a Research Agenda Pediatrics Nov 2012, 130 (Supplement 2) S160-S168;
"The strong correlation of gastrointestinal symptoms with autism severity indicates that children with more severe autism are likely to have more severe gastrointestinal symptoms and vice versa. It is possible that autism symptoms are exacerbated or even partially due to the underlying gastrointestinal problems. The low level of SCFA's was partly associated with increased probiotic use, and probably partly due to either lower production (less sacchrolytic fermentation by beneficial bacteria and/or lower intake of soluble fiber) and/or greater absorption into the body (due to longer transit time and/or increased gut permeability)...This suggests that there are either lower amounts of beneficial bacteria which produce SCFA's, a lower intake of soluble fiber, a longer transit time, and/or increased absorption due to increased gut permeability...
The autism group had a low level of SCFA's, partly associated with probiotic usage, and probably partly due to either lower sacchrolytic fermentation by beneficial bacteria, due to their relative absence, lower intake of soluble fiber, longer transit time, and/or increased gut permeability.
The lower levels of Bifidobacterium and higher levels of Lactobacillus suggests an imbalance in beneficial bacteria."
Adams, James B et al. “Gastrointestinal Flora and Gastrointestinal Status in Children with Autism -- Comparisons to Typical Children and Correlation with Autism Severity.” BMC Gastroenterology 11 (2011)
"Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism."
Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, et al. (2011) Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances. PLoS ONE 6(9): e24585. doi:10.1371/journal.pone.0024585
"Children with ASDs can benefit from the adaptation of general pediatric guidelines for the diagnostic evaluation of abdominal pain, chronic constipation, and other gastrointestinal symptoms. The diagnostic evaluation begins with a thorough medical history and physical examination. The expression of disease can be as diverse in individuals with ASDs as in the general pediatric population. Health care providers also should be alert to behavioral manifestations of gastrointestinal disorders in patients with ASDs. Information from the medical history, including the presence of red-flag findings, the characterization or definition of a problem (as for chronic constipation), and the age of symptom onset (as for chronic diarrhea), can clarify the clinical picture and help determine the need for further evaluation."
Buie, T. et al; Recommendations for Evaluation and Treatment of Common Gastrointestinal Problems in Children With ASDs
Pediatrics Jan 2010, 125 (Supplement 1) S19-S29;
"Gastrointestinal pathology, characterized by lymphoid nodular hyperplasia and entero-colitis, has been demonstrated in a cohort of children with autistic spectrum disorder (ASD). Systemic and intestinal mucosal immune dysregulation was assessed in ASD children with gastrointestinal (GI) symptoms (n=18), and typically developing controls (n=27), including non-inflamed controls (NIC) and inflamed GI control children with Crohn's disease (CD), by analysis of intracellular cytokines in CD3+ lymphocytes. In both peripheral blood and mucosa, CD3+ TNFα+ and CD3+ IFNγ+ were increased in ASD children compared with NIC (p<0.004) and reached levels similar to CD. In contrast, peripheral and mucosal CD3+ IL-10+ were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls (p<0.02). In addition, mucosal CD3+ IL-4+ cells were increased (p<0.007) in ASD compared with NIC. There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort."
Ashwood, Paul et al. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms Journal of Neuroimmunology 2006 Volume 173 , Issue 1 , 126 - 134
"Recent clinical studies have revealed a high prevalence of gastrointestinal symptoms, inflammation, and dysfunction in children with autism. Mild to moderate degrees of inflammation were found in both the upper and lower intestinal tract. In addition, decreased sulfation capacity of the liver, pathologic intestinal permeability, increased secretory response to intravenous secretin injection, and decreased digestive enzyme activities were reported in many children with autism. Treatment of digestive problems appears to have positive effects on autistic behavior."
Horvath, K. & Perman, J.A. Curr Gastroenterol Rep (2002) 4: 251. https://doi.org/10.1007/s11894-002-0071-6
"Of the GI problems reported in subsets of autistic individuals, the most common are chronic constipation, diarrhea, and abdominal pain4–6 (see Figure 1). Gastroesophageal reflux, bloody stools, vomiting, and gaseousness are also elevated in some autistic individuals, as are signs of GI inflammation, such as lymphoid nodular hyperplasia, complement activation, and elevated pro-inflammatory cytokines, and intestinal pathologies, such as enterocolitis, gastritis, and esophagitis.4,6 Increased intestinal permeability is linked to autism and hypothesized to have detrimental effects not only on intestinal barrier integrity 7,8 but also on the systemic metabolome, with potential for translocation of intestinal metabolites or bacteria and consequent immune activation.9 Furthermore, food allergies, altered dietary nutrient intake, and metabolic disruptions have been associated with ASD.10–12 Autistic individuals with comorbid GI abnormalities exhibit altered carbohydrate digestion.13 Taken together, the variety of GI conditions, dietary issues, and enteric immune abnormalities reported in ASD individuals suggests that GI dysfunction can contribute to the manifestation of core symptoms of autism."
Elaine Y. Hsiao, PhD Gastrointestinal Issues in Autism Spectrum Disorder
Harvard Review of Psychiatry; Vol 2, number 22 March/April 2014